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The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia. Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 microM PSC 833 (P = 0.025), 1.5-fold using 4 microM CsA (P = 0.003) and 1.6-fold using 6 microM Vp (P = 0.012) whereas the adverse effect of 25 microM genistein was median 1.8-fold (P < 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of P-gp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.

[Illness related early pensioning of high school teachers]. The problem of premature unfitness for work of (grammar school) teachers is of great social and social-medical interest. The possible causes and suitable measures of intervention remain a subject of controversy. The aim of this study was, on the basis of a random sample of a large number of cases, to gain a differentiated overview of the extent and type of early retirement due to illness of grammar school teachers, in order to be able to develop evidence-based strategies for prevention and intervention. In a prospective evaluation, all the assessments of illness-related unfitness for work drawn up for civil servants and teachers between 1.1.1996 and 31.12.1999 in Bavaria were first of all systematically evaluated. In addition, from the total collective a subgroup was formed of grammar school teachers and this was analysed separately. The answers given in a standardized, anonymous questionnaire provided the database. The evaluation included e.g. socio-demographic and occupational factors, the morbidity spectrum, medical judgement, medical rehabilitation and evaluation of performance. The medical diagnoses of the main and accompanying illnesses were classified according to ICD 10 in organ-related groups. Evaluation was carried out by means of descriptive statistics. Of the 655 grammar school teachers assessed, 65% (n = 429) were men, 35% (n = 226) women. The median age for male teachers was 58 years old (range: 30-64 years old), for female teachers 55 years old (range: 32-63 years old). Previous conflicts at the school workplace were reported in 12% of the cases. Among the main medical diagnoses, psychic/psychosomatic complaints (41%) predominated over muscular/skeletal illnesses (14%) and cardio-vascular diseases (12%). 80% of those examined were judged unfit for work. 56% of the grammar school teachers had participated in at least one medical rehabilitation measure before the proceedings for determining unfitness for work were instigated. Psychic and psychosomatic illnesses took first place among the decisive complaints leading to early retirement, and made up 45% of these. Further differentiation revealed the predominance of depressive illnesses and exhaustion (burnout). The main somatic complaints were far less common: muscular/skeletal illnesses (13%), cardio-vascular diseases (12%) and malignant growths (8%). The performance of 70% of the grammar school teachers judged unfit for work was regarded as so severely reduced that even activity outside of the teaching profession was no longer feasible. In this first representative evaluation of illness-related early retirement in grammar school teachers, the high prevalence and great social-medical importance of psychic and psychosomatic illnesses is noteworthy. In Bavaria, almost every second grammar school teacher therefore becomes unfit for work as a result of such complaints long before they reach the normal retiring age. From a social-medical and occupational-medical point of view, there is urgent need for further research into potential illness-inducing occupational and non-occupational stress factors and the development and implementation of effective and efficient strategies for prevention and intervention.

Whole-body cryotherapy (extreme cold air exposure) for preventing and treating muscle soreness after exercise in adults. Recovery strategies are often used with the intention of preventing or minimising muscle soreness after exercise. Whole-body cryotherapy, which involves a single or repeated exposure(s) to extremely cold dry air (below -100 °C) in a specialised chamber or cabin for two to four minutes per exposure, is currently being advocated as an effective intervention to reduce muscle soreness after exercise. To assess the effects (benefits and harms) of whole-body cryotherapy (extreme cold air exposure) for preventing and treating muscle soreness after exercise in adults. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CINAHL, the British Nursing Index and the Physiotherapy Evidence Database. We also searched the reference lists of articles, trial registers and conference proceedings, handsearched journals and contacted experts.The searches were run in August 2015. We aimed to include randomised and quasi-randomised trials that compared the use of whole-body cryotherapy (WBC) versus a passive or control intervention (rest, no treatment or placebo treatment) or active interventions including cold or contrast water immersion, active recovery and infrared therapy for preventing or treating muscle soreness after exercise in adults. We also aimed to include randomised trials that compared different durations or dosages of WBC. Our prespecified primary outcomes were muscle soreness, subjective recovery (e.g. tiredness, well-being) and adverse effects. Two review authors independently screened search results, selected studies, assessed risk of bias and extracted and cross-checked data. Where appropriate, we pooled results of comparable trials. The random-effects model was used for pooling where there was substantial heterogeneity. We assessed the quality of the evidence using GRADE. Four laboratory-based randomised controlled trials were included. These reported results for 64 physically active predominantly young adults (mean age 23 years). All but four participants were male. Two trials were parallel group trials (44 participants) and two were cross-over trials (20 participants). The trials were heterogeneous, including the type, temperature, duration and frequency of WBC, and the type of preceding exercise. None of the trials reported active surveillance of predefined adverse events. All four trials had design features that carried a high risk of bias, potentially limiting the reliability of their findings. The evidence for all outcomes was classified as 'very low' quality based on the GRADE criteria.Two comparisons were tested: WBC versus control (rest or no WBC), tested in four studies; and WBC versus far-infrared therapy, also tested in one study. No studies compared WBC with other active interventions, such as cold water immersion, or different types and applications of WBC.All four trials compared WBC with rest or no WBC. There was very low quality evidence for lower self-reported muscle soreness (pain at rest) scores after WBC at 1 hour (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -1.42 to -0.12; 20 participants, 2 cross-over trials); 24 hours (SMD -0.57, 95% CI -1.48 to 0.33) and 48 hours (SMD -0.58, 95% CI -1.37 to 0.21), both with 38 participants, 2 cross-over studies, 1 parallel group study; and 72 hours (SMD -0.65, 95% CI -2.54 to 1.24; 29 participants, 1 cross-over study, 1 parallel group study). Of note is that the 95% CIs also included either no between-group differences or a benefit in favour of the control group. One small cross-over trial (9 participants) found no difference in tiredness but better well-being after WBC at 24 hours post exercise. There was no report of adverse events.One small cross-over trial involving nine well-trained runners provided very low quality evidence of lower levels of muscle soreness after WBC, when compared with infrared therapy, at 1 hour follow-up, but not at 24 or 48 hours. The same trial found no difference in well-being but less tiredness after WBC at 24 hours post exercise. There was no report of adverse events. There is insufficient evidence to determine whether whole-body cryotherapy (WBC) reduces self-reported muscle soreness, or improves subjective recovery, after exercise compared with passive rest or no WBC in physically active young adult males. There is no evidence on the use of this intervention in females or elite athletes. The lack of evidence on adverse events is important given that the exposure to extreme temperature presents a potential hazard. Further high-quality, well-reported research in this area is required and must provide detailed reporting of adverse events.

[T cell repertoires correlate with pathogenesis of chronic idiopathic thrombocytopenic purpura]. To determine the T lymphocytic clones that correlate with the pathogenesis of idiopathic thrombocytopenic purpura (ITP) by investigating complementarity determining region (CDR3) repertoires of T cell receptors (TCRs) beta chain variable region (BV). Twenty-five patients with idiopathic thrombocytopenic purpura (including 15 patients with acute ITP and 10 patients with chronic ITP), twenty normal peoples and 20 normal umbilical cord blood samples were enrolled. Reverse transcription-polymerase chain reaction (RT-PCR) was used to amplify 24 subfamily genes of the TCR (BV from the peripheral blood lymphocytes (PBLs) of the ITP patients and normal controls, the implications underwent electrophoresis on denatured polyacrylamide sequencing gel, establishing a map of TCR BV CDR3 gene expressing repertoire. The bands that widened or disappeared of the TCR BV gene repertoire on the electrophoresis gel were used to analyze the variety of T cell clones in the cases of ITP. Comparing the sequences of TCR BV CDR3 gene repertoire in normal and abnormal T cell clones made it possible to understand the relationship between TCR BV gene and ITP. (1) In aITP, TCR BV CDR3 size distribution was similar to that of the normal controls and oligoclonality could be observed in 15 cases with an average value of 2.7 +/- 0.9 per person. Abnormal TCR BV CDR3 size distribution in aITP had little difference compared with that in the healthy controls (P = 0.179). There was no common expanded T cell clones in aITP, while abnormal TCR BV CDR3 distribution could be observed significantly different between the cITP patients and healthy controls (P < 0.05), with oligoclonality at an average value of 7 +/- 3 per person in 10 cases. Common clonal T cell expansions could be observed in BV8, BV13.1, BV14 and BV17 subfamilies. In 10 cITP patients, sequence could be read from 18 out of 20 dense and strong T cell clone bands on the map of TCR BV CDR3, which suggested that a dominant monoclonal T cell expanded in cITP. (2) Different patients shared a common or similar CDR3 encoded by the TCR BV gene of the expanded T cell clones. The same CDR3 was found in 2/4 expanded BV 17 T cell clones, with only 2 amino acids different in framework four (FR4). Two T cell clones had almost the same sequence of CDR3 of BV17 except for only four basepair differences in their full sequences. The full TCRBV gene sequences remained the same in 2 T cell clones for TCRBV8 and in other 2 T cell clones for TCRBV13.1 in cITP group. It showed that an expanded T cell clones with common function existed and could recognize common antigen in the body of patients with cITP. In analyzing the common motif in CDR3 of different cITP, three common motifs were found: GANVLTFGAG, E/DTQYFGPG and N (K) EQFFGPG, which were separately used in different TCRBVCDR3 of 18 expanded T cell clones. Among these motifs, TCRBV17 of 3 T cell clones had common GANVLTFGAG; TCRBV of 4 T cell clones had common N (K) EQFFGPG; and TCRBV of 7 T cell clones had common E/DTQYFGPG. aITP has no significant T cell clones expanded, while cITP usually demonstrates some expanded abnormal oligoclones which may correlate with the pathogenesis of cITP. cITP patients share 3 common motifs for TCRBV CDR3, which is possibly related to recolonization of the similar autoantigens.

Glutathione S-transferase activity in epithelial ovarian cancer: association with response to chemotherapy and disease outcome. Conflicting data have been reported about the association between glutathione S-transferase (GST), a family of proteins implicated in detoxification of cytotoxic drugs in human ovarian in vitro models, and response to chemotherapy and prognosis in ovarian cancer patients. The aim of this study was to analyze the possible clinical role of GST activity in a large series of primary ovarian cancer patients. The study included a large series of primary untreated ovarian cancer patients who underwent cytoreductive surgery and chemotherapy and who were followed up in a single institution. GST activity levels were assessed in tumor extracts by using a biochemical assay. A cut-off of 250 units of enzymatic activity was chosen according to the receiver operating characteristics (ROC) curve. GST activity levels were distributed in an asymmetrical manner (median: 266 units; range: 4-918 units) and did not seem to be associated with stage, histopathological grading, ascites, or residual tumor after surgery. Higher GST activity levels were found in patients who responded to chemotherapy (median: 298 units, range: 50-691) than in those who responded only partially (median: 227 units, range: 19-747) or not at all to chemotherapy (median: 246 units, range: 4-811) (H = 7.02, P = 0.029). Moreover, the percentage of cases with > 250 units was significantly higher among complete responders (66%) than partial responders (37%) or non-responders (48%) (chi 2 = 7.32; P = 0.025). When multivariate analysis, including clinico-pathological parameters and GST activity status as predictors of response to chemotherapy, was carried out, residual tumor, stage and GST status retained independent predictive value. Patients with high GST activity had more favourable prognosis than those with low GST activity. The median PFS was 42 months for patients with high GST activity compared to 17 months for those with low GST activity (P = 0.037). The median overall survival was 72 months for high-GST-activity and 42 months for low-GST-activity patients (P = 0.043). Substantially similar results were obtained in the subgroup of stage II-III-IV ovarian cancer patients. Multivariate analysis including the clinico-pathological parameters and GST activity status was performed in stage III-IV ovarian cancer patients: Stage IV disease, residual tumor > 2 cm, the presence of ascites and low GST activity status retained independent negative prognostic roles. A direct association between high GST activity and a better clinical outcome in terms of response to chemotherapy and survival has been observed in a large series of primary untreated ovarian cancer patients. These results, which are contrary to the expectations raised by in vitro studies, emphasize the need for caution when translating in vitro-generated hypotheses to the clinical setting.

Efficacy and tolerability of adding prescription omega-3 fatty acids 4 g/d to simvastatin 40 mg/d in hypertriglyceridemic patients: an 8-week, randomized, double-blind, placebo-controlled study. Patients with elevated serum triglyceride (TG) levels often have elevations in non-high-density lipoprotein cholesterol (non-HDL-C) levels as well. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) has identified non-HDL-C as a secondary therapeutic target in these patients, but treatment goals may not be reached with statin monotherapy alone. This study evaluated the effects on non-HDL-C and other variables of adding prescription omega-3-acid ethyl esters (P-OM3; Lovaza, formerly Omacor [Reliant Pharmaceuticals, Inc., Liberty Corner, New Jersey]) to stable statin therapy in patients with persistent hypertriglyceridemia. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in adults who had received > or = 8 weeks of stable statin therapy and had mean fasting TG levels > or = 200 and < 500 mg/dL and mean low-density lipoprotein cholesterol levels < or = 10% above their NCEP ATP III goal. The study regimen consisted of an initial 8 weeks of open-label simvastatin 40 mg/d and dietary counseling, followed by 8 weeks of randomized treatment with double-blind P-OM3 4 g/d plus simvastatin 40 mg/d or placebo plus simvastatin 40 mg/d. The main outcome measure was the percent change in non-HDL-C from baseline to the end of treatment. The evaluable population included 254 patients, of whom 57.5% (146) were male and 95.7% (243) were white. The mean (SD) age of the population was 59.8 (10.4) years, and the mean weight was 92.0 (19.6) kg. At the end of treatment, the median percent change in non-HDL-C was significantly greater with P-OM3 plus simvastatin compared with placebo plus simvastatin (-9.0% vs -2.2%, respectively; P < 0.001). P-OM3 plus simvastatin was associated with significant reductions in TG (29.5% vs 6.3%) and very-low-density lipoprotein cholesterol (27.5% vs 7.2%), a significant increase in high-density lipoprotein cholesterol (HDL-C) (3.4% vs -1.2%), and a significant reduction in the total cholesterol:HDL-C ratio (9.6% vs 0.7%) (all, P < 0.001 vs placebo). Adverse events (AEs) reported by > or= 1% of patients in the P-OM3 group that occurred with a higher frequency than in the group that received simvastatin alone were nasopharyngitis (4 [3.3%]), upper respiratory tract infection (4 [3.3%]), diarrhea (3 [2.5%]), and dyspepsia (3 [2.5%]). There was no significant difference in the frequency of AEs between groups. No serious AEs were considered treatment related. In these adult, mainly white patients with persistent hypertriglyceridemia, P-OM3 plus simvastatin and dietary counseling improved non-HDL-C and other lipid and lipoprotein parameters to a greater extent than simvastatin alone.

Quantitative kinetic analysis of gene expression during human osteoblastic adhesion on orthopaedic materials. Little information was found in the literature about the expression on hydroxyapatite (HA) materials of genes specific of cellular adhesion molecules although more were found on titanium-based substrates. Hence, the goal of this work was to study by a kinetic approach from 30 min to 4 days the adhesion of Saos-2 cells on microporous (mHA) and non-microporous hydroxyapatite (pHA) in comparison to polished titanium. Our strategy associated the visualization of adhesion proteins inside the cells by immunohistochemistry and the quantitative expression of genes at mRNA level by real-time PCR. The cell morphology was assessed using scanning electron microscopy and the number of cells thanks to biochemical techniques. The cellular attachment was the highest on mHA from 30 min to 24 h although the cell growth on mHA was the lowest after 4 days. Generally, the Saos-2 osteoblastic cells morphology on mHA was radically different than on other surfaces with the particularity of the cytoplasmic edge, which appeared un-distinguishable from the surface. The revelation by specific antibodies of proteins of the cytoskeleton (actin) and the focal adhesions (FAK, phosphotyrosine) confirmed that adhesion and spreading were different on the 3 materials. The actin stress fibres were less numerous and shorter on mHA ceramics. Cells had more focal contacts after 4 h on mHA compared to other substrates but less after 24 h. The highest values of total proteins were extracted from mHA at 0.5 and 24 h and from pHA at 1, 4, and 96 h. The alphav and beta1 integrin, actin, FAK, and ERK gene expression were found to be different with adhesion time and with materials. C-jun expression was comparable on mHA, titanium and plastic but was largely higher than on pHA at 0.5 and 1 h. On the contrary, c-fos expression was the highest on pHA after 0.5 h and the lowest after 1h. This difference between c-fos and c-jun expression on pHA after 0.5 h could be related to the fact that these two genes may differ in their signalling pathways. The expression of the alkaline phosphatase gene after 4 days was lower on mHA compared to other materials demonstrating that the microstructure of the mHA ceramic was not favourable to Saos-2 cells differentiation. Finally, it was demonstrated in this study that HA and titanium surfaces influence as well gene expression at early times of adhesion as the synthesis of adhesion proteins but also proliferation and differentiation phases. Indeed, the signal transduction pathways involved in adhesion of Saos-2 cells on HA and titanium were confirmed by the sequential expression of alphav and beta1 integrins, FAK, and ERK genes followed by the expression of c-jun and c-fos genes for proliferation and alkaline phosphatase gene for differentiation.

Synthesis and messenger ribonucleic acid expression of apolipoproteins E and A-I by the bovine corpus luteum during the estrous cycle and pregnancy. In an attempt to characterize proteins secreted by the corpus luteum, explant cultures of luteal slices from cows taken on Days 3, 7, 11, 14, 17, and 19 of the estrous cycle, and Days 17, 88, 180, and > 240 of pregnancy were incubated with H-leucine for 24 h. Proteins in luteal-conditioned medium were separated by two-dimensional PAGE, transferred to polyvinylidene fluoride membrane, and subjected to N-terminal amino acid microsequencing. Microsequence analysis revealed that the bovine corpus luteum synthesized and released de novo synthesized apolipoproteins (Apo) E and A-I in culture during the estrous cycle and pregnancy. Release of Apo E was observed only on Day 3 of the estrous cycle. Release of Apo A-I was observed on Days 11, 14, 17, and 19 of the estrous cycle, and on all days of pregnancy examined. To demonstrate the presence of the appropriate mRNA and characterize the temporal relationship for these identified proteins, total RNA was isolated from corpora lutea on Days 2, 3, 7, 16, 17, and 20 of the estrous cycle, and on Days 17, 90, 170, 180, and 272 of pregnancy, and submitted to Northern and dot blot analysis. Apo E mRNA was expressed only on Days 2-3 of the estrous cycle and was not expressed on the other days of the cycle or during pregnancy. A single Apo E mRNA transcript about 1.0 kilobase (kb) in size was observed. Expression of Apo A-I mRNA was detected on all days of the estrous cycle and pregnancy examined. Apo A-I cDNA hybridized with a single mRNA transcript about 1.0 kb in size. Apo A-I mRNA levels did not differ among days of the estrous cycle, although higher levels of Apo A-I mRNA were observed during later stages of pregnancy. Serum concentrations of Apo A-I and progesterone were correlated across the estrous cycle but not during the prepartum period or after parturition. This study demonstrates for the first time that the corpus luteum synthesizes Apo E and Apo A-I and expresses their respective mRNAs. The pattern of expression of Apo E and Apo A-I mRNAs paralleled that of de novo synthesis of their respective proteins after incubation of luteal tissue with [H]leucine. The role of luteal apolipoproteins may involve an autocrine/paracrine function influencing luteal development, tissue remodeling, and steroidogenesis.

Lung cancer knowledge among secondary school male teachers in Kudat, Sabah, Malaysia. The objective of this study is to determine knowledge about lung cancer among secondary school male teachers in Kudat, Sabah, Malaysia. A cross-sectional study was conducted among three secondary schools located in Kudat district, Sabah, Malaysia during the period from June until September 2012. The protocol of this study was approved by ethics committee of Management and Science University, Malaysia. The aims were explained and a consent form was signed by each participant. Respondents were chosen randomly from each school with the help of the headmasters. Self-administrated questionnaires, covering socio-demographic characteristics and general knowledge of lung cancer, were distributed. Once all 150 respondents completed the questionnaire, they passed it to their head master for collecting and recording. All the data were analyzed using Statistical Package for the Social Sciences (SPSS) version 13. ANOVA and t-test were applied for univariate analysis; and multiple linear regression for multivariate analysis. A total of 150 male secondary school teachers participated in this study. Their mean age was 35.6 ∓ 6.5 (SD); maximum 50 and minimum 23 years old. More than half of the participants were Malay and married (52%, 79%; respectively). Regarding the knowledge about lung cancer, 57.3% of the participants mentioned that only males are affected by lung cancer. Some 70.7% mentioned that lung cancer can be transmitted from one person to another. More than half (56.7%) reported that lung cancer is not the leading cause of death in Malaysian males. As for risk factors, the majority reported that family history of lung cancer is not involved. However, 91.3% were aware that cigarettes are the main risk factor of lung cancer and more than half (52%) believed that second-hand smoking is one of the risk factor of lung cancer. More than half (51.3%) were not aware that asbestos, ionizing radiation and other cancer causing substances are risk factors for lung cancer. Quitting smoking, avoiding second-hand smoking and avoiding unnecessary x-ray image of the chest (53.3%, 96.0%, 87.3%; respectively) are the main preventive measures mentioned by the participants. For the factors that influence the participants knowledge, univariate and multivariate analysis showed that only race was significant. Overall, the knowledge of school male teachers about lung cancer was low. However, few items were scored high: cigarettes are the main risk factor; avoiding second-hand smoking; and avoiding x-rays. Interventions to increase lung cancer awareness are needed to improve early detection behavior. Increase the price of pack of cigarettes to RM 20 and banning smoking in public places such as restaurants are highly recommended as primary preventive measures.

Heterogeneity of Stem Cells in the Ovary. Every organ in the body is thought to harbor two populations of stem cells, including the quiescent and the actively dividing, that leads to heterogeneity among them. It is generally believed that the ovary harbors a fixed number of follicles at birth that differentiate during fetal development from the primordial germ cells. The numbers of follicles decrease by age, leading to menopause. However, in 2004, it was suggested that ovary may harbor stem cells that are possibly involved in the formation of new follicles throughout reproductive life. Research over little more than a decade shows that ovarian stem cells include a quiescent population of very small embryonic-like stem cells (VSELs) and slightly bigger, actively dividing ovarian stem cells (OSCs). This heterogeneity among ovarian stem cells is similar to the presence of VSELs along with spermatogonial stem cells (SSCs) in the testis or hematopoietic stem cells (HSCs) in the hematopoietic system. VSELs express embryonic markers, including nuclear OCT-4, and are lodged in the ovary surface epithelium (OSE). Ovarian VSELs undergo asymmetric cell division to self-renew and give rise to OSCs that in turn undergo symmetric cell divisions and clonal expansion (germ cell nest) followed by meiosis to form an oocyte that gets assembled as a primordial follicle. Both VSELs and OSCs also express receptors for follicle-stimulating hormone (FSHR) and are directly activated by FSH to undergo neo-oogenesis and primordial follicle assembly. Whether stimulation of ovaries by FSH in Infertility Clinics activates the stem cells leading to the formation of multiple follicles needs further investigation. Epithelial cells lining the surface of ovary provide a niche to the stem cells under normal circumstances and undergo epithelial-mesenchymal transition (EMT) to form granulosa cells for primordial follicle assembly. Compromised function of the epithelial cells with age possibly leads to inability of stem cells to form follicles, leading to menopause. More than 90% of ovarian cancers arise in the OSE, possibly due to excessive self-renewal of VSELs. Altered biology of the OSE cells results in the formation of myofibroblasts by EMT and may provide a cancerous niche that supports excessive expansion of the stem cells lodged in the OSE, leading to ovarian cancer. Ovarian cancer cells express markers like OCT-4 and FSHR, which are also expressed by the VSELs lodged in the OSE, whereas the epithelial cells are distinctly negative for the same. Lot more research is required in the field to gain further understanding of ovarian stem cell biology.

An extreme learning machine model for the simulation of monthly mean streamflow water level in eastern Queensland. A predictive model for streamflow has practical implications for understanding the drought hydrology, environmental monitoring and agriculture, ecosystems and resource management. In this study, the state-or-art extreme learning machine (ELM) model was utilized to simulate the mean streamflow water level (Q WL) for three hydrological sites in eastern Queensland (Gowrie Creek, Albert, and Mary River). The performance of the ELM model was benchmarked with the artificial neural network (ANN) model. The ELM model was a fast computational method using single-layer feedforward neural networks and randomly determined hidden neurons that learns the historical patterns embedded in the input variables. A set of nine predictors with the month (to consider the seasonality of Q WL); rainfall; Southern Oscillation Index; Pacific Decadal Oscillation Index; ENSO Modoki Index; Indian Ocean Dipole Index; and Nino 3.0, Nino 3.4, and Nino 4.0 sea surface temperatures (SSTs) were utilized. A selection of variables was performed using cross correlation with Q WL, yielding the best inputs defined by (month; P; Nino 3.0 SST; Nino 4.0 SST; Southern Oscillation Index (SOI); ENSO Modoki Index (EMI)) for Gowrie Creek, (month; P; SOI; Pacific Decadal Oscillation (PDO); Indian Ocean Dipole (IOD); EMI) for Albert River, and by (month; P; Nino 3.4 SST; Nino 4.0 SST; SOI; EMI) for Mary River site. A three-layer neuronal structure trialed with activation equations defined by sigmoid, logarithmic, tangent sigmoid, sine, hardlim, triangular, and radial basis was utilized, resulting in optimum ELM model with hard-limit function and architecture 6-106-1 (Gowrie Creek), 6-74-1 (Albert River), and 6-146-1 (Mary River). The alternative ELM and ANN models with two inputs (month and rainfall) and the ELM model with all nine inputs were also developed. The performance was evaluated using the mean absolute error (MAE), coefficient of determination (r (2)), Willmott's Index (d), peak deviation (P dv), and Nash-Sutcliffe coefficient (E NS). The results verified that the ELM model as more accurate than the ANN model. Inputting the best input variables improved the performance of both models where optimum ELM yielded R(2) ≈ (0.964, 0.957, and 0.997), d ≈ (0.968, 0.982, and 0.986), and MAE ≈ (0.053, 0.023, and 0.079) for Gowrie Creek, Albert River, and Mary River, respectively, and optimum ANN model yielded smaller R(2) and d and larger simulation errors. When all inputs were utilized, simulations were consistently worse with R (2) (0.732, 0.859, and 0.932 (Gowrie Creek), d (0.802, 0.876, and 0.903 (Albert River), and MAE (0.144, 0.049, and 0.222 (Mary River) although they were relatively better than using the month and rainfall as inputs. Also, with the best input combinations, the frequency of simulation errors fell in the smallest error bracket. Therefore, it can be ascertained that the ELM model offered an efficient approach for the streamflow simulation and, therefore, can be explored for its practicality in hydrological modeling.

Plasma cortisol response to 1-24 adrenocorticotropin in patients with treated/untreated sellar & suprasellar mass lesions. One microgram short synacthene test is widely recommended as a screening test for evaluation of hypothalamo-pituitary-adrenocortical axis in patients with secondary adrenal insufficiency. Information on adequacy of cortisol response to this dose at different periods of the day in patients with hypothalamic-pituitary disorders is not available. Hence, this study was designed to assess the adequacy of cortisol response to 1 microg 1-24 adrenocorticotropin (ACTH) at 0800 h and 1600 h in patients with sellar and suprasellar mass lesions. Thirty five consecutive patients with sellar and suprasellar mass lesions with mean age of 43.0+/-14.4 yr and 36 healthy controls with mean age of 32.3+/-9.0 yr were studied after obtaining informed consent. Maintenance doses of glucocorticoids in these patients were discontinued appropriately. On day 1, prestimulated and stimulated plasma cortisol samples at 0800 h and at 30 and 60 min following i.v. bolus of 1 microg 1-24 ACTH were collected. While on day 3, plasma cortisol samples were similarly collected at 1600 h. Cortisol estimation was done by a sensitive and specific radioimmunoassay. Stimulated plasma cortisol of 500 nmol/l or higher was defined as a normal response. In healthy controls, the prestimulated and peak cortisol levels at 0800 h (377.5+/-93.3 and 729.1+/-183.2 nmol/l) were higher (P<0.001 and P<0.01) than those at 1600 h (230.1+/-75.7 and 665.8+/-138.6 nmol/l). All subjects had a cortisol response of 500 nmol/l or higher in response to 1 microg 1-24 ACTH both at 0800 and 1600 h. In the patients' group, the prestimulated plasma cortisol at 0800 h (250.3+/-169.7 nmol/l) was higher (P<0.001) than that at 1600 h (166.3+/-128.9 nmol/l), while the peak cortisol response was comparable (P>0.05) in the morning as well as in the evening (490.9+/-309.4 vs 464.8+/-318.4). In 27 patients (77%) the morning and evening stimulated cortisol response to 1 microg 1-24 ACTH was consistent (normal in 13 and subnormal in 14) but was discrepant in the remaining 8 (23%). In 7 of these 8 patients, cortisol response was normal at 0800 h but not at 1600 h, while in only one, normal response was seen at 1600 h but not at 0800 h. The demonstration of normal peak cortisol response to 1 microg 1-24 ACTH at 0800 h but not at 1600 h in substantial number of patients with sellar and suprasellar mass lesions suggests preference to morning for performing this test.

Task switching and the measurement of "switch costs". The measurement of "switch costs" is held to be of interest because, as is widely believed, they may reflect the control processes that are engaged when subjects switch between two (or more) competing tasks. [In task-switching experiments, the reaction time (RT) switch cost is typically measured as the difference in RT between switch and non-switch (repeat) trials.] In this report we focus on the RT switch costs that remain even after the subject has had some time to prepare for the shift of task, when the switch cost may be approximately asymptotic (so-called residual switch costs). Three experiments are presented. All three experiments used Stroop colour/word, and neutral stimuli. Participants performed the two tasks of word-reading and colour-naming in a regular, double alternation, using the "alternating runs" paradigm (R. D. Rogers & S. Monsell, 1995). The experiments were designed to test the hypothesis that RT switch costs depend on a form of proactive interference (PI) arising from the performance of a prior, competing task. A. Allport, E. A. Styles and S. Hsieh (1994) suggested that these PI effects resulted from "task-set inertia", that is, the persisting activation-suppression of competing task-sets, or competing task-processing pathways. The results confirmed the existence of long-lasting PI from the competing task as a major contributor to switch costs. Non-switch trials, used as the baseline in the measurement of switch costs, were also shown to be strongly affected by similar PI effects. However, task-set inertia was not sufficient to account for these results. The results appeared inconsistent also with all other previous models of task switching. A new hypothesis to explain these between-task interference effects was developed, based on the stimulus-triggered retrieval of competing stimulus-response (S-R) associations, acquired (or strengthened) in earlier trials. Consistent with this retrieval hypothesis, switch costs were shown to depend primarily on the S-R characteristics of the preceding task (the task that was switched from) rather than the upcoming task. Further, the effects of the other, competing task were found to persist over many successive switching trials, affecting switch costs long after the stimulus overlap (and hence the principal S-R competition) between the current tasks had been removed. Switch costs were also found to be affected by recent, item-specific experience with a given stimulus, in either the same or the competing task. Finally, the results showed that switch costs were massively affected by the ratio of the number of prior trials, in response to the same stimuli, that had implemented either the currently intended or the competing S-R mappings. None of these effects are predicted by current models of residual switch costs, which appeal to the differences in control processes assumed to be engaged in switch versus non-switch trials.

Studies on aorta during development. II. Differences in ontogeny of the key enzymes involved in cholesteryl ester synthesis and hydrolysis in rabbit aorta. It is well known that cholesteryl ester accumulation is dramatically increased in the atherosclerotic artery. The enzymes acyl-CoA: cholesterol acyltransferase (ACAT), acid cholesteryl esterase (ACE) and neutral cholesteryl esterase (NCE) may play key roles in the accumulation of cholesteryl esters in the arterial wall. However, very little is known regarding the developmental pattern of the key enzymes involved in cholesteryl ester synthesis and hydrolysis. The total activities of ACAT, ACE and NCE were measured by radioassay using liposomal substrates in rabbit aortic homogenates. Our results indicate that ACAT activity decreases as a quadratic function with age (P less than 0.05). ACAT activity (pmol/100 mg protein/min) decreased from a high value in the fetus at term (63.3 +/- 7.4) to gradually lower values with increasing age. On the other hand, ACE activity (pmol/mg protein/min) was low in the fetus at term, and changed as a quadratic function with age (P less than 0.05) increasing gradually to higher activities with age up to a maximum at 12 weeks then decreased at 21 weeks. NCE activity (pmol/mg protein/min) increased dramatically from a low value in the fetus at term (3.34 +/- 0.48) to a maximum value at 1.5 weeks (14.65 +/- 2.73) then decreased as a linear function with increasing age up to 21 weeks (P less than 0.05). Plasma total cholesterol (mg/dl) also increased sharply from the fetal value at term of 98.5 +/- 5.2 to a maximum value at 1.5 weeks of 666.4 +/- 33.4, then decreased as a quadratic function with increasing age up to 21 weeks (40.8 +/- 6.7) (P less than 0.05). The free cholesterol content (microgram/mg protein) of the aortic tissue was initially high in the fetus (24.8 +/- 5.9) then increased with age. Examination of the ratio of synthesis to hydrolysis of cholesteryl esters as an index of enzyme activity units demonstrated a very high index in the fetus of 6.1 that rapidly decreased with increasing age in the young adult rabbit down to a value of 0.4 by 21 weeks of age. Correlation coefficients between enzyme activities, plasma cholesterol levels and aortic cholesterol levels indicated (a) a positive correlation of NCE activity with plasma cholesterol, (b) a negative correlation of NCE and ACE with aortic-cholesteryl ester content, and (c) no significant correlation of ACAT activity with either plasma cholesterol or aortic cholesterol content, indicating other factors are involved.(ABSTRACT TRUNCATED AT 400 WORDS)

Effect of a 1 min hand wash on the bactericidal efficacy of consecutive surgical hand disinfection with standard alcohols and on skin hydration. In most surgical theatres, a 1 min or even longer hand wash is routine as part of the pre-operative hand disinfection. But its benefit has recently been seen critically. We have therefore investigated the effect of a 1 min hand wash on skin hydration and on the efficacy of consecutive surgical hand rubbing with three standard alcohols (60% propan-1-ol, 60% propan-2-ol, 80% ethanol; all v/v) on the resident hand flora. Three types of treatment were performed: (i) a 1 min pre-wash before surgical hand disinfection, (ii) no pre-wash before surgical hand disinfection and (iii) no pre-wash but use of a brush for 1 min during disinfection procedure. The efficacy of the alcohols was determined according to prEN 12791 with the same 20 volunteers in paired groups. To assess the effect of the hand wash on skin hydration, 10 volunteers washed their hands with sapo kalinus for 1 min and dried hands with a paper towel. Skin hydration was measured with a corneometer before the hand wash and subsequently up to 10 min thereafter both on the palm and dorsum of hands. We also tested the reduction of bacterial spores by a 15 s hand wash according to EN 1499 after artificial contamination of hands of 14 volunteers with spores of B. stearothermophilus. Propan-1-ol (60%) was most effective with a mean log10 reduction of 2.11, followed by ethanol (80%) with a mean log10 reduction of 1.76 and propan-2-ol (60%) with a mean log10 reduction of 0.57 (all immediate effect without hand wash). The efficacy of the alcohols was neither significantly improved nor impaired by a preceding 1 min hand wash, but there is a trend towards better efficacy on dry hands. Using a brush for 1 min during disinfection resulted in a better efficacy with all alcohols. An anaylsis of variance revealed that the immediate effect of ethanol (p = 0.013) and propan-2-ol (p = 0.001) is significantly influenced by the variation of treatments which is mainly explained by the effect of brushing during disinfection. But no significant difference between treatment variations was found in the sustained effect with any of the alcohols. Skin hydration increased significantly by a 1 min hand wash for up to 10 min despite drying hands with a paper towel. A 15 s hand wash reduced the number of bacterial spores significantly from log10 3.84 to log10 1.99 (p = 0.001). There is no benefit of a hand wash as part of surgical hand disinfection except that a short hand wash of 15 s can effectively reduce spores. The best time for this short hand wash is at the beginning of work in hospital, but at the latest in the sluice of the operating theatre about 10 min before applying an alcohol-based hand rub to give the skin enough time to dry.

Ovulation timing and conception risk after automated activity monitoring in lactating dairy cows. Using 1 market-available activity monitor, 3 experiments were conducted in dairy cows to determine timing of ovulation, compare within-herd conception risk of cows inseminated based on activity monitors versus timed artificial insemination (AI), and determine conception risk of cows inseminated at various intervals after achieving an activity threshold. In experiment 1, ovaries were scanned every 3h by transrectal ultrasonography to determine the time of ovulation beginning 14 ± 0.5 h after the achieved activity threshold (n=132) or first standing event (n=59), or both (n=59). Progesterone at the first ovarian scan (0.1 ± 0.01 ng/mL) and ovarian structures [1 or 2 preovulatory-sized follicles (16.5 ± 0.2 mm)] confirmed that 88.6% of cows identified by activity were in estrus. The remaining 15 cows (11.4%) with a corpus luteum and elevated progesterone concentration (5.3 ± 0.5 ng/mL) were classified as false positives. The average interval from first standing event to ovulation (n=59) differed slightly from the interval after the achieved threshold (26.4 ± 0.7 vs. 24.6 ± 0.7 h, respectively). In 97 cows fitted with activity monitors, that interval was 25.7 ± 0.4 h. In experiment 2, the conception risk in 394 cows in 1 herd fitted with activity monitors was compared with that of 413 cows submitted to a timed AI program through 3 AI services. Days to first AI were reduced in cows fitted with activity monitors, and conception risk after activity threshold was less than that for timed AI at first service because of differing days in milk at first AI. Both median and mean days to pregnancy, however, were reduced in activity-group cows by 10 and 24 d, respectively, compared with timed AI cows. In experiment 3, 4,019 cows in 19 herds were inseminated after achieving the activity threshold. Conception risk was determined for cows inseminated at various intervals after the achieved activity threshold. A curvilinear conception risk curve peaked at 47.9% for primiparous cows inseminated between 13 and 16 h, whereas conception risk in multiparous cows was steady at 34% through 12 h and decreased thereafter. These experiments demonstrate that time of ovulation after activity threshold closely resembles the time of ovulation after first standing estrus. Time of insemination up to 12h after the activity threshold produced similar conception risks for multiparous cows, whereas intervals shorter than 13 and greater than 16 h in primiparous cows seemed to compromise their conception risk. Although conception risk may not be improved at individual inseminations after achieving an activity threshold, the rate of achieving pregnancy is hastened. Activity monitors can accurately predict ovulation and time of AI.

Dose-response relationship between probability of pathologic tumor control and glucose metabolic rate measured with FDG PET after preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer. To determine the dose-response relationship between the probability of tumor control on the basis of pathologic tumor response (pTCP) and the residual metabolic rate of glucose (MRglc) in response to preoperative chemoradiotherapy in locally advanced non-small-cell lung cancer and to define the level of residual MRglc that corresponds to pTCP 50% and pTCP > or = 95%. Quantitative dynamic 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography was performed to measure regional MRglc at the primary lesion before and 2 weeks after preoperative chemoradiotherapy in an initial group of 13 patients with locally advanced NSCLC. A simplified kinetic method was developed subsequently from the initial dynamic study and used in the subsequent 16 patients. The preoperative radiotherapy programs consisted of (1) a split course of 42 Gy in 28 fractions within a period of 28 days using a twice-daily treatment schedule for Stage IIIA(N2) NSCLC (n = 18) and (2) standard once-daily radiation schedule of 45-63 Gy in 25-35 fractions during a 5-7-week period (n = 11). The preoperative chemotherapy regimens included two cycles of cisplatin, vinblastine, and 5-fluorouracil (n = 24), cisplatin and etoposide (n = 2), and cisplatin, Taxol, and 5-fluorouracil (n = 3). Patients free of tumor progression after preoperative chemoradiotherapy underwent surgery. The degree of residual MRglc measured 2 weeks after preoperative chemoradiotherapy and 2 weeks before surgery was correlated with the pathologic tumor response. The relationship between MRglc and pTCP was modeled using logistic regression. Of 32 patients entered into the study, 29 (16 men and 13 women; 30 lesions) were evaluated for the correlation between residual MRglc and pathologic tumor response. Three patients did not participate in the second study because of a steady decline in general condition. The median age was 60 years (range 42-78). One of the 29 patients had two separate lesions, and MRglc was measured in each separately. The tumor histologic types included squamous cell carcinoma (n = 9), adenocarcinoma (n = 13), large cell carcinoma (n = 6), and poorly differentiated carcinoma (n = 2). The extent of the primary and nodal disease was as follows: Stage IIB (T3N0M0), Pancoast tumor (n = 2); Stage IIIA, T2-T3N2M0 (n = 18); Stage IIIB: T1-T3N3M0 (n = 5) and T4N0M0 (n = 2); a second lesion, T1 (n = 1); and localized stump recurrence (n = 2). A pathologically complete response was obtained in 14 (47%) of the 30 lesions. The remaining 16 lesions had residual cancer. The mean baseline value of the maximal MRglc was 0.333 +/- 0.087 micromol/min/g (n = 16), and it was reduced to 0.0957 +/- 0.059 micromol/min/g 2 weeks after chemoradiotherapy (p = 0.011). The correlation between residual MRglc and pTCP was made using an increment value of 0.02 micromol/min/g between the maximal and minimal values of MRglc. A pathologically complete response was obtained in 6 of 6 patients with residual MRglc of < or = 0.050 micromol/min/g, 3 of 4 with < or = 0.070, 4 of 7 with < or = 0.090, 0 of 4 with < or = 0.110, 1 of 3 with < or = 0.130, and 0 of 6 with > or = 0.130 micromol/min/g. The fitted logistic model showed that residual MRglc corresponding to pTCP 50% and pTCP > or = 95% was 0.076 and < or = 0.040 micromol/min/g, respectively. The correlation between the gradient of residual MRglc after chemoradiotherapy and pTCP is an inverse dose-response relationship. Residual MRglc of 0.076 and < or = 0.040 micromol/min/g, representing pTCP 50% and pTCP > or = 95%, respectively, may be useful surrogate markers for the tumor response to radiotherapy or chemoradiotherapy in lung cancer.

Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions. Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease. The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date. The primary objective was to assess the efficacy of local or systemic use of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures. Secondary objectives were to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or Von Willebrand disease and to further establish the effects of these agents on bleeding in oral or dental procedures for each of these populations. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched PubMed, Embase and The Cochrane Library. Additional searches were performed in ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP).Date of last search of the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 14 December 2015. Randomised and quasi-randomised controlled trials in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid) to prevent perioperative bleeding compared to no intervention or usual care with or without placebo. Two authors independently screened the titles and abstracts of all identified articles. Full texts were obtained for potentially relevant abstracts and two authors independently assessed these for inclusion based on the selection criteria. A third author verified trial eligibility. Two authors independently performed data extraction and risk of bias assessments using standardized forms. While there were no eligible trials in people with Von Willebrand disease identified, two randomised, double-blind, placebo-controlled trials (total of 59 participants) in people with haemophilia undergoing dental extraction were included. One trial of tranexamic acid published in 1972 included 28 participants with mild, moderate or severe haemophilia A and B and one of epsilon aminocaproic acid published in 1971 included 31 people with haemophilia with factor VIII or factor IX levels less than 15%. Overall, the two included trials showed a beneficial effect of tranexamic acid and EACA, administered systemically, in reducing the number of bleedings, the amount of blood loss and the need for therapeutic clotting factor concentrates. Regarding postoperative bleeding, the tranexamic acid trial showed a risk difference of -0.64 (95% confidence interval -0.93 to - 0.36) and the EACA trial a risk difference of -0.50 (95% confidence interval 0.77 to -0.22). The combined risk difference of both trials was -0.57 (95% confidence interval -0.76 to -0.37), with the quality of the evidence (GRADE) for this outcome is rated as moderate. Side effects occurred once and required stopping epsilon aminocaproic acid (combined risk difference of -0.03 (95% CI -0.08 to 0.13). There was heterogeneity between the two trials regarding the proportion of people with severe haemophilia included, the concomitant standard therapy and fibrinolytic agent treatment regimens used. We cannot exclude that a selection bias has occurred in the epsilon aminocaproic acid trial, but overall the risk of bias appeared to be low for both trials. Despite the discovery of a beneficial effect of systemically administered tranexamic acid and epsilon aminocaproic acid in preventing postoperative bleeding in people with haemophilia undergoing dental extraction, the limited number of randomised controlled trials identified, in combination with the small sample sizes and heterogeneity regarding standard therapy and treatment regimens between the two trials, do not allow us to conclude definite efficacy of antifibrinolytic therapy in oral or dental procedures in people with haemophilia. No trials were identified in people with Von Willebrand disease.

A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus. Pioglitazone is a member of a recently developed class of glucose-lowering agents, the thiazolidinediones, used in the treatment of type 2 diabetes mellitus. In the United States, it is approved for use both as monotherapy and in combination with metformin, a sulfonylurea, or insulin; in Europe, it is approved for use in combination with metformin or a sulfonylurea but not insulin. This article presents a systematic review of the published literature on the effectiveness of pioglitazone in the treatment of type 2 diabetes, both as monotherapy and in combination with other antidiabetic agents. The peer-reviewed English- and foreign-language literature was searched using MEDLINE, PubMED, EMBASE, Science Citation Index, the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the UK National Health Service Centre for Reviews and Dissemination databases, and the Office of Health Economics Health Economic Evaluations Database. Searches were not limited to specific publication types, study designs, dates, or languages. The latest search was performed in March 2001. For a trial to be included in the review, at least 1 outcome measure had to involve the effects of pioglitazone on glycemic control or cardiovascular risk factors, or its side effects. Because of the heterogeneity of studies, no formal meta-analysis was performed. Eleven studies met the inclusion criteria, 6 involving pioglitazone monotherapy and 5 involving combination therapy. Full reports were available for only 6 of the 11 studies. No studies directly compared pioglitazone with other antidiabetic drugs. Both as monotherapy and in combination therapy, pioglitazone produced decreases in blood glucose levels (up to 95 mg/dL) and glycosylated hemoglobin (up to 2.6%). At doses of > or = 30 mg/d, pioglitazone was associated with reductions in triglyceride levels (-30-70 mg/dL) and increases in high-density lipoprotein cholesterol (HDL-C) levels (-4-5 mg/dL). Pioglitazone treatment was associated with significant weight gain (up to 4 kg over 16 weeks). Adverse effects included mild edema (in up to 11.7% of patients) and a clinically nonsignificant decrease in hemoglobin concentrations. Abnormal results on liver function testing were no more common in treated patients than in control groups. Pioglitazone has been shown to reduce blood glucose levels in patients with type 2 diabetes. Although the observed decreases in triglyceride levels and increases in HDL-C levels could be expected to lead to a reduction in cardiovascular risk, the effects of weight gain may counteract this benefit. The evidence suggests that the preferred role for pioglitazone may be as an adjunct to metformin or a sulfonylurea in patients whose condition is not well controlled with monotherapy and for whom a metformin-sulfonylurea combination is contraindicated. There is a need for large-scale, long-term studies comparing the effectiveness of combination therapy that includes pioglitazone with that of other combinations of antidiabetic drugs.

[Ionizing radiation]. Everyone is exposed to radiation from natural, man-made and medical sources, and world-wide average annual exposure can be set at about 3.5 mSv. Exposure to natural sources is characterised by very large fluctuations, not excluding a range covering two orders of magnitude. Millions of inhabitants are continuously exposed to external doses as high as 10 mSv per year, delivered at low dose rates, very few workers are exposed above the legal limit of 50 mSv/year, and referring to accidental exposures, only 5% of the 116,000 people evacuated following the Chernobyl disaster encountered doses above 100 mSv. Epidemiological survey of accidentally, occupationally or medically exposed groups have revealed radio-induced cancers, mostly following high dose-rate exposure levels, only above 100 mSv. Risk coefficients were derived from these studies and projected into linear models of risk (linear non-threshold hypothesis: LNT), for the purpose of risk management following exposures at low doses and low dose-rates. The legitimacy of this approach has been questioned, by the Academy of sciences and the Academy of medicine in France, arguing: that LNT was not supported by Hiroshima and Nagasaki studies when neutron dose was revisited; that linear modelling failed to explain why so many site-related cancers were obviously non-linearly related to the dose, and especially when theory predicted they ought to be; that no evidence could be found of radio-induced cancers related to natural exposures or to low exposures at the work place; and that no evidence of genetic disease could be shown from any of the exposed groups. Arguments were provided from cellular and molecular biology helping to solve this issue, all resulting in dismissing the LNT hypothesis. These arguments included: different mechanisms of DNA repair at high and low dose rate; influence of inducible stress responses modifying mutagenesis and lethality; bystander effects allowing it to be considered that individual cellular responses reflected in fact the results of multiple cellular interactions. Following the conclusion of the French Academy of medicine, LNT modelling resulted in public anxiety by changing an hypothetical residual risk at low doses into a real one, calling on regulators, continuously, for a more and more severe control of tiny sources which may result in considerable collective doses when considered as being exposed to billions of people for hundreds of years. Examples were provided that showed that the perception of risk of radioactive sources was not related to the severity of the risk itself but to the importance attributed to the situation by the media. In some instances, such as those resulting from the loss of gammagraphy sources, it resulted in a dangerous underestimate of the necessary remedial actions.

Recovery of renal function and the discontinuation of dialysis in patients treated with continuous peritoneal dialysis. Previous studies have shown that patients with end-stage renal disease (ESRD) treated with continuous peritoneal dialysis (CPD) have better preservation of endogenous renal function than patients treated with hemodialysis (HD). We wondered if this better preservation of endogenous renal function seen with CPD patients translates into the improved likelihood of recovery of endogenous renal function in those patients with potentially reversible causes of renal failure. To evaluate this question, we reviewed the records of all 1200 patients that completed CPD training at a large, freestanding peritoneal dialysis center in New Haven, Connecticut, between 1979 and 1999, and the records of all patients completing CPD training in New England between 1993 and 1998. In New Haven, about half the new patients with ESRD were started on CPD compared to only 15% in New England. We then compared the chances of recovery of renal function in these two cohorts of CPD patients to the chances of recovery of renal function in two groups of HD patients. The first group consisted of all patients that started on HD in New England between 1993 and 1998. The second group consisted of all patients that started HD in our HD unit in New Haven, Connecticut, between 1993 and 1999. The data on the New England patients were provided by the ESRD Network of New England. All patients entered into the present study had to have been on dialysis for a minimum of 3 months, as in the United States Renal Data System database, and had to have recovered sufficient renal function to be able to be maintained off dialysis for a minimum of 30 days. 29 of 1,200 CPD patients (2.4%) trained in New Haven recovered sufficient renal function to permit the discontinuation of dialysis for a minimum of 30 days. In comparison, only 305 of 19,032 patients (1.6%) managed with HD in New England (p < 0.05 compared to New Haven CPD patients) and 3 of 430 patients (0.7%) in our HD center (p < 0.05 compared to New Haven CPD patients) recovered sufficient glomerular filtration rate (GFR) to allow the discontinuation of dialysis for at least 30 days. If only those CPD patients that initiated dialysis between 1993 and 1999 in New Haven were analyzed, 15 of 369 (4.1%) recovered sufficient GFR to allow discontinuation of dialysis for at least 30 days (p < 0.025 compared to both groups of HD patients). Of the 2,924 patients completing CPD training in New England, 60 (2.1%) recovered renal function; this percentage is not significantly different from the percent of HD patients in New England recovering renal function. Although the present study is a retrospective study and the actual criteria for selection of CPD and HD therapy are not controlled for, the data raise the question of whether there may be a therapeutic advantage to treating newly diagnosed ESRD patients, that have a potentially reversible cause of renal failure, with CPD.

Smooth muscle-epithelial interactions in normal and neoplastic prostatic development. A hypothesis is proposed that unifies prostatic developmental biology and carcinogenesis. The foundation of this hypothesis is the reciprocal interaction of epithelium and mesenchyme during prostatic development followed thereafter by a reciprocal homeostatic interaction of epithelium and smooth muscle in adulthood. This smooth muscle-epithelial cell interaction is perturbed during prostatic carcinogenesis with adverse sequelae for both epithelium and smooth muscle. The following sequence of events is proposed to occur: (1) Under the influence of androgens, urogenital sinus mesenchyme (UGM) induces urogenital sinus epithelium to undergo prostatic ductal morphogenesis and differentiation. (2) As prostatic epithelium differentiates, it in turn signals the UGM to differentiate into smooth muscle cells that closely surround the epithelial ducts. Differentiation of prostatic smooth muscle requires both an inductive signal from epithelium and androgens. (3) Once formed, prostatic smooth muscle participates in reciprocal homeostatic interactions. We propose that prostatic smooth muscle under the influence of androgens signals to prostatic epithelium to maintain epithelial differentiation and to repress epithelial proliferation, while prostatic epithelium signals to prostatic smooth muscle to maintain smooth muscle differentiation. In adulthood, homeostasis is maintained through reciprocal interactions between smooth muscle and epithelial cells with minimal proliferation of either cell type. Prostatic carcinogenesis, which is initiated following genetic damage to prostatic epithelium, is surmised to involve a sequential disruption in these reciprocal homeostatic interactions with ensuing dedifferentiation of both the emerging prostatic carcinoma cells and smooth muscle. Thus, following genetic insult to prostatic epithelium the epithelium fails to signal appropriately to the smooth muscle, which then begins to dedifferentiate. As smooth muscle differentiation begins to deviate, signaling from prostatic smooth muscle to prostatic epithelium becomes anomalous resulting in progressive loss of control over epithelial differentiation and proliferation. During progression of prostatic carcinogenesis a vicious cycle is established in which both prostatic epithelium and smooth muscle dedifferentiate. This hypothesis is based on the ontogeny of prostatic smooth muscle differentiation during development and by the fact that the amount of smooth muscle progressively diminishes in human prostatic adenocarcinomas during progression from low- to high-grade cancers. Finally, in experimental tissue recombinants in which various normal or neoplastic prostatic epithelia were grown in combination with embryonic rat UGM, only normal (non-neoplastic) epithelia were capable of inducing differentiation of prostatic smooth muscle in UGM. Based on several lines of evidence, it is now apparent that smooth muscle-epithelial interactions are the operative cell-cell interaction in the postnatal prostate which plays a key role in regulating epithelial differentiation, proliferation and carcinogenesis.

Maternal and developmental toxicity in mice by aminophenylnorharman, formed from norharman and aniline. 9-(4'-Aminophenyl)-9H-pyrido [3,4-b] indole (aminophenylnorharman, APNH) is a novel mutagenic heterocyclic amine, produced by the reaction of norharman with aniline in the presence of S9 mix. In the present study, the maternal and developmental toxicity of APNH were investigated in ICR mice administered oral doses of 0, 0.625, 1.25, 2.5 or 5 mg/kg/day on gestational days (GD) 6 through 15 or 0, 5, 10, or 20 mg/kg on GD 12. Maternal and foetal parameters were evaluated on day 18 of gestation. Foetuses of dams treated on GD 6-15 were examined for external and skeletal malformations and variations, and foetuses of dams treated on GD 12 were inspected for cleft palate. Maternal death occurred when APNH was administered at 5 mg/kg/day on GD 6-15. No significant decrease in body weight gain during the administration period was observed at doses of 2.5 mg/kg/day or less when applied on GD 6-15. Adverse changes in general condition of dams were observed in the groups treated at doses of 2.5 mg/kg/day and above on GD 6-15, whereas no adverse effects on dams were noted even when APNH was applied at a fairly high dose on GD 12. Intracytoplasmic vacuolation in hepatocytes, necrosis of proximal tubular epithelial cells and desquamation of necrotic epithelial cells in the tubular lumen were observed in dams treated with APNH at 2.5 or 5 mg/kg/day on GD 6-15. Increased preimplantation loss was observed at 5 mg/kg/day and post-implantation loss was observed at 2.5 mg/kg/day and above when applied on GD 6-15, or at 20 mg/kg when applied on GD 12. Foetal body weight was decreased by APNH in a dose-dependent manner. The frequency of external malformations (cleft palate) was significantly increased in the group treated with APNH at 2.5 mg/kg/ day on GD 6-15 compared to the controls. However, there were no foetuses with cleft palate even when APNH was given at 20 mg/kg on GD 12. No significant increases in skeletally malformed foetuses were found in any APNH-treated group. The frequency of lumbar ribs was increased dose dependently. This study demonstrated the developmental toxicity of a mutagenic compound, APNH, in mice at maternally toxic doses, and that cleft palate observed in term foetuses resulted from the adverse effect of APNH on the maternal environment during organogenesis. More detailed studies are warranted to assess the possible risks to pregnant women from exposure to APNH.

Population cytogenetics of the malaria vector Anopheles leucosphyrus group. Until recently, very little was known of Anopheles species complexes and their relationships to epidemiology and malaria transmission in Southeast Asia. During the past eight years, extensive studies on the genetics of natural populations of anopheline mosquitoes in this region, involving the interdisciplinary efforts of taxonomists, operational entomologists and biologists, have revealed groups of cryptic species of Anopheles vectors, particularly the An. leucos phyrus group. This species group comprise seventeen species and two subspecies widely distributed in the forested areas of Southeast Asia. Among these species. An. dirus Peyton and Harrison, has been shown by cytogenetic and morphological studies to be a complex of at least seven isomorphic species, provisionally designated species A, B, C, D, E, F and takasagoensis, on the Southeast Asian mainland. Cytological identification of these species is based on distinct banding patterns of salivary gland polytene chromosomes as well as heterochromatin differences in mitotic karyotypes. The five species found in Thailand (A-D, F) exhibit distinct geographic distributions. Species A is widespread throughout Thailand except in the south. Species B had been found in sympatry with species C in southern Thailand and both seem to show north-south clinal geographic variation. Species D is common on the west side of southern Thailand and along the Thai-Burmese border in sympatry with species A. Species F, An. nemophilous Peyton and Ramalingam, has been found in a population at the Thai-Malaysian border in this study although it was known to be common in southern and western Thailand and Peninsular Malaysia. Species E is known only from western India. The five species found in Thailand also exhibit seasonal variation in relative abundance and different nocturnal biting cycles. Chromosomal polymorphisms have been observed in mitotic and polytene chromosomes of An. dirus A and D. Species B and C also show heterochromatin variation in the sex chromosomes, but are monomorphic for the standard sequence in polytene chromosomes. These biological characteristics of the An. dirus complex may have implications for understanding the epidemiology of malaria in Southeast Asia. Recent cytogenetic studies of wild-caught samples of An. leucosphyrus from Sumatra, Kalimantan and southern Thailand have revealed the presence of two distinct species within this taxon. Species A is widely distributed in southern Thailand, East Malaysia and Kalimantan, while species B is confined to Sumatra. The two isomorphic species are vectors of human malaria within their range of distribution.(ABSTRACT TRUNCATED AT 400 WORDS)

Aqueous solutions at the interface with phospholipid bilayers. In a sense, life is defined by membranes, because they delineate the barrier between the living cell and its surroundings. Membranes are also essential for regulating the machinery of life throughout many interfaces within the cell's interior. A large number of experimental, computational, and theoretical studies have demonstrated how the properties of water and ionic aqueous solutions change due to the vicinity of membranes and, in turn, how the properties of membranes depend on the presence of aqueous solutions. Consequently, understanding the character of aqueous solutions at their interface with biological membranes is critical to research progress on many fronts. The importance of incorporating a molecular-level description of water into the study of biomembrane surfaces was demonstrated by an examination of the interaction between phospholipid bilayers that can serve as model biological membranes. The results showed that, in addition to well-known forces, such as van der Waals and screened Coulomb, one has to consider a repulsion force due to the removal of water between surfaces. It was also known that physicochemical properties of biological membranes are strongly influenced by the specific character of the ions in the surrounding aqueous solutions because of the observation that different anions produce different effects on muscle twitch tension. In this Account, we describe the interaction of pure water, and also of aqueous ionic solutions, with model membranes. We show that a symbiosis of experimental and computational work over the past few years has resulted in substantial progress in the field. We now better understand the origin of the hydration force, the structural properties of water at the interface with phospholipid bilayers, and the influence of phospholipid headgroups on the dynamics of water. We also improved our knowledge of the ion-specific effect, which is observed at the interface of the phospholipid bilayer and aqueous solution, and its connection with the Hofmeister series. Nevertheless, despite substantial progress, many issues remain unresolved. Thus, for example, we still cannot satisfactorily explain the force of interaction between phospholipid bilayers immersed in aqueous solutions of NaI. Although we try to address many issues here, the scope of the discussion is limited and does not cover such important topics as the influence of ionic solutions on phases of bilayers, the influence of salts on the properties of Langmuir monolayers containing lipid molecules, or the influence of aqueous solutions on bilayers containing mixtures of lipids. We anticipate that the future application of more powerful experimental techniques, in combination with more advanced computational hardware, software, and theory, will produce molecular-level information about these important topics and, more broadly, will further illuminate our understanding of interfaces between aqueous solutions and biological membranes.

Nicotine replacement therapy for smoking cessation. The aim of nicotine replacement therapy (NRT) is to replace nicotine from cigarettes. This reduces withdrawal symptoms associated with smoking cessation to help resist the urge to smoke cigarettes. The aims of this review were to determine the effectiveness of the different forms of nicotine replacement therapy (chewing gum, transdermal patches, nasal spray, inhalers and tablets) in achieving abstinence from cigarettes; to determine whether the effect is influenced by the clinical setting in which the smoker is recruited and treated, the dosage and form of the NRT used, or the intensity of additional advice and support offered to the smoker; and to determine whether combinations of NRT are more effective than one type alone. We searched the Cochrane Tobacco Addiction Group trials register. Randomized trials in which NRT was compared to placebo or no treatment, or where different doses of NRT were compared. We excluded trials which did not report cessation rates, and those with follow-up of less than six months. We extracted data in duplicate on the type of subjects, the dose and duration and form of nicotine therapy, the outcome measures, method of randomisation, and completeness of follow-up. The main outcome measure was abstinence from smoking after at least six months of follow-up. We used the most rigorous definition of abstinence for each trial, and biochemically validated rates if available. Where appropriate, we performed meta-analysis using a fixed effects model. We identified 49 trials of nicotine gum, 32 of transdermal nicotine patch, four of intranasal nicotine spray, four of inhaled nicotine and two of nicotine sublingual tablet. Three trials compared combinations of two forms of nicotine therapy with one form alone. The odds ratio for abstinence with NRT compared to control was 1.72 (95% confidence interval 1.60 to 1.84), The odds ratios for the different forms of NRT were 1.63 for gum, 1.77 for patches, 2.27 for nasal spray, 2.08 for inhaled nicotine and 1.73 for nicotine sublingual tablet. These odds were largely independent of the intensity of additional support provided or the setting in which the NRT was offered. Eight weeks of patch therapy was as effective as longer courses and there was no evidence that tapered therapy was better than abrupt withdrawal. Wearing the patch only during waking hours (16 hours/day) was as effective as wearing it for 24 hours/day. The odds ratio for abstinence in the trials which directly compared 4 mg versus 2 mg gum in highly dependent smokers found a significant benefit in favour of 4 mg gum (odds ratio 2.67, 95% confidence interval 1.69 to 4.22). There is no strong evidence that combinations of forms of NRT are more effective. Only one study directly compared NRT against another pharmacotherapy (bupropion) and found that the latter was significantly more effective either alone or used in combination with nicotine patch than if nicotine patch was used alone. All of the commercially available forms of NRT (nicotine gum, transdermal patch, and in some countries, the nicotine nasal spray, nicotine inhaler and nicotine sublingual tablets) are effective as part of a strategy to promote smoking cessation. They increase quit rates approximately 1.5 to 2 fold regardless of setting. The effectiveness of NRT appears to be largely independent of the intensity of additional support provided to the smoker. Since all the trials of NRT reported so far have included at least some form of brief advice to the smoker, this represents the minimum which should be offered in order to ensure its effectiveness. Provision of more intense levels of support, although beneficial in facilitating the likelihood of quitting, is not essential to the success of NRT. There is promising evidence that bupropion may be more effective than NRT (either alone or in combination). (ABSTRACT

Determination of arsenic species in fish, crustacean and sediment samples from Thailand using high performance liquid chromatography (HPLC) coupled with inductively coupled plasma mass spectrometry (ICP-MS). Suitable techniques have been developed for the extraction of arsenic species in a variety of biological and environmental samples from the Pak Pa-Nang Estuary and catchment, located in Southern Thailand, and for their determination using HPLC directly coupled with ICP-MS. The estuary catchment comprises a tin mining area and inhabitants of the region can suffer from various stages of arsenic poisoning. The important arsenic species, AsB, DMA, MMA, and inorganic arsenic (As III and V) have been determined in fish and crustacean samples to provide toxicological information on those fauna which contribute to the local diet. A Hamilton PRP-X100 anion-exchange HPLC system employing a step elution has been used successfully to achieve separation of the arsenic species. A nitric acid microwave digestion procedure, followed by carrier gas nitrogen addition- (N2)-ICP-MS analysis was used to measure total arsenic in sample digests and extracts. The arsenic speciation of the biological samples was preserved using a Trypsin enzymatic extraction procedure. Extraction efficiencies were high, with values of 82-102%(As) for fish and crustacean samples. Validation for these procedures was carried out using certified reference materials. Fish and crustacean samples from the Pak Pa-Nang Estuary showed a range for total arsenic concentration, up to 17 microg g(-1) dry mass. The major species of arsenic in all fauna samples taken was AsB, together with smaller quantities of DMA and, more importantly, inorganic As. For sediment samples, arsenic species were determined following phosphoric acid (1 M H3PO4) extraction in an open focused microwave system. A phosphate-based eluant, pH 6-7.5, with anion exchange HPLC coupled with ICP-MS was used for separation and detection of AsIII, AsV, MMA and DMA. The optimum conditions, identified using an estuarine sediment reference material (LGC), were achieved using 45 W power and a 20 minute heating period for extraction of 0.5 g sediment. The stability and recovery of arsenic species under the extraction conditions were also determined by a spiking procedure which included the estuarine sediment reference material. The results show good stability for all species after extraction with a variability of less than 10%. Total concentrations of arsenic in the sediments from the Pak Pa-Nang river catchment and the estuary covered the ranges 7-269 microg g(-1)and 4-20 [micro sign]g g(-1)(dry weight), respectively. AsV was the major species found in all the sediment samples with smaller quantities of AsIII. The presence of the more toxic inorganic forms of arsenic in both sediments and biota samples has implications for human health, particularly as they are readily 'available'.

Graft-tunnel mismatch in endoscopic anterior cruciate ligament reconstruction: a new technique of intraarticular measurement and modified graft harvesting. The purpose of this study was to determine the incidence of bitunnel interference fixation and accurate femoral insertion site targeting using a modified technique of endoscopic anterior cruciate ligament (ACL) reconstruction. Thirty-four consecutive central-third bone-patellar tendon-bone autograft modified endoscopic ACL reconstructions were prospectively studied. A new technique was used intraoperatively to directly measure (a) intraarticular (graft) distance (IAD) and (b) patellar tendon graft length, thereby allowing calculation of optimal tibial tunnel length for each case. Accuracy of guide pin placement through this tibial tunnel into the proposed femoral insertion site was assessed, as was the ability to achieve interference fixation in both tunnels (minimum of 20 mm bone interference fixation within the tibial tunnel). A new technique for patellar tendon-bone harvesting and proximal graft fixation to address graft mismatch is described. The average IAD from tibial origin to femoral ACL insertion measured 26.3 +/- 3.0 mm (range 21-33). The average patellar tendon length (LP) was 48.4 +/- 6.0 mm (range 40-63). The average calculated tibial tunnel length (TT) necessary to achieve bitunnel fixation (TT > or = LP + 20 - IAD) was 42.1 +/- 5.3 mm (range 36-57). Establishment of the calculated tibial tunnel length was achieved in 25 cases (74%) (no graft-tunnel mismatch). Graft-tunnel mismatch, in which the tibial tunnel could not be established to the length calculated necessary to accommodate a minimum of 20 mm of bone graft, occurred in nine cases (26%). Graft-tunnel mismatch occurred more frequently in patients whose patellar lengths were > or = 50 mm (p < 0.005), but was not found to correlate specifically to IAD. Recession of the graft up into the femoral tunnel allowed accommodation of the mismatched graft (bitunnel interference screw fixation) in these nine cases, averaging 22.0 +/- 2.98 mm (range 16-29 mm) of available distal bone block fixation. Tibial tunnel fixation of > or = 20 mm was achieved in 30 patients (88%), 18 mm in two, 17 mm in one, and 16 mm in one. Measurement error resulted in inadequate distal graft accommodation in four patients in whom error averaged 3 mm. Targeting of the femoral insertion site guide pin was achieved without requiring any knee manipulation for all cases. Patellar tendon graft protrusion through the tibial tunnel and potentially suboptimal graft fixation poses a frequent problem during endoscopic ACL reconstruction.(ABSTRACT TRUNCATED AT 400 WORDS)

[Identification of Campylobacter spp. isolates with phenotypic methods and multiplex polymerase chain reaction and their antibiotic susceptibilities]. The aims of this study were to detect the frequency of isolation of thermophilic Campylobacter spp. from acute gastroenteritis cases by phenotypic and molecular methods and to evaluate the antibiotic susceptibilities of the isolates. A total of 3287 stool samples obtained from diarrheal patients who were admitted to Kayseri Training and Research Hospital, Kayseri, Turkey, between March 2010 - March 2011 and sent to the microbiology laboratory, were included in the study. Cefoperazone, amphotericin B and teicoplanin (CAT) supplemented Campylobacter Blood-free Selective Medium (modified CCDA-Preston, Oxoid CM739, UK) was used for the isolation of Campylobacter spp. The media inoculated with stool samples were incubated at 42°C microaerobically for 72 to 96 hours. The genus and species level identifications of the thermophilic Campylobacter spp. isolates defined by phenotypic tests were carried out with multiplex polymerase chain reaction (mPCR). Antibiotic susceptibilities of the isolates were detected by disc diffusion method and the results were evaluated according to the CLSI guidelines. The thermophilic Campylobacter spp. were isolated from 5.4% (179/3287) of the patients' stool samples. Of Campylobacter positive cases 71% (127/179) were children and 58% (104/179) were male. The prevalence rate was estimated as 7.5% (127/1683) for children and 3.2% (52/1604) for adults. Of the isolates, 146 (82%) were identified as C.jejuni, 24 (13%) were C.coli, 6 (3%) were C.lari and 3 (2%) were C.upsaliensis with phenotypic tests. By using mPCR, 152 (85%) and 27 (15%) of 179 isolates were identified as C.jejuni and C.coli, respectively. Three of the six isolates identified as C.lari by the phenotypic methods were identified as C.jejuni and the remaining three as C.coli by mPCR. Phenotypically identified three C.upsaliensis isolates were shown to be C.jejuni (n= 2) and C.coli (n= 1). On the other hand one C.coli isolate was found to be C.jejuni by mPCR. The rates of resistance of the isolates were 92.6% for trimethoprim-sulfamethoxazole, 79.5% for nalidixic acid, 75.6% for levofloxacin, 73.9% for ciprofloxacin, 40.3% for ampicillin, 35% for cefotaxime, 33.4% for piperacillin-tazobactam, 24% for tetracycline, 14.6% for clindamycin, 11.2% for amikacin and 6.3% for erythromycin. During the 13 months study period, the highest isolation rates were detected between March-June (mean rate 66%). Our data concerning the prevalence and antibiotic resistance rates revealed the significance of campylobacters in gastroenteritis cases. Therefore, specific microbiological isolation and identification methods should be applied in routine microbiology laboratories to investigate the presence of campylobacters in gastroenteritis etiology. Besides, determination of the antibiotic susceptibilities of the isolates on routine basis should be encouraged to help to guide the antimicrobial treatment approaches in case of gastroenteritis. The results of this study also indicated that phenotypic tests were adequate for the identification of campylobacters at the genus-level, however, for accurate identification at the species level and for reliable epidemiological data molecular analysis might be added to the detailed identification procedures.

Craniocervical tuberculosis: protocol of surgical management. Craniovertebral junction tuberculosis (CVJ-TB) is rare and occurs in only 0.3 to 1% of patients with tuberculous spondylitis. In the available literature, the treatment options offered for this entity have ranged from a purely conservative approach to radical surgery without well-defined guidelines. In this study, we attempt to establish the most effective strategy for the management of this condition. Twenty-five patients with CVJ-TB were treated during the past 8 years. Severe neck pain, restricted neck movement, and myelopathy were the predominant symptoms. The patients were graded according to their disability as follows: Grade I (n = 7), only neck pain with no pyramidal tract involvement; Grade II (n = 8), independent with minor disability; Grade III (n = 1), partially dependent on others for assistance with activities of daily living; and Grade IV (n = 9), completely dependent on others for assistance with all activities of daily living. Nine patients in Grade IV also had severe respiratory compromise. In all patients, lateral radiographs of the CVJ in flexion and extension were used to determine the presence of atlantoaxial dislocation (AAD). Bony destruction, paraspinal abscess, and thecal compression were seen on intrathecal contrast computed tomographic scans (n = 9) and magnetic resonance imaging studies (n = 22). Under the cover of antituberculous therapy (ATT) administered for 18 months, the patients were placed under a management protocol that took into account the patient's preoperative grade, the presence of mobile or fixed AAD, bony destruction and retropharyngeal abscess formation at the CVJ, and the clinicoradiological response to ATT within 3 months. Thus, 14 patients were kept on conservative management, with their neck movements stabilized with an external orthosis; 4 patients underwent a single-stage transoral decompression and posterior fusion procedure; and 7 patients underwent direct posterior fusion. In a follow-up period that ranged from 6 months to 7 years (mean, 2.5 yr), the patients in Grades I and II maintained their neurological status. The single patient in Grade III improved to Grade II. Seven of the nine patients in Grade IV returned to normal, and one improved to Grade II. Neck pain improved in all patients. The only death in the series occurred as a result of aspiration pneumonitis leading to septicemia in a child in Grade IV with poor respiratory status and multilevel tuberculous involvement who had undergone transoral decompression and posterior fusion for fixed AAD. This study discusses the clinicoradiological presentation as well as the management of CVJ-TB, in which ATT is administered for 18 months. In the patients with minor deficits (Grades I and II), conservative neck stabilization is adopted; in the patients with severe deficits (Grades III and IV) due to significant cervicomedullary compression caused by fixed AAD or bone destruction and granulation, anterior decompression and posterior fusion are performed. Patients with persistent reducible AAD undergo direct posterior fusion. A significant improvement is possible even in poor-grade patients with judicious use of the surgical options and ATT.

Comparison between different dialysate calcium concentrations in nocturnal hemodialysis. Benefits of dialysate with greater calcium (Ca) concentration are reported in nocturnal hemodialysis (NHD) to prevent Ca depletion and subsequent hyperparathyroidism. Studies with patients dialyzing against 1.25 mmol/L Ca baths demonstrate increases in alkaline phosphatase (ALP) and parathyroid hormone (PTH) and increasing dialysate Ca subsequently corrects this problem. However, whether 1.5 or 1.75 mmol/L dialysate Ca is most appropriate for NHD is yet to be determined, and differences in the effect on mineral metabolism of daily vs. alternate daily NHD have also not been well defined. We retrospectively analyzed mineral metabolism in 48 patients, from 2 institutions (30 at Monash and 18 at Geelong), undergoing home NHD (8 hr/night, 3.5-6 nights/week) for a minimum of 6 months. Thirty-seven patients were dialyzed against 1.5 mmol/L Ca bath and 11 patients against 1.75 mmol/L. We divided patients into 4 groups, based on dialysate Ca and also on the hours per week of dialysis, <40 (1.5 mmol/L, n=29 and 1.75 mmol/L, n=8) or > or =40 (n=4 and 7). We compared predialysis and postdialysis serum markers, time-averaged over a 6-month period, and the administration of calcitriol and Ca-based phosphate binders between 1.5 and 1.75 mmol/L Ca dialysate groups. Baseline characteristics between all groups were similar, with a slightly longer, but nonsignificant, duration of NHD in both 1.75 mmol/L dialysate groups compared with 1.5 mmol/L. The mean predialysis Ca, phosphate, and Ca x P were similar between the 1.5 and 1.75 mmol/L groups, regardless of NHD hr/week. Postdialysis Ca was significantly greater, with 1.75 vs. 1.5 mmol/L in those dialyzing <40 hr/week (2.64+/-0.19 vs. 2.50+/-0.12 mmol/L, p=0.046), but postdialysis Ca x P were similar (2.25+/-0.44 vs. 2.16+/-0.29 mmol(2)/L(2), p=0.60). Parathyroid hormone was also lower with 1.75 vs. 1.5 mmol/L baths in the <40 hr/week groups (31.99+/-26.99 vs. 14.47+/-16.36 pmol/L, p=0.03), although this difference was not seen in those undertaking NHD > or =40 hr/week. Hemoglobin, ALP, and albumin were all similar between groups. There was also no difference in vitamin D requirement when using 1.75 mmol/L compared with the 1.5 mmol/L dialysate. Multivariate analysis to determine independent predictors of postdialysis serum Ca showed a statistically significant positive association with predialysis Ca, dialysate Ca, and total NHD hr/week. An elevated dialysate Ca concentration is required in NHD to prevent osteopenia but differences in serum markers of mineral metabolism between 1.5 and 1.75 mmol/L Ca dialysate in NHD in our study were few. This was similar for patients undertaking NHD <40 or > or =40 hr/week, although differences in the frequency of NHD may also be as important as dialysate Ca with regard to serum Ca levels. With concerns that prolonged higher Ca levels contribute to increased cardiovascular mortality, the optimal Ca dialysate bath is still unknown and further studies addressing bone metabolism with larger NHD numbers are required.

Cryopreservation of hormonally induced sperm for the conservation of threatened amphibians with Rana temporaria as a model research species. The survival of hundreds of threatened amphibian species is increasingly dependent on conservation breeding programs (CBPs). However, there is an ongoing loss of genetic variation in CBPs for most amphibians, reptiles, birds, and mammals. Low genetic variation results in the failure of CBPs to provide genetically competent individuals for release in supplementation or rehabitation programs. In contrast, in the aquaculture of fish the perpetuation of genetic variation and the production of large numbers of genetically competent individuals for release is accomplished through the cryopreservation of sperm. Successful protocols for the cryopreservation of amphibian sperm from excised testes, and the use of motile frozen then thawed sperm for fertilisation, have been adapted from those used with fish. However, there have been no protocols published for the cryopreservation of amphibian hormonally induced sperm (HIS) that have achieved fertility. We investigated protocols for the cryopreservation of amphibian HIS with the European common frog (Rana temporaria) as a model research species. We induced spermiation in R. temporaria through the intraperitoneal administration of 50 μg LHRHa and sampled HIS through expression in spermic urine. Highly motile HIS at a concentration of 200 × 10(6)/mL was then mixed 1:1 with cryodiluents to form cryosuspensions. Initial studies showed that; 1) concentrations of ∼15 × 10(6)/mL of HIS achieve maximum fertilisation, 2) TRIS buffer in cryodiluents did not improve the recovery of sperm after cryopreservation, and 3) high concentrations of DMSO (dimethylsulphoxide) cryoprotectant reduce egg and larval survival. We then compared four optimised cryopreservation protocols for HIS with the final concentrations of cryodiluents in cryosuspensions of; 1) DMSO, (½ Ringer Solution (RS), 10% sucrose, 12% DMSO); 2) DMSO/egg yolk, (½ RS, 10% sucrose, 12% DMSO, 10% egg yolk), 3) DMFA, (½ RS, 10% sucrose, 12% dimethylformamide (DMFA)), and 4) MIS/glycerol, (Motility Inhibiting Saline (MIS), 5% glycerol, 2.5% sucrose, 5% egg yolk). Cryosuspensions were frozen in LN(2) vapour, stored in LN(2), thawed in 40° C water bath, and activated by slow equilibration with 1:3 dilutions of cryosuspensions with 20 mM/L NaCl. Protocol efficacies were assessed through the post-thaw percentage of; 1) sperm motility, 2) sperm membrane integrity, 3) fertilisation, 4) fertilised eggs hatching, and 5) larval survival from fertilised eggs to 7 d. The DMFA cryodiluent proved superior to the DMSO based cryodiluents in recovery of sperm motility and fertility after cryopreservation. MIS/glycerol cryodiluent provided low sperm viability and no fertility. Considering the ease of obtaining HIS from many Rana species, the success of our protocols offer the potential for the perpetuation of the genetic variation of the 42 threatened Rana species and the 193 threatened Ranid species in total.

Micropercutaneous nephrolithotomy (microperc) vs retrograde intrarenal surgery for the management of small renal calculi: a randomized controlled trial. To compare micropercutaneous nephrolithotomy (microperc) and retrograde intrarenal surgery (RIRS) for the management of renal calculi <1.5 cm with regard to stone clearance rates and surgical characteristics, complications and postoperative recovery. Seventy patients presenting with renal calculi <1.5 cm were equally randomized to a microperc or a RIRS group between February 2011 and August 2012 in this randomized controlled trial. Randomization was based on centralized computer-generated numbers. Patients and authors assessing the outcomes were not blinded to the procedure. Microperc was performed using a 4.85-F (16-gauge) needle with a 272-μm laser fibre. RIRS was performed using a uretero-renoscope. Variables studied were stone clearance rates, operating time, need for JJ stenting, intra-operative and postoperative complications (according to the Clavien-Dindo classification system), surgeon discomfort score, postoperative pain score, analgesic requirement and hospital stay. Stone clearance was assessed using ultrasonography and X-ray plain abdominal film of kidney, ureter and bladder at 3 months. There were 35 patients in each group. All the patients were included in the final analysis. The stone clearance rates in the microperc and RIRS groups were similar (97.1 vs 94.1%, P = 1.0). The mean [sd] operating time was similar between the groups (51.6 [18.5] vs 47.1 [17.5], P = 0.295). JJ stenting was required in a lower proportion of patients in the microperc group (20 vs 62.8%, P < 0.001). Intra-operative complications were a minor pelvic perforation in one patient and transient haematuria in two patients, all in the microperc group. One patient in each group required conversion to miniperc. One patient in the microperc group needed RIRS for small residual calculi 1 day after surgery. The decrease in haemoglobin was greater in the microperc group (0.96 vs 0.56 g/dL, P < 0.001). The incidence of postoperative fever (Clavien I) was similar in the two groups (8.6 vs 11.4%, P = 1.0). None of the patients in the study required blood transfusion. The mean [sd] postoperative pain score at 24 h was slightly higher in the microperc group (1.9 [1.2] vs 1.6 [0.8], P = 0.045). The mean [sd] analgesic requirement was higher in the microperc group (90 [72] vs 40 [41] mg tramadol, P < 0.001). The mean [sd] hospital stay was similar in the two groups (57 [22] vs 48 [18] h, P = 0.08). Microperc is a safe and effective alternative to RIRS for the management of small renal calculi and has similar stone clearance and complication rates when compared to RIRS. Microperc is associated with higher haemoglobin loss, increased pain and higher analgesic requirements, while RIRS is associated with a higher requirement for JJ stenting.

[Effect of drug therapy for chronic obliterating diseases of lower-limb arteries on the state of the microcirculatory bed]. Search for an optimal method of conservative treatment of patients presenting with chronic obliterating disease of lower limb arteries (CODLLA) still remains an important and hitherto unsolved problem. Comparative studies of different drugs and objective assessment of their efficacy may be carried out using the method of laser Doppler flowmetry (LDF) with wavelet analysis of fluctuations in blood flow. The study was aimed at assessing efficacy of using Actovegin in conservative treatment of patients presenting with chronic obliterating disease of the lower extremities induced by occlusive and stenotic lesions of the arterial bed. The study included a total of 80 patients with stage 2B chronic ischaemia of the lower limbs. The patients were subdivided into two groups. Group One comprised 40 patients undergoing a course of intravenous infusions of Actovegin (at a dose of 250 ml, 4 mg/ml) as monotherapy for 10 days. Group Two comprised 40 patients receiving intravenous infusion of dextranes, as well as pentoxyphyllin at a dose of 100 mg/day. The state of microcirculation before and after the course of the infusion therapy was assessed by means of LDF with wavelet analysis of blood follow fluctuations. The basal blood flow was registered at a temperature of + 32° C for 10 minutes followed by a thermal test, i. e., heating to + 42oC for 30-40 minutes. The course of infusion therapy in Group One patients was followed by an increase of the amplitude of myogenic fluctuation by 56% (p=0.006) and a decrease in the index of blood flow shunting (p=0.1) with basal perfusion, as well as an increase in the maximum level of perfusion (p=0.006). Group Two patients showed were found to have only statistically significant shortening of the time of reaching the maximum level of thermal hyperaemia. The increase of the pain-free walking distance averagely amounted to 58.8% in Group One patients and 60.7% in Group Two (p=0.068). Patients of the both groups showed satisfactory tolerance of the carried out therapy. No undesirable adverse events were observed. LDF with wavelet analysis of fluctuations of blood flow makes it possible to thoroughly study the mechanisms of action of therapeutic agents on microcirculation in patients with CODLLA . The use of Actovegin as monotherapy in CODLLA patients leads to a decrease in the myogenic tonus of precapillary arterioles and capillary sphincters, to a decrease in the arteriolar-venular shunting of blood flow with predominant supply of blood to the capillary bed, to an increase in the oxide-synthase function of the endothelium of microvessels (endothelioprotective effect), as well as to an increase in the maximum level of thermal vasodilatation. Hence, Actovegin may be considered as a promising therapeutic agent for pharmacotherapy of CODLLA.

Associations of Intraoperative Radial Arterial Systolic, Diastolic, Mean, and Pulse Pressures with Myocardial and Acute Kidney Injury after Noncardiac Surgery: A Retrospective Cohort Analysis. Arterial pressure is a complex signal that is characterized by three primary components - systolic, diastolic, and mean pressure, along with a derived component, pulse pressure (systolic minus diastolic pressure)Each blood pressure component reflects distinct hemodynamic variables, and therefore presumably differently influences perfusion of various organsPrevious work identifies associations between intraoperative systolic and mean hypotension with myocardial and kidney injury WHAT THIS ARTICLE TELLS US THAT IS NEW: For each blood pressure component, the authors report significant and clinically meaningful associations between the lowest pressure sustained for 5 min and myocardial and kidney injuryAbsolute population risk thresholds were similar for myocardial and kidney injury, being roughly 90 mmHg for systolic, 65 mmHg for mean, 50 mmHg for diastolic, and 35 mmHg for pulse pressuresThe odds for myocardial and kidney injury progressively increased with duration and severity of hypotension below each threshold, even after adjusting for potential baseline confounding factors BACKGROUND:: Arterial pressure is a complex signal that can be characterized by systolic, mean, and diastolic components, along with pulse pressure (difference between systolic and diastolic pressures). The authors separately evaluated the strength of associations among intraoperative pressure components with myocardial and kidney injury after noncardiac surgery. The authors included 23,140 noncardiac surgery patients at Cleveland Clinic who had blood pressure recorded at 1-min intervals from radial arterial catheters. The authors used univariable smoothing and multivariable logistic regression to estimate probabilities of each outcome as function of patients' lowest pressure for a cumulative 5 min for each component, comparing discriminative ability using C-statistics. The authors further assessed the association between outcomes and both area and minutes under derived thresholds corresponding to the beginning of increased risk for the average patient. Out of 23,140 patients analyzed, myocardial injury occurred in 6.1% and acute kidney injury in 8.2%. Based on the lowest patient blood pressure experienced for greater than or equal to 5 min, estimated thresholds below which the odds of myocardial or kidney injury progressively increased (slope P < 0.001) were 90 mmHg for systolic, 65 mmHg for mean, 50 mmHg for diastolic, and 35 mmHg for pulse pressure. Weak discriminative ability was noted between the pressure components, with univariable C-statistics ranging from 0.55 to 0.59. Area under the curve in the highest (deepest) quartile of exposure below the respective thresholds had significantly higher odds of myocardial injury after noncardiac surgery and acute kidney injury compared to no exposure for systolic, mean, and pulse pressure (all P < 0.001), but not diastolic, after adjusting for confounding. Systolic, mean, and pulse pressure hypotension were comparable in their strength of association with myocardial and renal injury. In contrast, the relationship with diastolic pressure was poor. Baseline factors were much more strongly associated with myocardial and renal injury than intraoperative blood pressure, but pressure differs in being modifiable.

[Factors associated with successful smoking cessation among adolescent smokers undergoing a smoking cessation program involving nicotine replacement therapy]. To identify factors associated with successful smoking cessation among adolescent smokers in a smoking cessation program involving nicotine replacement therapy. We recruited adolescent smokers who were prepared to quit smoking and participated in the smoking cessation program in Kanagawa prefecture. All participants fulfilled a questionnaire beforehand, covering gender, age at the beginning of the study, age at onset of smoking, the number of quit attempts, the number of cigarettes per day and the smoking status of their families and friends. Seven nicotine patches (nicotine 52.5 mg/day) were given to them free of charge for daily use. Their smoking status and the use of nicotine patches were confirmed by telephone or postcard at the 1 and 6 month follow-ups. The relationships between successful smoking cessation and different factors among eligible participants were analyzed using the Fisher's exact test and the Mann-Whitney U test. The subjects included 39 adolescent smokers (mean 16.4 years). The mean age at onset of smoking and the mean duration of smoking were 13.3 years and 2.3 years, respectively. The average daily number of cigarettes smoked was 12.8. Of 39 eligible participants at the one month follow up, 14 (35.9%) were found to be abstaining from smoking. The subjects treated with nicotine patches were significantly more likely to be abstinent than those without them (P<0.05). However, no significant associations with other factors were found. Of 39 participants at the six months follow up, 10 (25.6%) were still abstinent but there were no significant associations with any of the factors, including use of nicotine patches. Subjects living with smokers were significantly less likely to be successful in their efforts to quit than those living with non-smokers (P< 0.05). There were no significant associations with other factors, including using nicotine patches. No adverse events relating to the use of the nicotine patches were encountered during the study period. The smoking cessation program involving NRT provided for adolescent smokers appeared effective at the one month follow up. Those adolescents living with smokers had more difficulties in quitting smoking than those with non-smokers at the 6 month follow up. In order to increase the number of adolescent smokers in the smoking cessation study, the need to obtain parental consent might be considered as a barrier to be overcome. Additionally, more effective follow-up procedures should be considered for the purpose of avoiding dropouts during the study.

Reduced postoperative pain scores and narcotic use favor per-oral endoscopic myotomy over laparoscopic Heller myotomy. Per-oral endoscopic myotomy (POEM) is a less invasive therapy for achalasia with a shorter hospitalization but with similar short- and long-term outcomes as a laparoscopic Heller myotomy (LHM). Previous literature comparing POEM to LHM has focused primarily on postoperative outcome parameters such as complications, dysphagia scores and gastro-esophageal reflux severity. This study specifically compares postoperative pain following POEM to pain following LHM, the current gold-standard operation. A retrospective review of all patients undergoing POEM or LHM for achalasia was performed from 2006 to 2015. Data collection included demographics, comorbidities, length of stay (LOS) and pain scores (arrival to the recovery room, 1 h postoperative, average first 24 h and upon discharge). Statistical analysis was performed using Student's t test and Chi-square test. Forty-four POEM patients and 122 LHM patients were identified. The average age (52.2 ± 20.75 vs 50.9 ± 17.89 years, p = 0.306) and BMI (28.1 ± 7.62 vs 27.6 ± 7.07 kg/m2, p = 0.824) did not differ between the POEM and LHM groups, respectively; however, the American Society of Anesthesiology scores were higher in the POEM patients (2.43 ± 0.62 vs 2.11 ± 0.71, p = 0.011). There were no differences in rates of smoking, diabetes, cardiac disease or pulmonary disease. The average pain scores upon arrival to the recovery room and 1 h postoperatively were lower in the POEM group (2.3 ± 3.014 vs 3.61 ± 3 0.418, p = 0.025 and 2.2 ± 2.579 vs 3.46 ± 3.063, p = 0.034, respectively). There was no difference in the average pain score over the first 24 h (2.7 ± 2.067 vs 3.29 ± 1.980, p = 0.472) or at the time of discharge (1.6 ± 2.420 vs 2.09 ± 2.157, p = 0.0657) between the POEM and LHM groups. After standardizing opioid administration against 10 mg of oral morphine, the POEM group used significantly less narcotics that the LHM group (35.8 vs 101.8 mg, p < 0.001) while hospitalized. The average LOS for the POEM group was 31.2 h and 55.79 for the LHM group (p < 0.0001). At discharge, fewer POEM patients required a prescription for a narcotic analgesic (6.81 vs 92.4 %, p < 0.0001). POEM demonstrated significantly less postoperative pain upon arrival to the recovery room and 1 h postoperatively. To achieve similar pain scores during the first 24 h and at discharge, LHM patients required more narcotic analgesic administration. Despite a significantly shorter LOS, fewer POEM patients require a prescription for narcotic analgesics compared to LHM. POEM is a less painful procedure for achalasia than LHM, permitting earlier hospital discharge with little need for home narcotic use.

Developing research management and governance capacity in primary care organizations: transferable learning from a qualitative evaluation of UK pilot sites. The capacity and capabilities for undertaking primary care research have increased both within and outside of the UK in recent years. The UK Department of Health aims to facilitate this further by establishing a national network of primary care organizations (PCOs) ready to act as hosts for shared research governance systems. However, it is unclear which models offer the most effective option. In addition, there is confusion over new processes and concern that researchers may be deterred from addressing important questions. The research ascertains how PCOs selected as pilot sites have organized research management and governance (RM&G). We adopted a case study approach involving interviews with key informants in a purposive sample of eight pilot PCO (RM&G) sites. Motivating factors for PCOs to host RM&G included the possibility of additional resources and more effective use of research to improve service delivery. A range of organizational models were adopted, often reflecting existing strategic alliances. It is envisaged that it will not be effective or cost-effective for many PCOs to make individual arrangements for RM&G, and so models are already developing among groups of PCOs and partner organizations. The extent of partnerships between PCOs varied with concern over critical mass and dilution of expertise in larger groupings. The development and implementation of systems in pilot sites was facilitated by the support of the wider PCO in recognizing research as a valued and integral part of the organization; the effective management of relationships and the establishment of equal partnership arrangements for RM&G, and the effective use of existing R&D infrastructure and expertise. RM&G partnerships vary according to local circumstances. It is likely that groupings will develop in the future with increasing co-terminosity and across wider health organization boundaries, such as Strategic Heath Authorities (in the UK) or primary care research networks. Critical mass of RM&G arrangements is likely to be linked to levels of research activity. There are real concerns over the levels of bureaucracy associated with the implementation of research governance; however, those PCOs that develop as RM&G sites have the opportunity to enrich their organizations and expand clinically relevant R&D. Partnership working within PCOs and with primary care research networks, academic departments or acute trusts, may be the key to success. Those undertaking research within primary care settings outside of the UK can learn important lessons from the UK experience and ensure development of high quality research that informs improvements in patient care.

Anisotropic conduction characteristics in ischemia-reperfusion induced chronic myocardial infarction. Anisotropic properties of cardiac tissue play an important role in initiation and perpetuation of ventricular tachycardia. However, anisotropic conduction properties in different morphologic types of chronic myocardial infarctions as well as frequency dependency still need to be elucidated. In the present study, the characteristics of anisotropic conduction were investigated in situ in the setting of ischemia-reperfusion induced chronic myocardial infarction. Myocardial infarction was induced in 12 dogs by a percutaneous transcatheter left anterior descending coronary artery occlusion-reperfusion technique. Four additional dogs served as normal controls. After 14 to 20 days, epicardial mapping was performed using simultaneous unipolar recordings from 240 electrodes of a plaque electrode array placed on the epicardial border zone overlying the infarctions. Constant rate pacing with five cycle lengths (CL) ranging from 500 to 200 ms as well as programmed electrical stimulation (PES) with four basic cycle lengths (BCL) ranging from 430 to 300 ms and single extrastimuli (S2) were performed. Two anatomically different patterns of epicardial surface morphology were analyzed, designated as type I and type II. In seven animals, there was a continuous thin layer of surviving epicardial muscle fibers overlying the infarction (type I). During pacing with CL of 500 vs 200 ms, conduction velocity longitudinal to fiber orientation (theta L) decreased significantly in the infarcted animals compared to control group (10.9% vs 5.2%, p < 0.05) whereas conduction velocity transverse to fiber axis (theta T) decreased to a similar degree in control and infarcted animals (6.9 vs 7.4%, n.s.). After premature stimulation, there was considerably greater reduction in theta L in infarcted animals than in controls (39.8% vs 31.5%, p < 0.05) whereas theta T decreased to a similar extend in infarcted and control animals (22.2% vs 21.4%, n.s.). During constant rate pacing and premature stimulation, no functional conduction block was induced in type I infarctions. In five animals, the transmural infarctions clearly extended to the epicardial surface, but continuous strands of surviving epicardial muscle fibers traversed the area of necrosis (type II). During PES with S2, functional conduction block and areas of very slow conduction were observed in each case. In ischemia-reperfusion induced chronic myocardial infarctions, different epicardial patterns of morphology were observed. Anisotropic conduction was frequency dependent in the longitudinal but not in the transverse direction. In type I infarctions, functional conduction block was not inducible during PES whereas in type II infarctions, prerequisites for reentrant arrhythmias like functional conduction block and very slow conduction were induced in each case by single extrastimuli.

Prediction of left ventricular mass changes after renal transplantation by polymorphism of the angiotensin-converting-enzyme gene. Cardiac complications are the main cause of death in renal transplant patients and left ventricular hypertrophy (LVH) may play a determinant role. An association between the insertion-deletion polymorphism of the angiotensin-converting enzyme (ACE) gene and LVH has been reported in adults. However, little is known about the genetic influence on left ventricular mass changes after renal transplantation, where unique environmental factors, such as cyclosporine A (CsA) and prednisone treatment concur. In fact, CsA treatment has recently been associated with the development of LVH. We prospectively determined the changes on cardiac structure and function, assessed by echocardiographic criteria, in 38 consecutive nondiabetic adults who received a cadaveric renal allograft. They were treated with cyclosporine and prednisone and maintained a good renal function during the follow-up. Echocardiographic studies (M-mode, 2-B and color flow Doppler) were performed without previous knowledge of the genetic typing, at the time of transplantation, and 6 and 12 months later. ACE alleles were typed using a PCR-based assay developed to ascertain the presence of an insertion (I)-deletion (D) polymorphism in intron 16 of the ACE gene. Patients with the so-called "unfavorable" DD genotype (N = 16) were compared with the ID or II genotypes (N = 22). The baseline left ventricular mass index was similar in patients with or without the unfavorable DD genotype (X +/- SE; 166.6 +/- 10.4 vs. 181.3 +/- 9 g/m2, respectively) and a similar proportion fulfilled the criteria of LVH (88% vs. 82%, respectively). The mean percent increase of the left ventricular mass index 12 months after renal transplantation was significantly higher in patients with the DD genotype compared to those with other genotypes (21.3 +/- 7.9 vs. -0.08 +/- 4.9%, respectively; P < 0.05). As a result, 94% of DD patients showed LVH at the end of the follow-up, while 68% of the ID or II patients had LVH (P < 0.05). In addition, the left ventricular ejection fraction significantly increased only in ID or II patients 12 months after transplantation with respect to baseline (ID/II patients, 70.4 +/- 1.5 vs. 63.7 +/- 1.8%; P < 0.05; DD patients, 68.3 +/- 2.1 vs. 63.3 +/- 2.9%). The deleterious effect of the DD genotype was independent of blood pressure, biochemical parameters, weight gain, and cumulative steroids dosages or cyclosporine levels. In conclusion, genetic factors determine the changes on cardiac structure and function after renal transplantation. The presence of the DD genotype of the ACE gene is a marker associated with an elevated risk of LVH in this population.

Development of a homologous radioimmunoassay for mouse growth hormone receptor. A RIA for mouse GH receptor (mGHR) was developed. A synthetic peptide corresponding to the carboxyl-terminal 14 amino acids of the mGHR (GHR-2 peptide) was used as the antigen for antiserum production. The synthetic peptide was also used as the standard and radioligand in the RIA. The ability of the antiserum to recognize the mGHR was demonstrated by quantitating receptor concentrations in liver and mammary gland from virgin and 15-day-pregnant mice. Serial dilutions of these samples yielded displacement curves parallel to the synthetic peptide. No significant cross-reactivity was seen with serum from virgin or 15-day-pregnant mice, mGH, recombinant mGH-binding protein (mGHBP), a synthetic peptide identical to the hydrophilic tail of mGHBP, or a 14-amino acid synthetic peptide corresponding to amino acids 338-351 of mGHR (GHR-1 peptide). The concentration range of the mGHR RIA was 0.5-200 nM, and the intra- and interassay coefficients of variation were 6.5% and 6.1%, respectively. The concentration of liver GHR increased significantly during pregnancy compared with that in virgin mice, from 0.246 +/- 0.045 pmol/mg protein (mean +/- SEM; n = 5) in the virgin animals to 1.015 +/- 0.159 pmol/mg protein (n = 5) in pregnant mice. In contrast, the mGHR concentration in the mammary gland decreased significantly during pregnancy from 0.606 +/- 0.201 pmol/mg protein (mean +/- SEM; n = 5) to 0.299 +/- 0.027 pmol/mg protein (n = 5). Comparison of the total number of binding sites in livers from virgin and pregnant mice using the GH RRA and the combined results of the mGHR and mGHBP RIAs showed that the two methods gave almost identical results for livers from virgin animals, or 0.363 +/- 0.063 pmol/mg protein (mean +/- SEM; n = 3) and 0.371 +/- 0.008 pmol/mg protein (n = 3) for the GH RRA and the mGHR plus mGHBP RIAs, respectively. However, in livers from pregnant animals, the combined results from the mGHR and mGHBP RIAs were approximately 1.8 times higher than those obtained by the GH RRA, or 6.732 +/- 0.612 pmol/mg protein (mean +/- SEM; n = 3) and 3.693 +/- 0.67 pmol/mg protein (n = 3) for the mGHR plus the mGHBP RIAs and the GH RRA, respectively. The increase in the total GH binding capacity in livers from pregnant mice compared with those from virgin animals was largely due to an increase in the GHBP content. The increase in GHR was only 2.4-fold, or from 0.153 +/- 0.01 pmol/mg protein (mean +/- SEM; n = 3) in virgin mice to 0.364 +/- 0.03 pmol/mg protein (n = 3) in the 15-day-pregnant mice, whereas GHBP increased almost 30-fold during pregnancy, or from 0.218 +/- 0.003 pmol/mg protein (mean +/- SEM; n = 3) in virgin animals to 6.369 +/- 0.607 pmol/mg protein (n = 3) in pregnant mice.

Including degradation products of persistent organic pollutants in a global multi-media box model. Global multi-media box models are used to calculate the fate of persistent organic chemicals in a global environment and assess long-range transport or arctic contamination. Currently, such models assume substances to degrade in one single step. In reality, however, intermediate degradation products are formed. If those degradation products have a high persistence, bioaccumulation potential and / or toxicity, they should be included in environmental fate models. The goal of this project was to gain an overview of the general importance of degradation products for environmental fate models, and to expand existing, exposure-based hazard indicators to take degradation products into account. The environmental fate model CliMoChem was modified to simultaneously calculate a parent compound and several degradation products. The three established hazard indicators of persistence, spatial range and arctic contamination potential were extended to include degradation products. Five well-known pesticides were selected as example chemicals. For those substances, degradation pathways were calculated with CATABOL, and partition coefficients and half-lives were compiled from literature. Including degradation products yields a joint persistence value that is significantly higher than the persistence of the parent compound alone: in the case of heptachlor an increase of the persistence by a factor of 58 can be observed. For other substances, the increase is much smaller (4% for alpha-HCH). The spatial range and the arctic contamination potential (ACP) can increase significantly, too: for 2,4-D and heptachlor, an increase by a factor of 2.4 and 3.5 is seen for the spatial range. However, an important increase of the persistence does not always lead to a corresponding increase in the spatial range: the spatial range of aldrin increases by less than 50%, although the persistence increases by a factor of 20 if the degradation products are included in the assessment. Finally, the arctic contamination potential can increase by a factor of more than 100 in some cases. Influences of parent compounds and degradation products on persistence, spatial range and ACP are discussed. Joint persistence and joint ACP reflect similar characteristics of the total environmental exposure of a substance family (i.e., parent compound and all its degradation products). The present work emphasizes the importance of degradation products for exposure-based hazard indicators. It shows that the hazard of some substances is underestimated if the degradation products of these substances are not included in the assessment. The selected hazard indicators are useful to assess the importance of degradation products. It is suggested that degradation products be included in hazard assessments to gain a more accurate insight into the environmental hazard of chemicals. The findings of this project could also be combined with information on the toxicity of degradation products. This would provide further insight into the importance of degradation products for environmental risk assessments.

Postoperative pain and neuropathy after caesarean operation featuring blunt or sharp opening of the fascia: a randomised, parallel group, double-blind study. The purpose of this study was to compare postoperative pain and neuropathy after primary caesarean sections with either blunt or sharp fascial expansions. A total of 123 women undergoing primary caesarean sections were included in the study. The sharp group had 61 patients, and the blunt group had 62. In the sharp group, the fascia was incised sharply and extended using scissors. In blunt group, the fascia was bluntly opened by lateral finger-pulling. The primary outcome was postoperative pain. The long-term chronic pain scores were significantly lower in the blunt group during mobilisation (p = .012 and p = .022). Neuropathy was significantly more prevalent in the sharp group at both 1 and 3 months postoperatively (p = .043 and p = .016, respectively). The odds ratio (OR) and 95%CI for postoperative neuropathy at 1 and 3 months were as follows; OR 3.71, 95%CI 0.97-14.24 and OR 5.67, 95%CI 1.18-27.08, respectively. The OR for postoperative pain after 3 months was 3.26 (95%CI 1.09-9.73). The prevelance of postsurgical neuropathy and chronic pain at 3 months were significantly lower in the blunt group. Blunt fascial opening reduces the complication rate of postoperative pain and neuropathy after caesarean sections. Impact statement What is already known on this subject? The anatomic relationship of the abdominal fascia and the anterior abdominal wall nerves is a known fact. The fascia during caesarean sections can be opened by either a sharp or blunt extension. Data on the isolated impact of different fascial incisions on postoperative pain is limited. What do the results of this study add? The postoperative pain scores on the incision area are lower in the bluntly opened group compared to the sharp fascial incision group. By extending the fascia bluntly, a decrease in trauma and damage to nerves was observed. What are the implications of these findings for clinical practice and/or future research? The lateral extension of the fascia during caesarean sections must be done cautiously to prevent temporary damage to nerves and vessels. The blunt opening of the fascia by lateral finger pulling might be a preferred method over the sharp approach that uses scissors. We included only primary caesarean cases, however, comparisons of blunt and sharp fascial incisions in patients with more than one abdominal surgery should be explored in future studies.

Assessment of the effects of developmental toxicants: pharmacological and stress vulnerability of offspring. From this brief summary of alterations in pharmacological and stress responsivity following gestational ethanol and cocaine exposure, a number of conclusions can be reached, although some of these conclusions are more speculative than others. Both pharmacological challenges and stress responsivity have been shown to be sensitive to the effects of prenatal ethanol as well as prenatal cocaine exposure. In terms of pharmacological sensitivity, there is some inconsistency in the findings obtained. Nevertheless, there is limited evidence to suggest that prenatal exposure to ethanol (and potentially cocaine) may increase later self-administration of the exposed drug. It should be recognized, however, that this possibility remains to be directly tested with cocaine, and needs further verification with ethanol using additional test procedures. It is interesting that a similar finding has been reported in the opiate literature: adult offspring exposed in utero to methadone exhibit an increase in subsequent morphine self-administration (Peters and Hovious 1983). Taken together, these data support the intriguing but still speculative suggestion that early chronic exposure to a drug of abuse may increase the propensity for later self-administration of that or related substances. More systematic research is needed to test this possibility and to determine whether alterations may be seen in later self-administration of other classes of abused drugs--that is, whether early drug exposure may increase the later propensity for general drug abuse. In terms of stress vulnerability, offspring exposed prenatally to ethanol predominantly have been assessed in terms of hormonal response measures, whereas the focus to date for offspring exposed prenatally to cocaine has been on alterations in behavioral responsivity to stressors. Yet prenatal exposure to either substance has been shown to result in consistent and long-lasting alterations in later responsivity to stressors in the absence of alterations in basal hormone levels in adulthood. For ethanol, these effects are particularly robust in female offspring; sex differences in stress responsivity in cocaine-exposed offspring have not been reported although few studies to date have been designed specifically to assess potential sex differences. As previously noted, the nervous system has a remarkable capacity to reorganize following insults at any age. The cost of neural reorganization following developmental insults may be associated with a decrease in adaptability that may not necessarily be evident under basal, nondrug, minimal stress, low distractibility testing conditions. Yet it is perhaps worth noting that these are the very conditions under which subjects are tested. In future work in developmental toxicity, it may prove useful to increase the demands of testing by assessing offspring under challenge conditions to reveal or unmask deficits that are not evident under basal test situations.

An outbreak of food-borne illness associated with methomyl-contaminated salt. On January 5, 1999, the California Department of Health Services was notified of the repeated occurrence (December 21, 1998, and January 2, 1999) of gastrointestinal tract illness among patrons at a Thai restaurant in central California. To identify the source of the outbreak. Case-control study; microbiological and toxicological laboratory testing of samples of food, stool, and vomitus. Thai food restaurant in central California. Patrons of the restaurant. A case (n = 107) was defined as dizziness, nausea, or vomiting occurring in a person who ate at the restaurant between December 20, 1998, and January 2, 1999, with onset of symptoms within 2 hours of eating. A control (n = 169) was a person who ate at the restaurant during the same period but reported no symptoms. Odds ratios (ORs) of illness associated with food exposures; ORs of shifts during which illness occurred associated with certain cooks; laboratory results. The median latency period was 40 minutes from beginning eating to first symptom and was 2 hours to onset of diarrhea. The median duration of symptoms was 6 hours. Twenty-six persons (24%) visited the emergency department or were treated by a physician; no person required hospitalization. Patients reported nausea (95%), dizziness (72%), abdominal cramps (58%), headache (52%), vomiting (51%), chills (48%), and diarrhea (46%). Fifty-one cases (48%) included dizziness, lightheadedness, or a feeling of disequilibrium as the initial symptom. Illness was statistically associated with several foods and ingredients, but no single dish or ingredient explained a substantial number of cases. The analysis of food exposures included salt added by cooks, as estimated by using the amount of salt in the recipe for each dish and the amount of each dish eaten by respondents. This association was stronger with increasing levels of salt: ORs for illness among persons who consumed more than 0.42 to 0.84, more than 0.84 to 1.25, and more than 1.25 tsp of salt added to foods in the kitchen were 1.9 (95% confidence interval [CI], 0.6-5.7), 3.0 (95% CI, 1.0-8.8), and 4.0 (95% CI, 1.3-13.5) compared with persons who consumed less than 0.42 tsp (P value for trend =.004). Methomyl, a highly toxic carbamate pesticide, was identified in a sample of vomitus (20 ppm) and in salt taken from containers in the storeroom (mean, 5600 ppm) and the stovetop (mean, 1425 ppm). The oral toxic dose causing illness in 50% of those exposed to methomyl was estimated to be 0.15 mg/kg of body weight (estimated range, 0.09-0.31 mg/kg of body weight). The presence of cook A was associated with shifts during which cases of illness occurred (OR, 10.4; 95% CI, 1.2-157.4). This outbreak of gastrointestinal illness was associated with the consumption of food seasoned with methomyl-contaminated salt. To allow rapid assessment for further investigational and control measures by health officials, physicians should report suspected outbreaks of illness to public health departments, however trivial the symptoms or cause may seem.

Germinal center-derived signals act with Bcl-2 to decrease apoptosis and increase clonogenicity of drug-treated human B lymphoma cells. Bcl-2 suppresses drug-induced apoptosis in vitro, although in many cases, this results only in a delayed onset of cell death. In vivo survival signals from the extracellular environment may also contribute to drug resistance and may act with Bcl-2 to promote long-term cell survival. Ligation of CD40 on B-lymphocytes in germinal centers (GCs) can suppress apoptosis induced by calcium ionophore or anti-IgM in vitro. We asked whether a combination of Bcl-2 expression and the provision of a culture environment that mimicked that of the GC [CD40 ligation and interleukin 4 (IL-4)] could increase the ability of B lymphoma cells to resist drug-induced apoptosis. A Burkitt lymphoma (BL) cell line transfected with either human bcl-2 (BL-bcl-2) or control plasmid (BL-Sv2) was used to examine the effects of Bcl-2 overexpression on the cellular response and long-term survival after treatment with the DNA-alkylating drug chlorambucil (CMB) in the presence or absence of CD40 ligation and IL-4. Administration of 20 microM CMB completely prevented cell proliferation. This was associated with an increase in p53 protein levels within 24 h, without an elevation in p21, Bax, or Mdm2 proteins. Analyses of cell cycle distribution and of cyclin B expression demonstrated that both cell lines arrested at G2/M, where they died. Fifty % of BL-Sv2 cells died within 2 days, whereas 50% cell death was not observed in the BL-bcl-2 cultures until 6 days had passed. Cross-linking of CD40 with a monoclonal antibody elevated Bcl-xL protein levels by 3 h and also provided a delay in CMB-induced death. Ninety-six h after the addition of 20 microM CMB, 78% of the BL-Sv2 cells were apoptotic, whereas ligation of CD40 on BL-Sv2 cells reduced the proportion of apoptotic cells to 38%. Overexpression of Bcl-2 (in BL-bcl-2 cells) reduced apoptosis to 41%. However, when the BL-bcl-2 cells were treated with CMB together with ligation of CD40, apoptosis was reduced further to only 17% at 96 h. The Bcl-2-mediated delay in the execution of CMB-induced apoptosis did not translate significantly to increased clonogenicity. In contrast, the provision of BL-Sv2 cells with an ability to interact with the adhesion molecule vascular cell adhesion molecule-1, CD40 ligation, and IL-4 significantly increased clonogenic survival, and this was improved in BL-bcl-2 cells exposed to these GC-derived signals. These data demonstrate that the kinetics of drug-induced apoptosis can be modulated by Bcl-2 as well as by IL-4, vascular cell adhesion molecule-1, and CD40 ligation, the latter possibly involving the function of Bcl-xL. That these factors appear to act together to enhance proliferative potential after DNA damage has important implications regarding the development of drug resistance in B-cell lymphomas and future strategies for improved chemotherapy.

The thermostatics and thermodynamics of cotransport. The thermostatics of cotransport are reviewed. A static-head equilibrium state across a cotransport system, without leaks, is thought to occur when the electrochemical potential of the driven solute, B prevents net flow of the driving solute, A. For a symport this gives the relationship (formula: see text) Where n is the stoichiometric coefficient, namely the number of moles of A transported per mole of B. (2) If either a symporter with a 2:1 stoichiometric coefficient and a 1:1 symporter, or alternatively, a 1:1 symporter and a 1:1 antiporter are placed in a series membrane array, then the predicted static-head equilibrium across the entire array conflicts with the zeroth law of thermodynamics. (3) There are two major reasons for this failure of cotransport theory; these are: (A) the thermostatic relationships derived shown in Point 1 are based on the assumption that the cotransport process takes place within a closed system. However, the membrane and the external reservoirs are open to the cotransported ligands. It follows that A and B in the external reservoirs can vary independently of the changes within the cotransport process. As no chemical reaction between A and B occurs in the external solutions, reactions within the membrane phase do not affect the equilibrium between the transported ligands in the open reservoirs. (B) It is assumed that the law of mass action can be applied to the cotransport chemical reactions within the membrane phase, without any allowance for the fact that these reactions occur within a 'small thermodynamic system'. Any proper analysis of the chemical potential of the transported intermediate must consider the effects of lower order ligand-carrier forms, which coexist and compete for space with the higher order cotransported forms on the binding matrix. If account is taken of this necessity, then a simple extension of the work of Hill and Kedem (1966) J. Theor. Biol. 10, 399-441 shows that: (a) the static-head equilibrium state cannot exist; (b) the stoichiometry of cotransport, whether symport, or antiport, does not affect the static-head distribution of cotransported ligands; (c) the hypothetical net charge of the transported ligand-carrier complex does not affect static-head equilibrium; (d) the only equilibrium state where there is zero net flow of both driving and driven transported ligand is at true equilibrium when the ligands are uniformly distributed across the membrane. (4) It is deduced that cotransport is not entirely an affinity-driven, but is partially an entropy-driven process.(ABSTRACT TRUNCATED AT 400 WORDS)

Assessing phonology in young children. We have presented a discussion of three important concepts regarding early phonological assessment. The first is that the child's language level must be considered in collecting and analyzing a sample and in interpreting the results. For a child with age-level language abilities, the sample should consist of both a single-word test and a running speech sample; both independent and relational analyses are appropriate. For a child with delayed expressive language and a small productive vocabulary, a sample comprised of spontaneous productions is more appropriate. In this case, the sample should be analyzed in terms of sound classes and syllable and word shapes that occur; a phonological process analysis is inappropriate. Lexical selection patterns should be noted. The results of the analyses should be interpreted in view of the expectations for the child's language level. A child with a normally developing language system is expected to have more advanced phonology than a child of the same age with delayed language. Thus, a child with a large vocabulary and word combinations is expected to have an expanding phonological system, with a full range of sound classes and syllable and word shapes. If a child is delayed in language and is still within the first 50-word stage, the expectation is that the phonological system will be more limited. Critical features for the phonology of early productive vocabulary have been identified. Lack of one or more of these features is indicative of atypical phonological development at any age and language level. The second concept is that the phonological system as a whole must be considered. In particular, the analyses and expectations should be based on the presence or absence of sound classes and syllable shapes rather than on sounds per se. Lack of an entire class or syllable structure would be cause for concern; lack of a particular sound, even though it has been shown to be acquired early, would not be. Thus, lack of the entire fricative class at 36 months would be of concern, whereas errors on /f/, which according to Prather et al., 1975, is mastered by this age, would not be. The third important concept emerges from the case studies; both studies demonstrate that longitudinal assessment is necessary to document changing profiles over the course of development. A child such as David, who has a normal-but-delayed profile in language and phonology at one age, may subsequently exhibit atypical patterns as phonology and language dissociate.(ABSTRACT TRUNCATED AT 400 WORDS)

Influence of postmortem treatment with nitric oxide on the muscle color and color stability of tilapia (Oreochromis niloticus) fillets. Nitric oxide (NO) has been recognized as pivotal for color and color stability of meat products and has an evident effect on inhibiting microbial growth in processed meat. The use of indirect NO (nitrate/nitrite) in industrial meat curing has potential deleterious effects and great concerns have been expressed over residual nitrite in meat after curing. To find a succedaneum, we have demonstrated the influence of direct NO (saturated NO solution) through euthanasia before slaughter on the fillets color of tilapia and the results suggested that direct NO treatment prior to slaughter is a good procedure to improve the color of tilapia fillets. To further investigate the effect of direct NO on the muscle color and shelf-life of fillets from tilapia, this study was conducted to investigate the muscle color and color stability of tilapia fillets postmortem treated with saturated NO solution and their shelf-life during refrigerated storage. Tilapia fillets were immersed in a saturated NO solution for 13 min, vacuum-packed and stored at refrigerated temperature for 15 days. Visual observations, color values and absorption maxima were used to evaluate the muscle color and color stability of tilapia fillets. Total volatile basic nitrogen (TVB-N) values were used to evaluate the shelf-life of tilapia fillets during refrigerated storage. By visual observation, NO treated tilapia fillets showed a brighter red color as compered to control samples after NO-treatment and during the whole storage. The redness (a*) values of NO treated tilapia fillets were significantly increased (P < 0.05) after NO-treatment, continuously increased (P < 0.05) during the earlier 9 days of the storage and remained roughly unchanged during the rest days of the storage. While the a* values of control samples decreased progressively during the storage. NO-treatment effectively improved the muscle color and color stability of tilapia fillets. The peak wavelengths of extract from the muscles of NO treated tilapia fillets increased from 418 nm to 421 nm at 15 d of the storage, while that of control decreased from 418 nm to 410 nm, indicated that color improvement in NO-treated tilapia fillets is mainly due to the formation of MbNO. Moreover, NO-treatment resulted in less TVB-N values than control (16.06 and 21.93 mg of N/100 g at the end of the storage, respectively), prolonging the shelf-life of tilapia fillets. The results suggested that postmortem treatment with NO is a good procedure not only for improving the muscle color and color stability but also for prolonging the shelf-life of tilapia fillets during the storage, which is valuable for industrial manufacturing of tilapia and possibly for other fish species.

[Incidence of vitreoretinal pathologic conditions in myopic eyes after laser in situ keratomileusis]. To determine the incidence of vitreoretinal pathologic conditions in myopic eyes after laser in situ keratomileusis. Vitreoretinal pathologic conditions of 1981 consecutive eyes (995 patients) having undergone laser-assisted in situ keratomileusis for the correction of myopia were studied. Preoperative and postoperative basic examinations included visual acuity, manifest and cycloplegic refraction, slit-lamp microscope examination, applanation tonometry and a fundus examination after pupil dilatation by indirect ophthalmoscopy and biomicroscopy with spherical lens of + 90 diopters. Before laser in situ keratomileusis, preventive treatment was carried out for predisposing lesion of retinal detachment in 8 eyes: 6 eyes for lattice degeneration and 2 eyes for atrophic holes. Postoperative examinations were conducted at 1, 3 and 12 months and once a year thereafter. All eyes were followed up for >/= 12 months. Eyes were followed for a mean of (18.40 +/- 4.50) months (range 12 - 28) after the surgery. Sixteen eyes of 13 patients (0.81%) developed vitreoretinopathy after LASIK, including 6 eyes with lattice degeneration (0.30%) in which one of them had previous laser treatment, 2 with posterior vitreous detachment (0.10%), 2 with macular hemorrhage (0.10%), 4 with rhegmatogenous retinal detachment (0.20%), and 2 with retinal tear without retinal detachment (0.10%) in which one of them had previous laser treatment for lattice degeneration. Five patients were males (5 eyes involved). Others were females. Mean age of the group with vitreoretinal pathologic conditions was 31.80 +/- 5.85 years (range 22 to 43). The interval between refractive surgery and development of vitreoretinal complication was (10.38 +/- 6.20) months (range 1 to 24). The eyes that developed vitreoretinopathy had myopia -4.75 to -15.00 diopters (mean -9.45 +/- 2.61 D) before LASIK. The comparison of incidences of vitreoretinopathy after LASIK between the group of >/= -6.00 D and < -6.00 D before surgery showed significant difference (P < 0.01, chi(2) = 60.78). The comparison of incidences of vitreoretinopathy after LASIK had also significant difference (P < 0.01, chi(2) = 138.64) between the eyes with pre-LASIK lattice degeneration and dry hole and eyes without such lesions. The cases of lattice degeneration and retinal tear were treated with laser retinopexy. All cases of rhegmatogenous retinal detachment were managed with cryoretinopexy and scleral buckling. Retinal reattachment was attained in all eyes and good visual acuities were recovered. No direct cause-effect relationship between LASIK and vitreoretinopathy can be proven from this study. Although the incidence of vitreoretinal pathologic conditions in myopic eyes after laser in situ keratomileusis is low, it is necessary to strictly filter candidates. Preoperatively and postoperatively, pay attention to the lattice degeneration and other retina lesions, and long-term follow-up is important.

[Neural mechanism underlying autistic savant and acquired savant syndrome]. It is well known that the cases with savant syndrome, demonstrate outstanding mental capability despite coexisting severe mental disabilities. In many cases, savant skills are characterized by its domain-specificity, enhanced memory capability, and excessive focus on low-level perceptual processing. In addition, impaired integrative cognitive processing such as social cognition or executive function, restricted interest, and compulsive repetition of the same act are observed in savant individuals. All these are significantly relevant to the behavioral characteristics observed in individuals with autistic spectrum disorders (ASD). A neurocognitive model of savant syndrome should explain these cognitive features and the juxtaposition of outstanding talents with cognitive disabilities. In recent neuropsychological studies, Miller (1998) reported clinical cases of "acquired savant," i.e., patients who improved or newly acquired an artistic savant-like skill in the early stage of frontotemporal dementia (FTD). Although the relationship between an autistic savant and acquired savant remains to be elucidated, the advent of neuroimaging study of ASD and the clarification of FTD patients with savant-like skills may clarify the shared neural mechanisms of both types of talent. In this review, we classified current cognitive models of savant syndrome into the following 3 categories. (1) A hypermnesic model that suggests that savant skills develop from existing or dormant cognitive functions such as memory. However, recent findings obtained through neuropsychological examinations imply that savant individuals solve problems using a strategy that is fairly different from a non-autistic one. (2) A paradoxical functional facilitation model (Kapur, 1996) that offers possible explanations about how pathological states in the brain lead to development of prodigious skills. This model emphasizes the role of reciprocal inhibitory interaction among adjacent or distant cortical regions, especially that of the prefrontal cortex and the posterior regions of the brain. (3) Autistic models, including those based on weak central coherence theory (Frith, 1989), that focus on how savant skills emerge from an autistic brain. Based on recent neuroimaging studies of ASD, Just et al. (2004) suggested the underconnectivity theory, which emphasizes the disruption of long-range connectivity and the relative intact or even more enhanced local connectivity in the autistic brain. All the models listed above have certain advantages and shortcomings. At the end of this review, we propose another integrative model of savant syndrome. In this model, we predict an altered balance of local/global connectivity patterns that contribute to an altered functional segregation/integration ratio. In particular, we emphasize the crucial role played by the disruption of global connectivity in a parallel distributed cortical network, which might result in impairment in integrated cognitive processing, such as impairment in executive function and social cognition. On the other hand, the reduced inter-regional collaboration could lead to a disinhibitory enhancement of neural activity and connectivity in local cortical regions. In addition, enhanced connectivity in the local brain regions is partly due to the abnormal organization of the cortical network as a result of developmental and pathological states. This enhanced local connectivity results in the specialization and facilitation of low-level cognitive processing. The disruption of connectivity between the prefrontal cortex and other regions is considered to be a particularly important factor because the prefrontal region shows the most influential inhibitory control on other cortical areas. We propose that these neural mechanisms as the underlying causes for the emergence of savant ability in ASD and FTD patients.

Quantitative analysis of the effects of lithium on the reverse tolerance and the c-Fos expression induced by methamphetamine in mice. To elucidate the mechanism of psychostimulant-induced reverse tolerance [A. Kifune, S. Tadokoro, Modification of stereotype producing and ambulation-increasing effects following repeated administration of methamphetamine in rats, Jpn. J. Psychopharmacol. 11 (1991) 207-214 [11]; N.J. Leith, R. Kuczenski, Chronic amphetamine: tolerance and reverse tolerance reflect different behavioral actions of the dog, Pharmacol. Biochem. Behav. 15 (1981) 399-405 [13]; S. Tadokoro, H. Kuribara, Reverse tolerance to the ambulation-increasing effect of methamphetamine in mice as an animal model of amphetamine-psychosis, Psychopharmacol, Bull. 22 (1986) 757-762 [18]; S. Tadokoro, H. Kuribara, Modification of the behavioral effects of drugs after repeated administration: special reference to the reverse tolerance, Folia Pharmacologica Japonica 95 (1990) 229-238 [19]], the effects of lithium on ambulatory activity [P. Cappeliez, E. Moore, Effects of lithium on an amphetamine animal model of bipolar disorder, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 14 (1990) 347-358 [1]; M. Hirabayashi, M.K. Alam, Enhancing effect of methamphetamine on ambulatory activity produced by repeated administration on mice, Pharmacol. Biochem. Behav. 15 (1981) 925-932 [7]; M. Hirabayashi, S. Okada, S. Tadokoro, Comparison of sensitization to ambulation-increasing effects of cocaine and methamphetamine after repeated administration in mice, J. Pharm. Pharmacol. 43 (1991) 827-830 [8]; T. Miyauchi, K. Kikuchi, S. Satoh, Further studies on the potentiating effect of lithium chloride on methamphetamine-induced stereotypy in mice, Jpn. J. Pharmacol. 31 (1981) 61-68 [14]; H. Ozawa, T. Nozu, H. Aihara, F. Akiyama, M. Sasajima, Pharmacokinetics and general pharmacological actions of lithium salts administered singly or repeatedly, Folia Pharmacologica Japonica 72 (1976) 433-443 [15].] and cerebral c-Fos expression [S. Ceccatelli, M.J. Villar, M. Goldstein, T. Hokfelt, Expression of c-Fos immunoreactivity in transmitter-characterized neurons after stress, Proc. Natl. Acad. Sci. USA 86 (1989) 9569-9573 [2]; L. Giovannelli, P.J. Shiromani, G.F. Jirikoski, F.E. Bloom, Expression of c-fos protein by immunohistochemically identified oxytocin neurons in the rat hypothalamus upon osmotic stimulation, Brain Research 588 (1992) 41-48 [4]; B.T. Hope, H.E. Nye, M.B. Kelz, D.W. Self, M.J. Iadarola, Y. Nakabeppu, R.S. Duman, E.J. Nestler, Induction of a long-lasting AP-1 complex composed of altered Fos-like proteins in brain by chronic cocaine and other chronic treatments, Neuron 13 (1994) 1235-1244 [10]; T. Miyauchi, K. Kikuchi, S. Satoh, Further studies on the potentiating effect of lithium chloride on methamphetamine-induced stereotypy in mice, Jpn. J. Pharmacol. 31 (1981) 61-68 [14]; F.R. Sharp, S.M. Sager, K. Hicks, D. Lowenstein, K. Hisanaga, c-fos mRNA, Fos, and Fos-related antigen induction by hypertonic saline and stress, J. Neurosci. 11 (1991) 2321-2331 [16].] were investigated in mice injected with methamphetamine (2 mg/kg, s.c., one to five times). The ambulatory activity enhanced by either acute or chronic methamphetamine injection was delayed or diminished by lithium chloride (LiCl) pretreatment [R.G. Fessler, R.D. Sturgeon, S.F. London, H.Y. Meltzer, Effects of lithium on behaviour induced by phencyclidine and amphetamine in rats. Psychopharmacology 78 (1982) 373-376 [3].]. How the Li-sensitive c-Fos expression in the dorsolateral geniculate nucleus and striatum is related to methamphetamine-induced behavioral excitation is unclear. This protocol, in combination with c-Fos expression of mouse cerebral regions, may provide a useful tool for quantitation of ambulatory activity during c-Fos expression.

Interventions to improve water quality and supply, sanitation and hygiene practices, and their effects on the nutritional status of children. Water, sanitation and hygiene (WASH) interventions are frequently implemented to reduce infectious diseases, and may be linked to improved nutrition outcomes in children. To evaluate the effect of interventions to improve water quality and supply (adequate quantity to maintain hygiene practices), provide adequate sanitation and promote handwashing with soap, on the nutritional status of children under the age of 18 years and to identify current research gaps. We searched 10 English-language (including MEDLINE and CENTRAL) and three Chinese-language databases for published studies in June 2012. We searched grey literature databases, conference proceedings and websites, reviewed reference lists and contacted experts and authors. Randomised (including cluster-randomised), quasi-randomised and non-randomised controlled trials, controlled cohort or cross-sectional studies and historically controlled studies, comparing WASH interventions among children aged under 18 years. Two review authors independently sought and extracted data on childhood anthropometry, biochemical measures of micronutrient status, and adherence, attrition and costs either from published reports or through contact with study investigators. We calculated mean difference (MD) with 95% confidence intervals (CI). We conducted study-level and individual-level meta-analyses to estimate pooled measures of effect for randomised controlled trials only. Fourteen studies (five cluster-randomised controlled trials and nine non-randomised studies with comparison groups) from 10 low- and middle-income countries including 22,241 children at baseline and nutrition outcome data for 9,469 children provided relevant information. Study duration ranged from 6 to 60 months and all studies included children under five years of age at the time of the intervention. Studies included WASH interventions either singly or in combination. Measures of child anthropometry were collected in all 14 studies, and nine studies reported at least one of the following anthropometric indices: weight-for-height, weight-for-age or height-for-age. None of the included studies were of high methodological quality as none of the studies masked the nature of the intervention from participants.Weight-for-age, weight-for-height and height-for-age z-scores were available for five cluster-randomised controlled trials with a duration of between 9 and 12 months. Meta-analysis including 4,627 children identified no evidence of an effect of WASH interventions on weight-for-age z-score (MD 0.05; 95% CI -0.01 to 0.12). Meta-analysis including 4,622 children identified no evidence of an effect of WASH interventions on weight-for-height z-score (MD 0.02; 95% CI -0.07 to 0.11). Meta-analysis including 4,627 children identified a borderline statistically significant effect of WASH interventions on height-for-age z-score (MD 0.08; 95% CI 0.00 to 0.16). These findings were supported by individual participant data analysis including information on 5,375 to 5,386 children from five cluster-randomised controlled trials.No study reported adverse events. Adherence to study interventions was reported in only two studies (both cluster-randomised controlled trials) and ranged from low (< 35%) to high (> 90%). Study attrition was reported in seven studies and ranged from 4% to 16.5%. Intervention cost was reported in one study in which the total cost of the WASH interventions was USD 15/inhabitant. None of the studies reported differential impacts relevant to equity issues such as gender, socioeconomic status and religion. The available evidence from meta-analysis of data from cluster-randomised controlled trials with an intervention period of 9-12 months is suggestive of a small benefit of WASH interventions (specifically solar disinfection of water, provision of soap, and improvement of water quality) on length growth in children under five years of age. The duration of the intervention studies was relatively short and none of the included studies is of high methodological quality. Very few studies provided information on intervention adherence, attrition and costs. There are several ongoing trials in low-income country settings that may provide robust evidence to inform these findings.

Resveratrol prevents alveolar bone loss in an experimental rat model of periodontitis. Resveratrol is an antioxidant and anti-inflammatory polyphenol. Periodontitis is induced by oral pathogens, where a systemic inflammatory response accompanied by oxidative stress is the major event initiating disease. We investigated how resveratrol modulates cellular responses and the mechanisms related to this modulation in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (hGFs). We also explored whether resveratrol protects rats against alveolar bone loss in an experimental periodontitis model. Periodontitis was induced around the first upper molar of the rats by applying ligature infused with LPS. Stimulating hGFs with 5μg/ml LPS augmented the expression of cyclooxygenase-2, matrix metalloproteinase (MMP)-2, MMP-9, and Toll-like receptor-4. LPS treatment also stimulated the production of reactive oxygen species (ROS) and the phosphorylation of several protein kinases in the cells. However, the expression of heme oxygenase-1 (HO-1) and nuclear factor-E2 related factor 2 (Nrf2) was inhibited by the addition of LPS. Resveratrol treatment almost completely inhibited all of these changes in LPS-stimulated cells. Specifically, resveratrol alone augmented HO-1 induction via Nrf2-mediated signaling. Histological and micro-CT analyses revealed that administration of resveratrol (5mg/kg body weight) improved ligature/LPS-mediated alveolar bone loss in rats. Resveratrol also attenuated the production of inflammation-related proteins, the formation of osteoclasts, and the production of circulating ROS in periodontitis rats. Furthermore, resveratrol suppressed LPS-mediated decreases in HO-1 and Nrf2 levels in the inflamed periodontal tissues. Collectively, our findings suggest that resveratrol protects rats from periodontitic tissue damage by inhibiting inflammatory responses and by stimulating antioxidant defense systems. The aims of this study were to investigate how resveratrol modulates cellular responses and the mechanisms related to this modulation in lipopolysaccharide (LPS)-stimulated human gingival fibroblasts (hGFs) and protects rats against alveolar bone disruption in an experimental periodontitis model. Our findings suggest that resveratrol protects rats from periodontitic tissue damage by inhibiting inflammatory responses and by stimulating antioxidant defense systems. On the basis of our experiment studies, we proposed that resveratrol could be used as novel bioactive materials or therapeutic drug for the treatment of periodontitis or other inflammatory bone diseases like osteoporosis, arthritis etc. Furthermore, it could be also used for the modification or coating of implant materials as an antiinflammatory molecules which will help to accelerate bone formation. There are a few of reports suggesting antioxidant and anti-inflammatory potentials of resveratrol. However, our results highlight the cellular mechanisms by which resveratrol inhibits LPS-mediated cellular damages using human-originated gingival fibroblasts and also support the potential of resveratrol to suppress periodontitis-mediated tissue damages. We believe that the present findings might improve a clinical approach of using of resveratrol on human, although further detailed experiments will be needed.

Experience with oseltamivir in the control of a nursing home influenza B outbreak. Oseltamivir prophylaxis was very effective in protecting nursing home residents from ILI and in halting this outbreak of influenza B. A portion of the total ILI cases may have been due to influenza A, as this strain was isolated in one resident. The 10% attack rate in this facility, controlled with oseltamivir, compares favourably with another influenza B outbreak in a similar facility in the same region, over the same time frame (ILI onset 27 December to 17 January). Oseltamivir prophylaxis was not used to manage this second outbreak of laboratory-confirmed influenza B. Of the 236 residents, 45 developed ILI for an overall attack rate of 19%, nearly double the rate in the oseltamivir-controlled setting (10%). While oseltamivir was effective in controlling influenza B in this outbreak, further experience and evaluation is required before it can be routinely recommended for prophylaxis of influenza in nursing home outbreaks. Although earlier attempts by others using oseltamivir in the control of influenza A outbreaks have also met with success, it is not yet licensed for this purpose. Compared to amantadine, oseltamivir has a relatively high cost for the control of influenza A outbreaks and this may continue to limit its wider acceptance. The cost-effectiveness of oseltamivir in the control of influenza B outbreaks needs to be specifically addressed given the typically milder nature of influenza B strains. However, such a distinction is not clinically reliable and elderly residents of long-term care facilities remain vulnerable to serious complications associated with influenza infection in general. An alternate agent for influenza chemoprophylaxis that is effective against both influenza A and B, is easily administered and has few side effects, could greatly enhance current prevention and control measures and warrants serious assessment. The spread of this outbreak from the geographically separate ward to other areas of the facility in which residents had not received prophylaxis, underscores the likely role of staff as a vehicle for transmission during facility outbreaks. While accurate staff ILI rates could not be determined, their immunization rates were low, and many staff were ill during the outbreak. Isolation of residents with ILI and prophylaxis of non-ill residents on the initial outbreak wards was insufficient to prevent the spread of the outbreak, although it was subsequently halted once prophylaxis was extended to all residents. In view of the uncertainty over this medication's widespread use, in the absence of licensure or previous studies demonstrating its effectiveness in the prophylaxis and control of influenza B outbreaks, initiation of oseltamivir prophylaxis was staggered by ward. In a declared influenza A outbreak, the protocol in a long term care facility is to initiate amantadine prophylaxis on all residents, rather than ward-by-ward. While anti-viral prophylaxis may be an effective secondary control measure in the management of influenza outbreaks, optimal primary prevention would be more effective. This would require increased vaccine coverage of residents and particularly of staff, who play an important role in the importation and transmission of influenza within these facilities.

Are synchronous and metachronous bilateral breast cancers different? An immunohistochemical analysis focused on cell cycle regulation. The biology and pathomechanisms of bilateral breast cancers is not fully understood. We compared the morphological and immunohistochemical characteristics of primary tumors in patients with synchronous (sBBC) and metachronous bilateral breast cancers (mBBC), with special focus on cell cycle regulation and its correlation with markers determining intrinsic phenotype. Immunohistochemical expression of p16Ink4A, p21(WAF1/CIP1), p27Kip1, p53, cyclin A, cyclin B, cyclin D1, cyclin D3 and cyclin E was assessed in tissue microarrays containing primary breast tumor cores from 113 mBBC and 61 sBBC. Expression of these markers was correlated with tumor grade and expression of estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) and Ki-67. In univariate analysis, mBBC demonstrated higher expression of p16Ink4A (both cytoplasmic: p=0.002 and nuclear: p=0.014), cyclin A (p=0.024) and B (cytoplasmic; p=0.015). In multivariate analysis mBBC were associated with lower expression of p21: p=0.038 and higher cytoplasmic expression of cyclin B: p=0.019. Lower ER expression for all BBCs and mBBC, respectively, was associated with stronger p16 expression (cytoplasmic: both p<0.000001 and nuclear: p<0.000001, p=0.00002), p53: p<0.000001, p=0.000001, cyclin A: p=0.00002, p=0.00045, cyclin B (cytoplasmic: p=0.00037, 0.00015 and nuclear: both p=0.0004) and cyclin E: p=000003, p<0.000001, and weaker expression of p27: p=0.00003, p=0.0001 and cyclin D1: both p<0.000001; for sBBC some of these correlations were absent. Higher p27 score correlated with lower HER2 expression in sBBC: p=0.018, whereas higher HER2 expression was associated with higher p53: 0.024 and cyclin E: p=0.048 expression in all BBC and higher nuclear expression of cyclin B in sBBC: p=0.027. Higher Ki-67 expression was correlated with higher expression of p16 (cytoplasmic: p=0.000015, p=0.086, p=0.0002 and nuclear: p=0.000009, p=0.016, p=0.00003) in all subsets [all BBC, sBBC (non-significant for cytoplasmic score), mBBC, respectively], p21 (all BBC: p=0.05) and sBBC: p=0.017), p53 (all BBC: p=0.0003 and mBBC: p=0.0002), cyclin A: all p<0.000001, cyclin B (cytoplasmic: p<0.000001, p=0.004, p<0.000001, respectively and nuclear: p=0.0002, p=0.047, p=0.0026, respectively), cyclin D3 (all BBC: p=0.005 and mBBC: p=0.02) and cyclin E (all BBC: p<0.000001 and mBBC: p=0.000002), and lower expression of cyclin D1 (all BBC: p=0.046 and mBBC: p=0.035) and p27 (sBBC: p=0.048). Compared to sBBC, mBBC are characterized by lower expression of p21 and higher cytoplasmic expression of cyclin B, suggesting its more aggressive behavior. Correlations between cell-cycle regulation proteins and markers of breast cancer phenotype parallel those reported for unilateral breast cancer.

A prospective study of glycemic control during holiday time in type 2 diabetic patients. In the U.K. Prospective Diabetes Study, A1C increased from 1.2 to 1.7% and fasting plasma glucose from 1.0 to 2.8 mmol/l over 10 years in type 2 diabetic patients. It is not known whether the blood glucose increase observed in long-term studies of type 2 diabetes results from small, steady increases throughout the year or from increases during discrete periods. To estimate the variation of actual glycemic control and its relation to holiday times, we measured A1C and fructosamine in 110 patients with type 2 diabetes. These measurements were performed four times at intervals of 4-6 weeks; therefore, glycemic change was determined for three periods: preholiday period (from between November 13 and December 20 to between December 20 and January 20), holiday period (from between December 20 and January 20 to between January 28 and February 28), and postholiday period (from between January 28 and February 28 to between March 1 and April 10). A final measurement of A1C was obtained from 90 subjects in the following December or January. The mean A1C increased, but not significantly, during the preholiday (increase 0.135 +/- 0.723%, P = 0.055) and holiday (increase 0.094 +/- 0.828%, P = 0.239) periods. The mean A1C decreased, but not significantly, during the postholiday period (decrease 0.022 +/- 0.588%, P = 0.695). Altogether, the A1C change during these three periods increased significantly (increase 0.207 +/- 0.943%, P = 0.024). The mean fructosamine increased significantly during the preholiday period (increase 0.151 +/- 0.460 mmol/l, P = 0.001), but there was no significant change during the holiday period (increase 0.057 +/- 0.593 mmol/l, P = 0.321). However, fructosamine decreased significantly during the postholiday period (decrease 0.178 +/- 0.448 mmol/l, P < 0.001). Altogether, the fructosamine changes during the study periods showed no significant difference (increase 0.030 +/- 0.566 mmol/l, P = 0.579). Between March or early April and the following December or January, there was no additional change in A1C (decrease 0.009 +/- 1.039%, P = 0.935) for the 90 participants who returned for follow-up treatment. The present study demonstrates an influence of winter holidays on the glycemic control of patients who have type 2 diabetes, and this poor glycemic control might not be reversed during the summer and autumn months. Therefore, the cumulative effects of the yearly A1C gain during the winter holidays are likely to contribute to the substantial increase in A1C that occurs every year among type 2 diabetic individuals.

[Stereotaxic irradiation of brain metastasis in elderly patients]. Analysis of results of stereotactic irradiation for brain metastases for patients older than 70 years. From January 1994 to January 2002, 53 patients received stereotactic irradiation for a total of 105 brain metastases. There were 26 females and 27 males. Median age was 73 years (70-86). Median interval between cancer diagnosis and brain metastases was 18 months (0-216). Metastases were diagnosed after development of related clinical symptoms in 34 patients (64.1%). Patients were irradiated for one to 6 metastases. Twenty-nine patients (54.7%) were treated for only one metastasis. Median metastasis diameter and volume were respectively 24 mm (5-74.9 mm) and 2.1 cc (0.02-71.3). Eighty-three metastases were supratentorial (79%), and 22 subtentorial (21%). Forty-five underwent only one procedure (85%) and 8 patients underwent a second procedure for one or several new metastases. Three patients were irradiated with whole brain radiotherapy (WBRT) concomitantly of radiosurgery and three patients received WBRT after radiosurgery for development of more than four metastases or for carcinomatous meningitis. The median follow-up was 8 months (1-33). Median minimum and maximum doses delivered to the metastases were respectively, 16.42 Gy (6.5-20.5) and 20.36 Gy (13.2-41.9). The median overall survival duration was 9 months. Three-, 6-, 12- and 18-month overall survival rates were respectively, 85.6% +/- 5, 65.2% +/- 7.1, 35.5% +/- 7.8 and 26.6% +/- 8. According to unifactorial analysis, two prognostic factors of overall survival were retrieved, extra-cranial disease status and RPAa (Recursive Partitioning Analysis for aged patients) separated in three classes including Karnofsky index performance status and extra-cranial disease status, respectively p = 0.043 et p = 0.016. According to multifactorial analysis only RPAa was an independent prognostic factor of overall survival (p = 0.019, RR: 0.89, 95% confidence interval [0.017-0.47]). Median brain disease-free survival was 12 months. Three-, 6-, 12- and 18-month free-brain disease survival rates were, 81.5% +/- 6.4, 68.7% +/- 8, 47.2% +/- 9.9 and 35.4% +/- 12.6, respectively. No prognostic factor of free-brain disease survival was retrieved. Crude local control rate was 97%. Only three metastases relapsed. Six and 12-month local control rates were 98.6% +/- 1.4 and 88.5% +/- 7.6. Among 34 patients with initial clinical symptoms, one patient presented an aggravation, 9 improved up to complete response (26.5%), 13 patients presented a partial remission (38.2%) and 5 were stabilized (14.7%). For 6 patients, data were not available. We observed 3 radionecroses and 1 hemorrhage of the metastases. Radiosurgery in the elderly was efficient and well tolerated. Age alone should not be used to deny potentially beneficial radiosurgery to any patient with brain metastases.

The fateful encounter of mitochondria with calcium: how did it happen? A number of findings in the 1950s had offered indirect indications that mitochondria could accumulate Ca2+. In 1961, the phenomenon was directly demonstrated using isolated mitochondria: the uptake process was driven by respiratory chain activity or by the hydrolysis of added ATP. It could be accompanied by the simultaneous uptake of inorganic phosphate, in which case precipitates of hydroxyapatite were formed in the matrix, buffering its free Ca2+ concentration. The properties of the uptake process were established in the 1960s and 1970s: the uptake of Ca2+ occurred electrophoretically on a carrier that has not yet been molecularly identified, and was released from mitochondria via a Na+/Ca2+ antiporter. A H+/Ca2+ release exchanger was also found to operate in some mitochondrial types. The permeability transition pore was later also found to mediate the efflux of Ca2+ from mitochondria. In the mitochondrial matrix two TCA cycle dehydrogenases and pyruvate dehydrogenase phosphate phosphatase were found to be regulated in the matrix by the cycling of Ca2+ across the inner membrane. In conditions of cytoplasmic Ca2+ overload mitochondria could store for a time large amounts of precipitated Ca2+-phosphate, thus permitting cells to survive situations of Ca2+ emergency. The uptake process was found to have very low affinity for Ca2+: since the bulk concentration of Ca2+ in the cytoplasm is in the low to mid-nM range, it became increasingly difficult to postulate a role of mitochondria in the regulation of cytoplsmic Ca2+. A number of findings had nevertheless shown that energy linked Ca2+ transport occurred efficiently in mitochondria of various tissues in situ. The paradox was only solved in the 1990s, when it was found that the concentration of Ca2+ in the cytoplasm is not uniform: perimitochondrial micropools are created by the agonist-promoted discharge of Ca2+ from vicinal stores in which the concentration of Ca2+ is high enough to activate the low affinity mitochondrial uniporter. Mitochondria thus regained center stage as important regulators of cytoplasmic Ca2+ (not only of their own internal Ca2+). Their Ca2+ uptake systems was found to react very rapidly to cytoplasmic Ca2+ demands, even in the 150-200 msec time scale of processes like the contraction and relaxation of heart. An important recent development in the area of mitochondrial Ca2+ transport is its involvement in the disease process. Ca2+ signaling defects are now gaining increasing importance in the pathogenesis of diseases, e.g., neurodegenerative diseases. Since mitochondria have now regained a central role in the regulation of cytoplasmic Ca2+, dysfunctions of their Ca2+ controlling systems have expectedly been found to be involved in the pathogenesis of numerous disease processes.

Olaparib in combination with paclitaxel in patients with advanced gastric cancer who have progressed following first-line therapy (GOLD): a double-blind, randomised, placebo-controlled, phase 3 trial. Olaparib combined with paclitaxel has previously shown a significant improvement in overall survival versus placebo plus paclitaxel as second-line therapy in a phase 2 study in Asian patients with advanced gastric cancer, especially in those with ataxia-telangiectasia mutated protein (ATM)-negative tumours. Here, we report the primary efficacy and safety analyses from a subsequent phase 3 trial. This double-blind, randomised, placebo-controlled, phase 3 study (GOLD) recruited Asian patients aged 18 years or older (≥20 years if Japanese) with advanced gastric cancer that had progressed following, or during, first-line chemotherapy. Patients were randomly assigned (1:1) to receive oral olaparib (100 mg twice daily) plus paclitaxel (80 mg/m2 intravenously) or matching placebo plus paclitaxel. Randomisation was done through an interactive voice response system and no stratification factors were used. Patients and investigators were masked to treatment allocation. Two co-primary populations were assessed: the overall population of all patients and patients whose tumours were ATM-negative (identified after randomisation, before the data cutoff date, March 28, 2016). The primary endpoint in both populations was overall survival (defined as the time from the date of randomisation until death from any cause before data cutoff); a significant difference was defined as p<0·025. Efficacy was assessed in the intention-to-treat populations and safety in patients who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01924533 (study ID, D081BC00004), and is ongoing but no longer recruiting participants. Between Sept 3, 2013, and March 28, 2016, 643 patients were enrolled from 58 study sites in hospitals and medical centres in China, Japan, South Korea, and Taiwan. 525 eligible patients were randomly assigned: 263 to receive olaparib plus paclitaxel and 262 to receive placebo plus paclitaxel. 94 patients were determined to have ATM-negative tumours before unmasking for the primary analysis (48 in the olaparib plus paclitaxel group and 46 in the placebo plus paclitaxel group). Overall survival did not differ between treatment groups in the overall patient population (median overall survival 8·8 months [95% CI 7·4-9·6] in the olaparib group vs 6·9 months [6·3-7·9] in the placebo group; HR 0·79 [97·5% CI 0·63-1·00]; p=0·026) or in the ATM-negative population (12·0 months [7·8-18·1] vs 10·0 months [6·4-13·3]; 0·73 [0·40-1·34]; p=0·25). In the overall patient population, the most common grade 3 or worse adverse events in the olaparib plus paclitaxel group were neutropenia (78 [30%] of 262 patients), leucopenia (42 [16%]), and decreased neutrophil count (40 [15%]); in the placebo plus paclitaxel group, they were neutropenia (59 [23%] of 259 patients), leucopenia (27 [10%]), and decreased white blood cell count (21 [8%]). Adverse events with an outcome of death causally related to study treatment (according to investigator assessment) were reported in two patients: liver injury in one patient (<1%) in the olaparib plus paclitaxel group and cardiac failure in one patient (<1%) in the placebo plus paclitaxel group. The GOLD study did not meet its primary objective of showing a significant improvement in overall survival with olaparib in the overall or ATM-negative population of Asian patients with advanced gastric cancer. The study generated informative efficacy and safety data regarding the use of olaparib in combination with a chemotherapeutic agent and provides a foundation for future studies in this difficult-to-treat patient population. AstraZeneca.

First-lactation performance in cows affected by digital dermatitis during the rearing period. The long-term effects of prepartum digital dermatitis (DD) on first-lactation performance were evaluated in a cohort of 719 pregnant heifers. All heifers were followed for a period of 6 mo until calving and classified on the basis of the number of DD events diagnosed during this period as type I, type II, or type III (no DD, one DD event, and multiple DD events, respectively). Health during the initial 60d in milk (DIM), reproductive and hoof health outcomes, and milk production were compared between the 3 heifer type groups. All logistic and linear models were adjusted for age, height, and girth circumference at enrollment, and the type of trace mineral supplementation during the prepartum period. Overall, cows experiencing DD during the rearing period showed worse production and health outcomes compared with healthy heifers during the first lactation. The percentages of assisted calvings, stillbirths, culled before 60 DIM, and diseased cows during the fresh period were numerically higher in type III cows compared with type I cows. However, none of these differences were statistically significant at the 95% confidence level. Significantly lower conception at first service [odds ratio (OR)=0.55, 95% confidence interval (95% CI): 0.33, 0.89] and increased number of days open (mean=24d, 95% CI: 5.2, 43) were observed in type III cows compared with type I cows. In relation to hoof health, a significantly increased risk of DD during the first lactation was found in type II and III cows (OR=5.16, 95% CI: 3.23, 8.29; and OR=12.5, 95% CI: 7.52, 21.1, respectively), as well as earlier occurrence of DD following calving (OR=59d, 95% CI=20, 96, and OR=74d, 95% CI: 37, 109). Compared with type I cows, statistically significant milk production losses during the initial 305 DIM of 199 and 335kg were estimated in type II and III cows, respectively. This difference was due to a greater rate of production decline (less persistence) after peak yield. No differences in monthly fat and protein percentages or somatic cell counts were observed between the heifer types. Given the long-term effects of DD on health, reproduction, and production, one of the priorities during the rearing period of dairy heifers should be efficient DD prevention and control programs. Such intensive intervention programs based on active long-term DD surveillance, mitigation of risk factors, and prompt treatment are expected to increase overall animal well-being and farm profitability by minimizing the effect of DD during the first lactation.

Closed-circuit xenon delivery using a standard anesthesia workstation. Xenon (Xe) is an anesthetic with minimal side effects, now also showing promise as a neuroprotectant both in vitro and in vivo. Although scarce and expensive, Xe is insoluble and patient uptake is low, making closed circuits the optimum delivery method. Although the future of Xe anesthesia is uncertain, effective neuroprotection is highly desirable even if moderately expensive. A factor limiting Xe research in all these fields may be the perceived need to purchase special Xe anesthesia workstations that are expensive and difficult to service. We investigated the practicality of 1) true closed-circuit Xe delivery using an unmodified anesthesia workstation with gas monitoring/delivery attachments restricted to breathing hoses only, 2) a Xe delivery protocol designed to eliminate wastage, and 3) recovering Xe from exhaled gas. Sixteen ASA physical status I/II patients were recruited for surgery of > 2 h. Denitrogenation with 100% oxygen was started during induction and tracheal intubation under propofol/remifentanil anesthesia. This continued after operating room transfer for 30 min. All fresh gases were then temporarily stopped, metabolic oxygen consumption then being replaced with 250-mL Xe boluses until F(I)Xe = 50%. A basal oxygen fresh gas flow was thereafter restored with additional Xe given as required via the expiratory hose to maintain a F(I)Xe > or = 50%. At no time, apart from during circle flushes every 90 min, were the bellows allowed to completely fill and spill gas, ensuring the circle remained closed. On termination of anesthesia, the first 10 exhaled breaths were collected as was residual gas from the circle, allowing measurement of the Xe content of each. Total Xe consumption, including initial wash-in and circle flushes, was 12.62 (5.31) L or 4.95 (0.82) L/h, mean (sd). However, consumption during maintenance periods was lower: 3 L/h at 1 h and 2 L/h thereafter. Of the total Xe used, 8.98% (5.94%) could be recovered at the end of the procedure. We report that closed-circuit Xe delivery can be achieved with a modified standard anesthesia workstation with breathing hose alterations only and that the protocol was very gas efficient, especially during the normally wasteful Xe wash-in. A Xe mixture of > or = 50% was delivered for up to 341 min (5 h 41 min) and Xe consumption was 4.95 (0.82) L/h, maintenance being achieved with 2-3 L/h. With this degree of efficiency, Xe recovery/recycling at the end of anesthesia may be of little additional benefit.

Statement of Retraction: "Mohamad Goldust, Mahnaz Talebi, Jafar Majidi, Mohammad Amin Rezazadeh Saatlou, and Elham Rezaee. Evaluation of antiphospholipid antibodies in youths suffering from cerebral ischemia.". The Editors and Publisher would like to inform the readers the following article has been retracted from publication in the International Journal of Neuroscience: Mohamad Goldust, Mahnaz Talebi, Jafar Majidi, Mohammad Amin Rezazadeh Saatlou, Elham Rezaee. Evaluation of antiphospholipid antibodies in youths suffering from cerebral ischemia. Int J Neurosci. 2013 Mar;123(3):1247-57. Dr. Mahnaz Talebi contacted the Editors of the International Journal of Neuroscience to inform them that this article was a graduation thesis for his student Dr. Mohamadali Arami at Tabriz University of Medical Sciences, Tabriz, Iran, and previously published in print and in Persian by the Iranian Journal of Neurology: Mahnaz Talebi, Jafar Majidi, Mohamadali Arami, Seyed Ali Saderddini. Evaluation of antiphospholipid antibodies in youths suffering from cerebral ischemia. Iran J Neuro. 2005 Spring;15(3):26-34. Moreover, Dr. Talebi said he was listed as an author of the article published in the International Journal of Neuroscience without his knowledge or consent. When queried, Dr. Mohamad Goldust, the corresponding author of the article published in the International Journal of Neuroscience, admitted that he listed Dr. Talebi as a coauthor improperly and asked for the manuscript to be retracted; he did not respond to our questions regarding whether this manuscript was previously published in the Iranian Journal of Neurology or whether this manuscript was the original work of the authors listed in the published the International Journal of Neuroscience article. The coauthors listed on the article published in the International Journal of Neuroscience were contacted several times but did not respond to our queries. Since the article in the Iranian Journal of Neurology was published in Persian, we contacted Dr. Shahriar Nafissi, Editor in Chief of the Iranian Journal of Neurology, who confirmed that the two articles in question were the same. Our policy in this respect is clear: the International Journal of Neuroscience considers all manuscripts on the strict condition that they have been submitted only to the International Journal of Neuroscience, that they have not been published already, nor are they under consideration for publication or in press elsewhere. International Journal of Neuroscience published this article in good faith, and on the basis of signed statements made by the corresponding author regarding the originality of their work. The article is withdrawn from all print and electronic editions.

Morphometric evaluation of changes with time in optic disc structure and thickness of retinal nerve fibre layer in chronic ocular hypertensive monkeys. We examined the time course of changes in optic disc structure by means of a scanning laser ophthalmoscope (Heidelberg Retina Tomograph, HRT) in ocular hypertensive (experimental glaucoma) monkeys, and clarified the relationships between the histological RNFL thickness and HRT parameters. Further, the time course of changes in retinal nerve fiber layer (RNFL) thickness in individual eyes was measured using a scanning laser polarimeter with fixed corneal polarization compensator (GDx FCC). In the present study, two separate experiments were carried out. A chronic intraocular pressure (IOP) elevation was induced by laser trabeculoplasty in the left eye in 11 cynomolgus monkeys. In Experiment 1, the HRT and GDx parameters were measured 12 weeks after the laser treatment in 10 eyes in five monkeys. In Experiment 2, the time course of changes in the HRT and GDx parameters was examined before and 1, 3, 4, 5, 6, 8, 10, 12, 14, and 16 weeks after the laser treatment in 12 eyes in six monkeys. The retardation values (thickness parameters) obtained from the GDx were used to derive thickness and ratio parameters in the superior, inferior, nasal and temporal quadrants. Ratio parameters were expressed as a ratio of superior and inferior quadrant to nasal quadrant. After the last measurements, each eye was enucleated, and retinal cross sections were prepared for histological analysis. In the left (hypertensive) eyes, IOP was persistently elevated throughout the observation periods in both Experiments 1 and 2. In the HRT measurements in Experiment 1, seven out of eight global topographic parameters (exception, disc area) were statistically different between the hypertensive and control eyes 12 weeks after the laser treatment. In Experiment 2, the HRT parameters changed in a time-dependent manner, but each of them almost plateaued at about 4 weeks after the laser treatment. Significant correlations were seen between the histological mean RNFL thickness at 1.5 disc diameters from the optic disc margin and the HRT parameters in 21 eyes from 11 monkeys in Experiments 1 and 2. Especially good correlations with histological mean RNFL thickness were seen for the rim volume and cup volume. In Experiment 1, good correlations were found between GDx ratio parameters and histological RNFL thickness in individual right control eyes (n=5). In individual left experimental glaucoma eyes of Experiment 2 (n=6), GDx ratio parameters declined in a time-dependent manner alongside the IOP elevation. In conclusion, alongside the IOP elevation, time-related changes in optic disc topography and RNFL thickness were demonstrated in monkey eyes using HRT and GDx. HRT (rim and cup) parameters showed good correlations with histological RNFL thickness, and significant interrelations.

Laparoscopic treatment of endometrial cancer: systematic review. The objective of this review was to assess the efficacy and safety of laparoscopy compared with laparotomy for treatment of endometrial cancer. Trials were identified by searching the Cochrane Gynecological Cancer Collaborative Review Group Trial Register, MEDLINE, EMBASE, PubMed, BIOSIS Previews, the China Biological Medicine Database, China National Knowledge Infrastructure Whole Article Database, Wan Fang Data, and VIP Information, from January 1991 to May 2012, as well as the Cochrane Central Register of Controlled Trials (Cochrane Library, issue 5, 2012). We also hand searched unpublished and gray literature, reference lists of identified studies, gynecologic cancer handbooks, and conference abstracts. All randomized controlled trials (RCTs) comparing laparoscopic surgery with laparotomy for treatment of all stages of endometrial cancer were selected. Data extraction was performed independently by 2 review authors who assessed study quality and extracted data. The whole articles were assessed for method quality by using the Cochrane Collaboration Back Review Group method quality criteria. Heterogeneity between studies was assessed using the I2 statistic, which estimates the percentage of heterogeneity between trials. The outcomes were pooled statistically when no clinical heterogeneity was apparent. For time to event data, hazard ratios were pooled using the generic inverse variance facility of RevMan 5. Random effects models were used for all meta-analyses. The search yielded 9 eligible RCTs (1361 laparotomy and 2255 laparoscopy). There was no significant difference between laparoscopic and laparotomic approaches to endometrial cancer in 3-year overall survival (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.49 to 1.71; p = .77), 3-year disease-free survival (OR, 0.95; 95% CI, 0.29 to 1.80; p = .89), recurrence at 3-year follow-up (OR, 1.11; 95% CI, 0.60 to 2.06; p = .74), and pelvic node yield (mean difference [MD, 0.45; 95% CI, -0.41 to 1.32; p = .30). The benefits of laparoscopic surgery vs laparotomy were shorter length of hospital stay (MD, -3.42; 95% CI, -3.81 to -3.03; p < .01), and lower rates of postoperative complications (OR, 0.62; 95% CI, 0.52 to 0.73; p < .01). Disadvantages were higher rates of intraoperative complications (OR, 1.35; 95% CI, 1.05 to1.74; p = .02) and longer duration of surgical procedures (MD, 32.73; 95% CI, 16.34 to 49.13; p < .01). We conclude that, compared with laparotomy, laparoscopic surgery seems to be beneficial in women with endometrial cancer, in particular insofar as postoperative complications and length of hospital stay. However, more well-designed RCTs are needed to assess the long-term clinical outcomes, in particular the quality of life.

The effects of collection methods on oral fluid codeine concentrations. The use of a variety of alternative biological specimens such as oral fluid for the detection and quantitation of drugs has recently been the focus of considerable scientific research and evaluation. A disadvantage of drug testing using alternative specimens is the lack of scientific literature describing the collection and analyses of these specimens and the limited literature about the pharmacokinetics and disposition of drugs in the specimen. Common methods of oral fluid collection are spitting, draining, suction, and collection on various types of absorbent swabs. The effect(s) of collection techniques on the resultant oral fluid drug concentration has not been thoroughly evaluated. Reported is a controlled clinical study (using codeine) that was designed to determine the effects of five collection techniques and devices on oral fluid codeine concentrations. The collection techniques were control (spitting), acidic stimulation, nonacidic stimulation, and use of either the Salivette or the Finger Collector (containing Accu-Sorb) oral fluid collection devices. Preliminary data were collected from two subjects using the Orasure device. The in vitro drug recovery was also evaluated for the Salivette and the Finger Collector devices. With the exception of a single time point, codeine concentrations in specimens collected by the control method (spitting) were consistently higher than concentrations in specimens collected by the other methods. The control collection concentrations averaged 3.6 times higher than concentrations in specimens collected by acidic stimulation and 1.3 to 2.0 higher than concentrations in specimens collected by nonacidic stimulation or collection using either the Salivette or the Finger Collector devices. When calculated using oral fluid codeine concentrations from the clinical study, the elimination rate constant, t(1/2), AUC and the peak oral fluid concentrations demonstrated device differences. The slope of the elimination curve for codeine using the acidic collection method exceeded that of the other four methods. As a result, the t(1/2) for the acidic method was significantly less than that of the control method (1.8 vs. 3.0 h, respectively). Oral contamination contributed to the control method having higher AUC than that calculated using the other methods. There was considerable variation in peak codeine concentrations between devices and between individuals within each collection method. When samples were collected simultaneously with the Salivette and the Finger Collector, the mean codeine concentrations were similar. We were able to recover > or = 500 microL of oral fluid from 81.8% of the clinical samples collected with the Salivette. However, we were able to recover this volume from only 25.5% of the samples collected with the Finger Collector. In addition, the in vitro drug recoveries were lower using the Finger Collector. When oral fluid was collected nearly simultaneously by the control method and by use of the Salivette, mean control codeine concentrations were 2.3 times higher, but the duration of detection was similar for both methods.

Early referral to specialist nephrology services for preventing the progression to end-stage kidney disease. Early referral of patients with chronic kidney disease (CKD) is believed to help with interventions to address risk factors to slow down the rate of progression of kidney failure to end-stage kidney disease (ESKD) and the need for dialysis, hospitalisation and mortality. We sought to evaluate the benefits (reduced hospitalisation and mortality; increased quality of life) and harms (increased hospitalisations and mortality, decreased quality of life) of early versus late referral to specialist nephrology services in CKD patients who are progressing to ESKD and RRT. In this review, referral is defined as the time period between first nephrology evaluation and initiation of dialysis; early referral is more than one to six months, whereas late referral is less than one to six months prior to starting dialysis. All-cause mortality and hospitalisation and quality of life were measured by the visual analogue scale and SF-36. SF-36 and KDQoL are validated measurement instruments for kidney diseases. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2012; Issue 1) which contains the Cochrane Renal Group's Specialised Register; MEDLINE (1966 to February 2012), EMBASE (1980 to February 2012). Search terms were approved by the Trial Search Co-ordinator. Randomised controlled trials (RCTs), quasi-RCTs, prospective and retrospective longitudinal cohort studies were eligible for inclusion. Two authors independently assessed study quality and extracted data. Events relating to adverse effects were collected from the studies. No RCTs or quasi-RCTs were identified. There were 40 longitudinal cohort studies providing data on 63,887 participants; 43,209 (68%) who were referred early and 20,678 (32%) referred late.Comparative mortality was higher in patients referred to specialist services late versus those referred early. Risk ratios (RR) for mortality reductions in patients referred early were evident at three months (RR 0.61, 95% CI 0.55 to 0.67; I² = 84%) and remained at five years (RR 0.66, 95% CI 0.60 to 0.71; I² = 87%). Initial hospitalisation was 9.12 days shorter with early referral (95% CI -10.92 to -7.32 days; I² = 82%) compared to late referral. Pooled analysis showed patients referred early were more likely than late referrals to initiate RRT with peritoneal dialysis (RR 1.74, 95% CI 1.64 to 1.84; I² = 92%).Patients referred early were less likely to receive temporary vascular access (RR 0.47, 95% CL 0.45 to 0.50; I² = 97%) than those referred late. Patients referred early were more likely to receive permanent vascular access (RR 3.22, 95% CI 2.92 to 3.55; I² = 97%). Systolic blood pressure (BP) was significantly lower in early versus late referrals (MD -3.09 mm Hg, 95% CI -5.23 to -0.95; I² = 85%); diastolic BP was significantly lower in early versus late referrals (MD -1.64 mm Hg, 95% CI -2.77 to -0.51; I² = 82%). EPO use was significantly higher in those referred early (RR 2.92, 95% CI 2.42 to 3.52; I² = 0%). eGFR was higher in early referrals (MD 0.42 mL/min/1.73 m², 95% CI 0.28 to 0.56; I² = 95%). Diabetes prevalence was similar in patients referred early and late (RR 1.05, 95% CI 0.96 to 1.15; I² = 87%) as was ischaemic heart disease (RR 1.05, 95% CI 0.97 to 1.13; I² = 74%), peripheral vascular disease (RR 0.99, 95% CI 0.84 to 1.17; I² = 90%), and congestive heart failure (RR 1.00, 95% CI 0.86 to 1.15; I² = 92%). Inability to walk was less prevalent in early referrals (RR 0.66, 95% CI 0.51 to 0.86). Prevalence of chronic obstructive pulmonary disease was similar in those referred early and late (RR 0.89, 95% CI 0.70 to 1.14; I² = 94%) as was cerebrovascular disease (RR 0.90, 95% CI 0.74 to 1.11; I² = 83%).The quality of the included studies was assessed as being low to moderate based on the Newcastle-Ottawa Scale. Slight differences in the definition of early versus late referral infer some risk of bias. Generally, heterogeneity in most of the analyses was high. Our analysis showed reduced mortality and mortality and hospitalisation, better uptake of peritoneal dialysis and earlier placement of arteriovenous fistulae for patients with chronic kidney disease who were referred early to a nephrologist. Differences in mortality and hospitalisation data between the two groups were not explained by differences in prevalence of comorbid disease or serum phosphate. However, early referral was associated with better preparation and placement of dialysis access.

Effect of oral calcium bolus administration on milk production, concentrations of minerals and metabolites in serum, early-lactation health status, and reproductive performance of Holstein dairy cows. To determine the effects of oral Ca bolus administration in the early postpartum period of cows on milk yield and composition, blood metabolites, early-lactation health status, and reproductive performance. Multiparous Holstein dry cows (n=66) with a mean parity of 3.1 (SD 0.35) were fed a diet with a positive dietary cation-anion difference (DCAD) prior to calving. They were randomly assigned to receive no treatment (Control; n=33) or two oral Ca boluses (n=33, 45 g of Ca per bolus); one was administered immediately after calving (Day 0) and the second 24 hours (±30 minutes) later. Blood samples were collected at calving, and on Days 2 and 7 to determine concentrations in serum of Ca, P, Mg, glucose, non-esterified fatty acids (NEFA), and β-hydroxybutyric acid (BHBA). Milk yield was recorded daily and milk composition was determined weekly from calving until 28 day postpartum. Health and outcomes were determined during the first 30 days postpartum and reproductive outcomes to 180 days postpartum. Mean milk yields and composition over the first month of lactation were similar between cows in the two treatment groups (p>0.1). Mean concentrations of Ca in serum were not different between treatment groups on Day 0, but were higher on Day 2 for cows that received oral Ca boluses (1.77 (SE 0.07)) compared with Control cows (1.54 (SE 0.08)) (p=0.04). Concentrations in serum of P, Mg, glucose, NEFA and ΒHBA did not differ between treatment groups on any day of measurement. Fewer cows that received oral Ca were diagnosed with hypocalcaemia (total concentrations of Ca in serum <1.5 mmol/L) by Day 2 (2/33; 6%) compared with Control cows (12/33; 36%) (p=0.01). There was no difference in the prevalence of other health outcomes between treatment groups. The proportion of cows conceiving to first insemination was greater in cows that received an oral Ca bolus (19/29; 65%) than Control cows (12/29; 41%) (p=0.01). Oral Ca bolus administration increased concentrations of Ca in serum on Day 2 postpartum, and increased first service conception rates, in cows fed a diet with a positive DCAD prior to calving compared to cows that received no oral Ca bolus supplementation. Because of the small number of cows used in this study, further studies in large-scale dairy farms should be carried out to confirm these findings.

Stepwise Cluster Assembly Using VO(2)(acac) as a Precursor: cis-[VO(OCH(CH(3))(2))(acac)(2)], [V(2)O(2)(&mgr;-OCH(3))(2)(acac)(2)(OCH(3))(2)], [V(3)O(3){&mgr;,&mgr;-(OCH(2))(3)CCH(3)}(2)(acac)(2)(OC(2)H(5))], and [V(4)O(4)(&mgr;-O)(2)(&mgr;-OCH(3))(2)(&mgr;(3)-OCH(3))(2)(acac)(2)(OCH(3))(2)].2CH(3)CN(1). The studies of an underexplored synthetic reagent, VO(2)(acac) (Hacac = acetylacetone) and semirational strategies for the formation of a complete series of simple vanadium(V) alkoxide clusters in alcohol-containing solvents. The neutral mono-, di-, tri-, and tetranuclear oxovanadium(V) complexes [V(2)O(2)(&mgr;-OCH(3))(2)(acac)(2)(OCH(3))(2)] (1), [V(4)O(4)(&mgr;-O)(2)(&mgr;-OCH(3))(2)(&mgr;(3)-OCH(3))(2)(acac)(2)(OCH(3))(2)].2CH(3)CN (2), [V(4)O(4)(&mgr;-O)(2)(&mgr;-OCH(3))(2)(&mgr;(3)-OCH(3))(2)(acac)(2)(OCH(3))(2)] (3), [V(3)O(3){&mgr;,&mgr;-(OCH(2))(3)CCH(3)}(2)(acac)(2)(OR)] (R = CH(3) (4), C(2)H(5) (5)), and cis-[VO(OCH(CH(3))(2))(acac)(2)] (6) with alkoxide and acac(-) ligands were obtained by reaction of VO(2)(acac) with a monoalcohol and/or a tridentate alcohol. The structures of complexes 1-3, 5, and 6 were determined by X-ray diffraction methods. Complex 1 crystallized in the monoclinic system, P2(1)/n, with a = 7.8668(5) Å, b = 15.1037(9) Å, c = 8.5879(5) Å, beta = 106.150(1) degrees, V = 980.1(1) Å(3), Z = 2, and R (wR2) = 0.040 (0.121). Complex 2 crystallized in the monoclinic system, P2(1)/n, with a = 8.531(2) Å, b = 14.703(3) Å, c = 12.574(2) Å, beta = 95.95(2) degrees, V = 1568.7(5) Å(3), Z = 2, and R (wR2) = 0.052 (0.127). Complex 3 crystallized in the triclinic system, P&onemacr;, with a = 8.5100(8) Å, b = 8.9714(8) Å, c = 10.3708(10) Å, alpha = 110.761(1) degrees, beta = 103.104(1) degrees, gamma = 100.155(1) degrees, V = 691.85(11) Å(3), Z = 1, and R (wR2) = 0.040 (0.105). Complex 5 crystallized in the monoclinic system, P2(1)/n, with a = 14.019(2) Å, b = 11.171(2) Å, c = 19.447(3) Å, beta = 109.18(1) degrees, V = 2876.5(8) Å(3), Z = 4, and R (wR2) = 0.062 (0.157). Complex 6 crystallized in the monoclinic system, P2(1)/n, with a = 15.0023(8) Å, b = 8.1368(1) Å, c = 26.5598(2) Å, beta = 95.744(1) degrees, V = 3225.89(8) Å(3), Z = 8, and R (wR2) = 0.060 (0.154). Complex 1 is a discrete, centrosymmetric dimer in which two vanadium atoms are bridged by two methoxide ligands. Compound 2 contains a V(4)O(4) eight-membered ring with both &mgr;-oxo and &mgr;-alkoxo bridging ligands; the ring is capped above and below by two triply bridging methoxo ligands. Compound 3 has the same structure as 2. The three vanadium atoms in complex 5 are linked by four bridging oxygen atoms from two tridentate thme(3)(-) ligands to form a V(3)O(4) chain in which V-O bonds alternate in length. The V-O(isopropoxo) bond in 6 is cis to V=O, and the V-O(acac) bond trans to the oxo group is relatively long. The V(2)O(2) rings of complex 1 and the mononuclear 1:2 complex can be considered to be the basic building block of the trinuclear complexes 4 and 5 and the tetranuclear complex 2, acting to extend the vanadium-oxide framework. (51)V and (1)H NMR spectroscopic studies of the solution state of complexes 1-6 revealed dramatic differences in structural and hydrolytic stability of these complexes. Compounds 1 and 3 only remained intact at low temperature in CDCl(3) solution, whereas the mononuclear compound 6 could remain at ambient temperature for approximately 10 h. Compound 4 only maintained its solid-state structure at low temperature in CDCl(3) solution, whereas compound 5 was significantly more stable. The structural integrity of oligomeric vanadium-oxygen frameworks increased significantly when the coordinating alkoxide group showed more resistance to exchange reactions than the methoxide group. The solid state and solution properties of this new group of complexes not only testify to the versatility of VO(2)(acac) as a vanadium(V) precursor but also raise questions relating to solution structure and properties of related vanadium complexes with insulin-mimetic properties and catalytic properties.

Effect of sunflower oil supplementation and milking frequency reduction on sheep milk production and composition. The aim of this study was to investigate the effects of milking frequency reduction and dietary lipid supplementation on intake, BW, and milk yield and composition in high yielding dairy ewes. Ten lactating Assaf ewes were allocated into 2 experimental groups (n=5). Ewes were fed alfalfa hay ad libitum and 34 g·kg(-1) of BW of a concentrate feed with either 0 (Control group) or 43 g of sunflower oil·kg(-1) of DM (SO group). The experiment lasted 63 d and consisted of 3 periods. During Period 1 (from d 1 to 21), ewes were milked twice a day. During Period 2 (from d 22 to 49), ewes were unilaterally milked, so that each gland of each ewe was milked either once or twice daily. During Period 3 (from d 50 to the end of the experiment), both udder halves were again milked twice daily. Intake, BW, and milk composition were controlled weekly and milk production from each half udder was recorded twice a week. Total DM intake, BW, and milk yield in Period 1 were not significantly (P>0.10) affected by dietary treatments. Milk yield tended to be increased in the ewes fed the SO diet in periods 2 (P=0.093) and 3 (P=0.067). Oil supplementation (SO diet) significantly (P<0.05) decreased milk protein and total solids concentrations in the 3 experimental periods and fat content in Period 3, and tended (P=0.077) to decline fat content in Period 2. Lactose content and somatic cell count (SCC) were unaffected (P>0.10) by dietary lipid supplementation in any of the experimental periods. There were no significant (P>0.10) differences between half udders in milk yield and composition in Period 1, and in SCC in any of the experimental periods. Fat and total solids contents were unaffected (P>0.10) by reducing milking frequency. Nevertheless, milk protein content was increased (P<0.001) when glands were milked only once daily whereas milk yield and lactose content were decreased (P=0.001). The interaction between gland and diet was significant for lactose in Period 2, suggesting a greater effect of milking frequency reduction on tight junctions in Control ewes. In fact, the ratio between glands for milk yield was significantly (P<0.05) greater in SO (0.82) than in Control (0.72) ewes. In Period 3, this ratio increased but it was still lower in Control ewes (0.92 vs. 0.78, P<0.05). Thus, milking frequency reduction and SO supplementation seem to have counteracting effects on milk production and composition. Our results suggest that SO-supplemented ewes have a better capacity of adaptation to changes in milking frequency, probably due to processes induced in the mammary gland.

Role of Doppler ultrasound in predicting perinatal outcome in pregnancies complicated by late-onset fetal growth restriction at the time of diagnosis: a prospective cohort study. Pregnancies complicated by late-onset fetal growth restriction (FGR) are at increased risk of short- and long-term morbidities. Despite this, identification of cases at higher risk of adverse perinatal outcome when FGR is diagnosed is challenging. The aims of this study were to elucidate the strength of association and predictive accuracy of maternal and fetal Dopplers in predicting perinatal outcome of fetuses affected by late-onset FGR at the time of diagnosis. Prospective study of consecutive singleton pregnancies complicated by late-onset FGR. Estimated fetal weight (EFW), pulsatility index (PI) in the uterine, umbilical (UA), and middle cerebral (MCA) arteries, cerebro-placental ratio (CPR) and umbilical vein flow (normalized for fetal abdominal circumference) (UVBF/AC) were recorded at the time of the diagnosis of FGR. Composite adverse outcome was defined as the occurrence of either emergency caesarean section (CS) for fetal distress, 5' Apgar score < 7, umbilical artery pH < 7.10 and neonatal admission to special care unit. Logistic regression and area under the curve (AUC) analyses were used to elucidate the strength of association and diagnostic accuracy of different ultrasound parameters for the prediction of composite adverse outcome. 243 consecutive singleton pregnancies complicated by late-onset FGR were included in the study. Composite adverse perinatal outcome occurred 32.5% (95% CI 26.7-38.8) of cases. The z values of mean uterine artery PI (2.23±1.34 vs. 1.988±0.89, p= 0.02) were higher, while the z-values of UVBF/AC (-1.93±0.88 vs. 0.89±0.94 p≤0.0001), MCA PI (-1.56±0.93 vs. -1.22±0.84, p=0.004) and CPR (-1.89±1.12 vs. -1.44±1.02, p=0.002) were lower in pregnancies who experienced compared to those who did not experience composite adverse outcome. On multivariable logistic regression analysis, mean uterine artery PI (p= 0.04), CPR (p= 0.02) and UVBF/AC (p= 0.001) were independently associated with composite adverse perinatal outcome. UVBF/AC had an AUC of 0.723 (95% CI 0.64-0.80) for composite adverse outcome and with a better accuracy compared to mean uterine artery (AUC: 0.593), CPR (AUC: 0.615). A multiparametric prediction model including MCA, Uterine arteries and UVBF had an AUC of 0.745 (95% CI 0.66-0.83) for the prediction of composite adverse outcome. CPR and uterine artery Dopplers are independently associated with composite adverse perinatal outcome in pregnancies complicated by late-onset FGR at the time of diagnosis. Despite this, their diagnostic performance for adverse perinatal outcome is low. UVBF/AC showed a better accuracy for composite adverse outcome, although its usefulness in clinical practice as standalone test for adverse pregnancy outcome requires further evidence. This article is protected by copyright. All rights reserved.

Local infiltration analgesia or femoral nerve block for postoperative pain management in patients undergoing total hip arthroplasty. A randomized, double-blind study. Several methods for pain management following total hip arthroplasty (THA) have been described but the best postoperative pain management technique remains uncertain. We compared surgeon applied local infiltration analgesia (LIA) with anaesthesiologist performed femoral nerve block (FNB) using ultrasound. The primary aim was to assess pain intensity 24h after THA. In this randomized, double-blind study, 56 patients (ASA I-III) undergoing THA consented to participate. In Group FNB, patients received an ultrasound-guided femoral nerve block using 30ml of ropivacaine 7.5mg/ml (225mg) while Group LIA received a similar volume of saline. Spinal anaesthesia was then performed and bupivacaine heavy, 3-3.5ml injected depending on patient characteristics. During surgery, patients in Group LIA received a mixture of 300mg (150ml) ropivacaine, ketorolac 30mg (1ml) and adrenaline 0.5mg (0.5ml) (total volume 151.5ml) peri-articularly and subcutaneously while Group FNB received 151.5ml of saline peri-articularly in a systematic way by the surgeon. A multi-hole catheter was placed with the tip placed intra-articularly at the end of surgery in both groups. After 23h, the LIA mixture consisting of 20ml ropivacaine (7.5mg/ml), ketorolac 30mg (1ml), adrenaline 0.1mg (1ml) (total volume 22ml) was injected in Group LIA and the same volume of saline in Group FNB. Postoperative pain, analgesic consumption (postoperative and post-discharge), side effects, home discharge, quality of life and hip function were recorded, the latter up to 6 months after surgery. Postoperative pain intensity was significantly lower in Group LIA compared to Group FNB during mobilization at 24h (primary endpoint), mean difference 1.8 NRS units (95% CI 0.7-2.9) (P=0.006), at rest after 4h (P=0.029) and on standing after 24 (P=0.0003) and 48h (P=0.043). Rescue morphine consumption was also significantly lower in Group LIA during 0-24, mean difference 13.5mg (95% CI, 6.1-20.9) (P=0.002) postoperatively. Motor block was greater at 6h (P=0.029) postoperatively in Group FNB. Two patients (one in each group) had persistent post-surgical pain (NRS>3) at 3 months (3.6%) but none at 6 month. No other differences were found between the groups. Local infiltration analgesia significantly reduces pain intensity on standing and mobilization, and rescue analgesic consumption compared to femoral nerve block without causing significant side effects. The superior analgesia in the LIA group may result from the secondary injection at 23h postoperatively and needs to be further evaluated in future studies. No differences were found in home discharge, quality of life and hip dysfunction between the groups. Local infiltration analgesia is the preferred method for postoperative pain management following THA compared to single-shot femoral nerve block.

Curriculum change in dental education, 2003-09. This 2009 study of dental school curricula follows a similar one conducted in 2002-03. Through a web-based survey, the authors gathered information from dental schools about 1) past trends in curricular change over seven years; 2) current changes under way in dental school curricula; 3) significant challenges to curricular innovation; and 4) projected future trends in curricular change and innovation. Fifty-five schools (fifty U.S. and five Canadian) responded to the survey for a response rate of 86 percent. In addition to background information, the survey requested information in four broad areas: curriculum format, curriculum assessment, curriculum innovation, and resources needed for curriculum enhancement. Forty-nine percent of the respondents defined their curriculum format as primarily organized by disciplines. Half of the respondents reported the use of problem-based and case-reinforced learning for a section or specific component of some courses. In a significant change from the 2002-03 study, a high proportion (91 percent) of the responding schools require community-based patient care by all students, with just over half requiring five or more weeks of such experience. Competency-based education to prepare an entry-level general dentist seems well established as the norm in responding dental schools. Forty-three percent or less of the responding schools indicated that their students participate with other health professions education programs for various portions of their educational experience. Since the 2002-03 survey, dental schools have been active in conducting comprehensive curriculum reviews; 65 percent indicated that their most recent comprehensive curriculum review is currently under way or was conducted within the past two years. Respondents indicated that the primary reasons for the configuration of the current curriculum were "perceived success" (it works), "compatibility with faculty preferences," "faculty comfort," and "capacity/feasibility." Key catalysts for curricular change were "findings of a curriculum review we conducted ourselves," students' feedback about curriculum, and administration and faculty dissatisfaction. There was an increase in the percentage of schools with interdisciplinary courses, especially in the basic sciences since 2002-03, but no change in the use of problem-based and case-reinforced learning in dental curricula. Respondents reported that priorities for future curriculum modification included creating interdisciplinary curricula that are organized around themes, blending the basic and clinical sciences, provision of some elements of core curricula in an online format, developing new techniques for assessing competency, and increasing collaborations with other health professions schools. Respondents identified training for new faculty members in teaching skills, curriculum design, and assessment methods as the most critical need to support future innovation.

Synapse formation in developing neural circuits. The nervous system consists of hundreds of billions of neurons interconnected into the functional neural networks that underlie behaviors. The capacity of a neuron to innervate and function within a network is mediated via specialized cell junctions known as synapses. Synapses are macromolecular structures that regulate intercellular communication in the nervous system, and are the main gatekeepers of information flow within neural networks. Where and when synapses form determines the connectivity and functionality of neural networks. Therefore, our knowledge of how synapse formation is regulated is critical to our understanding of the nervous system and how it goes awry in neurological disorders. Synapse formation involves pairing of the pre- and postsynaptic partners at a specific neurospatial coordinate. The specificity of synapse formation requires the precise execution of multiple developmental events, including cell fate specification, cell migration, axon guidance, dendritic growth, synaptic target selection, and synaptogenesis (Juttner and Rathjen in Cell. Mol. Life Sci. 62:2811, 2005; Salie et al., in Neuron 45:189, 2005; Waites et al., in Annu. Rev. Neurosci. 28:251, 2005). Remarkably, during the development of the vertebrate nervous system, these developmental processes occur almost simultaneously in billions of neurons, resulting in the formation of trillions of synapses. How this remarkable specificity is orchestrated during development is one of the outstanding questions in the field of neurobiology, and the focus of discussion of this chapter. We center the discussion of this chapter on the early developmental events that orchestrate the process of synaptogenesis prior to activity-dependent mechanisms. We have therefore limited the discussion of important activity-dependent synaptogenic events, which are discussed in other chapters of this book. Moreover, our discussion is biased toward lessons we have learned from invertebrate systems, in particular from C. elegans and Drosophila. We did so to complement the discussions from other chapters in this book, which focus on the important findings that have recently emerged from the vertebrate literature. The chapter begins with a brief history of the field of synaptic biology. This serves as a backdrop to introduce some of the historically outstanding questions of synaptic development that have eluded us during the past century, and which are the focus of this review. We then discuss some general features of synaptic structure as it relates to its function. In particular, we will highlight evolutionarily conserved traits shared by all synaptic structures, and how these features have helped optimize these ancient cellular junctions for interneural communication. We then discuss the regulatory signals that orchestrate the precise assembly of these conserved macromolecular structures. This discussion will be framed in the context of the neurodevelopmental process. Specifically, much of our discussion will focus on how the seemingly disparate developmental processes are intimately linked at a molecular level, and how this relationship might be crucial in the developmental orchestration of circuit assembly. We hope that the discussion of the multifunctional cues that direct circuit development provides a conceptual framework into understanding how, with a limited set of signaling molecules, precise neural wiring can be coordinated between synaptic partners.

Prostaglandins mediate the effects of 1,25-(OH)2D3 and 24,25-(OH)2D3 on growth plate chondrocytes in a metabolite-specific and cell maturation-dependent manner. Prior studies have shown that 1,25-(OH)2D3 stimulates alkaline phosphatase, phospholipase A2 (PLA2), and protein kinase C (PKC)-specific activities, and production of prostaglandin E2 (PGE2) in growth zone chondrocytes. In contrast, 24,25-(OH)2D3 stimulates alkaline phosphatase and PKC-specific activities but inhibits PLA2-specific activity and PGE2 production in resting zone cells. This indicates that different mechanisms are involved in the action of 1,25-(OH)2D3 and 24,25-(OH)2D3 on their respective target cells. In this study, we examined the hypothesis that differential regulation of prostaglandin production modulates the activity of PKC and alkaline phosphatase. To do this, we examined the effect of the cyclooxygenase inhibitor indomethacin (Indo) on alkaline phosphatase, PLA2, and PKC-specific activities in growth plate chondrocytes treated with these two vitamin D metabolites. In addition, we examined whether inhibition of PKC altered PGE2 production. In growth zone cells, Indo inhibited basal alkaline phosphatase and blocked the 1,25-(OH)2D3-dependent increase in alkaline phosphatase. This effect was due to inhibition of both plasma membrane and matrix vesicle alkaline phosphatase. In resting zone cells, Indo increased basal alkaline phosphatase activity in a dose-dependent manner, but it did not further enhance the 24,25-(OH)2D3-dependent stimulation of this enzyme. The effect of Indo was found in both plasma membranes and matrix vesicles. These data indicate that 1,25-(OH)2D3-dependent increases in alkaline phosphatase-specific activity in growth zone cells are mediated through increased prostaglandin production, whereas 24,25-(OH)2D3-mediated changes in enzyme activity in resting zone cells are mediated through decreased prostaglandin production. Regulation of PLA2 by either 1,25-(OH)2D3 or 24,25-(OH)2D3 in their target cells was unaffected by Indo, indicating that the effect of the vitamin D metabolites on this enzyme is not dependent on changes in PGE2 production. The rapid increase in 1,25-(OH)2D3-dependent PKC-specific activity in growth zone cells was inhibited by Indo, whereas there was a potentiation of the effect of 24,25-(OH)2D3 on PKC activity in resting zone cells. In addition, inhibition of PKC blocked the 1,25-(OH)2D3-dependent increase in PGE2 production in growth zone cells and the 24,25-(OH)2D3-dependent decrease in PGE2 production by resting zone cells. These data indicate that prostaglandins are involved in mediating the rapid effects of 1,25-(OH)2D3 on growth zone cells, and contribute to the effects of 24,25-(OH)2D3 on resting zone cells; in both instances, the vitamin D metabolites exert their effects on PKC through changes in arachidonic acid via the action of PLA2. In addition, PKC by itself may mediate the production of PGE2.

Saquinavir. Clinical pharmacology and efficacy. Saquinavir is an HIV protease inhibitor with no, or limited, effect on the activity of other structurally related human aspartic proteinases. As with other HIV protease inhibitors, saquinavir inhibits the cleavage of the gag-pol protein substrate leading to the release of structurally defective and functionally inactive viral particles. It is active on both HIV-1 and HIV-2, and also has activity on chronically infected cells and HIV strains resistant to reverse transcriptase inhibitors. Synergy of action has been observed with other antiretroviral drugs. Saquinavir is characterised by a low bioavailability which is further reduced in the fasting state. Metabolism is mainly hepatic through cytochrome P450 (CYP) 3A4, but intestinal metabolism through the same system has also been reported. To achieve higher drug plasma concentrations and increase the antiviral effect, a new formulation of saquinavir with a higher bioavailability has recently been introduced. Higher plasma drug concentrations may also be obtained by combining the drug with CYP blockers, such as ritonavir or ketoconazole. Because of its metabolic interference with the CYP system, saquinavir cannot be coadministered with astemizole, terfenadine or cisapride. Rifampicin (rifampin) is also contraindicated because coadministration can lead to decreases in saquinavir concentrations. Interactions have also been reported with other drugs metabolised through the same system, including non-nucleoside reverse transcriptase inhibitors and HIV protease inhibitors. Resistance has been observed after both in vitro and in vivo drug exposure, with a relatively specific mutation profile compared with other protease inhibitors. Saquinavir is generally well tolerated, with mild gastrointestinal symptoms representing the most commonly observed adverse effects. Although characterized by low bioavailability, in phase III trials saquinavir has been shown to have clinical efficacy in terms of survival and progression rate. As with the other protease inhibitors, saquinavir should be used in combination with other antiretroviral drugs. Current therapeutic guidelines, however, recommend the selection of an initial treatment regimen with other protease inhibitors with higher in vivo activity in terms of RNA and CD4 response. The results of ongoing studies will clarify to what extent a new saquinavir formulation, recently introduced, is superior to the previous one in terms of antiviral activity and to provide comparisons with other protease inhibitors. Further studies are also needed to define the best place of saquinavir within treatment strategies based on protease inhibitors, particularly in respect to the optimal sequence for its use with other protease inhibitors, and the dynamics of cross-resistance and its role within regimens based on the combination of protease inhibitors.

Alterations in gene expression after induction of profound hypothermia for the treatment of lethal hemorrhage. We have previously demonstrated that induction of profound hypothermia improves long-term survival in animal models of complex injuries/lethal hemorrhage. However, the precise mechanisms have not been well defined. The aim of this high-throughput study was to investigate the impact of profound hypothermia on gene expression profiles. Wistar-Kyoto rats underwent 40% blood volume arterial hemorrhage over 10 minutes and were randomized into two groups based on core body temperatures (n = 7 per group): hypothermia (H, 15 degrees C) and normothermia (N, 37 degrees C). Hypothermia was induced by infusing cold isotonic solution using a cardiopulmonary bypass (CPB) setup. After reaching target body temperature, low-flow state (CPB flow rate of 20 mL x kg x min) was maintained for 60 minutes. Hypothermic rats were rewarmed to baseline temperature, and all rats were resuscitated on CPB and monitored for 3 hours. The N group underwent identical CPB management. Sham rats (no hemorrhage and no instrumentation) were used as controls. Blood samples were collected serially, and hepatic tissues were harvested after 3 hours. Affymatrix Rat Gene 1.0 ST Array (27,342 genes, >700,000 probes) was used to determine gene expression profiles (n = 3 per group), which were further analyzed using GeneSpring (Agilent Technologies, Santa Clara, CA) and GenePattern (Broad Institute, Cambridge, MA) programs. Data were further queried using network analysis tools including Gene Ontology, and Ingenuity Pathway Analysis (Ingenuity Systems). Key findings were verified using real-time polymerase chain reaction and Western blots. Induction of hypothermia significantly (p < 0.05) decreased the magnitude of lactic acidosis and increased the survival rates (100% vs. 0% in normothermia group). Five hundred seventy-one of 23,000 genes had altered expression in response to the induction of hypothermia: 382 were up-regulated and 187 were down-regulated. Twelve key pathways were specifically modulated by hypothermia. Interleukin-6, interleukin-10, p38 mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells, glucocorticoids, and other signaling pathways involved with acute phase reactants were up-regulated. Multiple metabolic pathways were down- regulated. The largest change was in the peroxisome proliferator-activated receptor gamma gene that codes for a transcriptional coactivator, which in turn controls mitochondrial biogenesis, glycerolipid, and other metabolic pathways in the liver. Apoptotic cell death cascades were activated in response to blood loss (H and N groups), but multiple specific anti-apoptotic genes (baculoviral Inhibitor of apoptosis protein repeat-containing 3, BCL3L1, NFKB2) displayed an increased expression specifically in the hypothermia treated animals, suggesting an overall pro-survival phenotype. Profound hypothermia increases survival in a rodent model of hemorrhagic shock. In addition to decreasing tissue oxygen consumption, induction of hypothermia directly alters the expression profiles of key genes, with an overall up-regulation of pro-survival pathways and a down- regulation of metabolic pathways.

Effect of chromium propionate on growth, carcass traits, pork quality, and plasma metabolites in growing-finishing pigs. Two experiments were conducted to determine the effects of dietary Cr, as Cr propionate, on growth, carcass traits, pork quality, and plasma metabolites in growing-finishing swine. Ninety-six crossbred gilts (Exp. 1; initial and final BW of 28 [SEM = 0.41] and 109 [SEM = 2.11] kg) or 144 PIC Cambrough 22 barrows (Exp. 2; initial and final BW of 26 [SEM = 0.39] and 111 [SEM = 2.52] kg) were allotted to six or four dietary treatments, respectively, with six replications and four (Exp. 1) or six (Exp. 2) pigs in each replicate pen blocked by weight in randomized complete block designs. The six dietary treatments for Exp. 1 were 1) corn-soybean meal (C-SBM), 2) C-SBM + 50 ppb Cr, 3) C-SBM + 100 ppb Cr, 4) C-SBM + 200 ppb Cr, 5) C-SBM low NE diet, and 6) C-SBM low NE diet + 200 ppb Cr. The four dietary treatments for Exp. 2 were C-SBM with 0, 100, 200, or 300 ppb Cr. Growth, carcass traits, and plasma metabolite (collected on d 29 and at each phase change) data were taken at the end of both experiments and pork quality data were taken at the end of Exp. 1. There was no effect (P > 0.10) on overall growth performance when pigs were fed graded levels of Cr (Exp. 1 and 2) or Cr in the positive control or low NE diets (Exp. 1). Longissimus muscle area, ham weight, ham fat-free lean, and total carcass lean were increased in pigs fed 200 ppb in the positive control diets but decreased in pigs fed 200 ppb Cr in the low NE diets (Cr x NE, P < 0.08). There was no effect of Cr concentration (P > 0.10) on carcass traits in Exp. 2. In Exp. 1, cook loss of a fresh or a frozen chop was decreased (P < 0.10) by 200 ppb Cr. In Exp. 1, NEFA concentration was decreased (P < 0.05) in pigs fed Cr in the positive control or low NE diets during the early-finishing period. In Exp. 2, the addition of Cr decreased NEFA (quadratic, P < 0.09) and plasma urea N (linear, P < 0.02) concentrations and tended to increase total cholesterol and high density lipoproteins (quadratic, P < 0.09). In these experiments, Cr propionate had no effect on overall growth performance, variable effects on carcass traits and plasma metabolites, and some positive effects on pork quality, especially water holding capacity of a fresh or frozen chop.

Alkyne Origami: Folding Oligoalkynes into Polyaromatics. Do not bend the triple bonds! This familiar undergraduate mantra must be disobeyed if the alkyne group is used as a building block in molecular construction. This Account will describe our exploits in "alkyne origami", that is, folding oligoalkynes into new shapes via cyclization cascades. This research stems from a set of guidelines for the cyclizations of alkynes that we suggested in 2011 ( Gilmore Chem. Rev. 2011 , 111 , 6513 ; Alabugin J. Am. Chem. Soc. 2011 , 133 , 12608 ). The guidelines blended critical analysis of ∼40 years of experimental research with computations into the comprehensive predictions of the relative favorability of dig-cyclizations of anions and radicals. In this Account, we will show how this new understanding has been instrumental in building polyaromatics. In particular, we illustrate the utility of these stereoelectronic models by developing a toolbox of practical, selective, and efficient synthetic transformations. The high energy and high carbon content render alkynes the perfect precursors for the preparation of polyaromatic ribbons and other carbon-rich materials with precisely controlled structure and reactivity. Still, the paradox of alkyne reactivity (alkynes store a lot of energy but are protected kinetically by their relatively strong π-bonds) requires precise use of stereoelectronic factors for lowering the activation barriers for alkyne cyclizations. These factors are drastically different in the "all-exo" and the "all-endo" cyclization cascades of oligoynes. This Account will highlight the interplay between the stereoelectronics of bond formation and topology of acyclic precursor "folding" into a polycyclic ribbon. The topology of folding is simpler for the endo cascades, which are compatible with initiation either at the edge or at the center. In contrast, the exo cascades require precise folding of an oligoalkyne ribbon by starting the cascade exactly at the center of the chain. These differences define the key challenges in the design of these two types of alkyne cyclization cascades. For the endo processes, the folding is simple, but these processes require a strategy ("LUMO Umpolung") for inverting the usual stereoelectronic requirements of alkyne cyclizations. We also show how alkenes can be used as alkyne equivalents in cyclizations coupled with fragmentations and how one can make endo cyclization products without ever going through an endo cyclization. In contrast, each elementary step of the exo cascades benefits from the inherent exo preference for the radical attack, but these cascades require precise initiation by starting exactly at the central alkyne unit of the oligoyne. This strict selectivity requirement led to the development of traceless directing groups capable of supramolecular assistance to the initiation step and self-terminating departure at the end of the cascade. With attention to electronic effects that can stop radical cascades, oligoalkynes can be selectively converted into precisely shaped and functionalized polyaromatic products. The generality of these concepts is further illustrated by the development of radical "peri annulations" at the zigzag edge of acenes.

The role of radiotherapy in the carotid stenosis. Cervical radiation for head and neck cancer has been associated with an increased incidence of carotid arterial stenosis. Modern radiation therapy delivers higher doses with increasing long-term survival. In our study 50 patients with head and neck malignancies treated with radiotherapy are analized with colour Doppler ultrasonographic scanning of the carotid arteries. These patients were compared with a population of asymptomatic historical controls (40) These findings suggest that radiation has an adverse effect on large vessels. Colour Doppler follow-up may be indicated for patients receiving head and neck radiation therapy. 50-70 Gy is the local dose that all patients received. during a period of about 8 weeks. The ecodoppler scan of carotid arteries was performed in all patients with estimation of Common and internal carotid artery's intimal medial thickness (IMT). Stenosis grade were divided into low (0-30%), moderate (31-49 %) and severe (= >50%). In add we considered ematochimics and flogosys parameters. Patients recruited from a hospital Radiation-oncology-surgery department from April 2007 to September 2011, 90 consecutive head and neck cancer patients were enrolled in this study. 50 of these patients had previously undergone RT (RT group) and 40 had no RT (control group). All patients were screened with bilateral carotid arterial duplex ultrasonography. We defined disease as "normal or mild" if the carotid stenosis was <50%, and "significant" if >50%. The relationship between standard demographic risk factors and screening outcomes was then analyzed. We found that severe carotid stenosis (= >50% ) was higher (41%) in patients who underwent to radiotherapy than in control group. The Eco Doppler examination demonstrated that the most affected site was Internal Carotid Arthery 's fork . There were no differences in age or gender between the two groups. The RT group had a significantly higher plaque score than the non-irradiated group. Bilateral plaque score was significantly correlated with age, hyperlipidemia, and RT. This analysis showed that in RT patients > 50 years old, age was inversely correlated with plaque score; however, in RT patients <or= 41 years old, age was positively correlated with plaque score. Literature evidences about this subject are few and similar to ours. Moritz et all found a severe carotid stenosis in 30% of irradiated and 5.6% in the control group. Lam found carotid stenosis in 78.9% of irradiated and 21.6% in the other group. We can conclude that radiotherapy is able to induce atherosclerotic lesions only in sites included in radiation field. Should be important to perform pre and post radiotherapy Carotid Arthery Ecodoppler of patients who are going to undergo cervical radiotherapy The prevalence of carotid arterial disease in patients with prior cervical radiation therapy is clinically significant and warrants aggressive screening as part of routine preradiation and postradiation care. Focused screening of this high-risk population may be cost effective and medically beneficial in terms of risk factor modification and stroke prevention Carotid stenosis, Cervical radiotherapy, Stroke prevention.

Primary somatosensory cortex in rats with pain-related behaviours due to a peripheral mononeuropathy after moderate ligation of one sciatic nerve: neuronal responsivity to somatic stimulation. Single-unit recordings were made under moderate gaseous anaesthesia in the hindpaw representation area of the two primary somatosensory motor cortices (SmI) of rats (n = 58) rendered mononeuropathic by four loose ligatures placed around one common sciatic nerve 2-3 weeks beforehand. The rats exhibited clear hyperalgesia and allodynia from the paw with the ligated sciatic nerve, to both mechanical and thermal stimuli. From the tested neuronal population (n = 640), about the same proportion could be activated by somatic stimuli in each cortex: 165/362 (45%) in the cortex contralateral to the ligated sciatic nerve (Cc), 105/278 (37%) in the cortex ipsilateral to the ligated sciatic nerve (Ci). Neurones driven by light touch, exhibited RFs strictly contralateral to the recording sites. Their proportion and response characteristics were similar regardless of recording side. However, the number of neurones with RFs in the sciatic nerve territory was above 95% in the Ci, and was dramatically reduced to 43% in the Cc. By contrast, the number of neurones with RFs supplied by the saphenous nerve reached 57% on this side. Although the RF size of all the neurones appeared roughly normal, there were fewer Cc than Ci neurones with RFs located on the paw itself and with RFs of extremely small size in the sciatic nerve territory. The proportion of neurones responding to a joint stimulus was significantly higher in the Cc than in the Ci. The neuronal responses to joint stimuli of the paw with the ligated sciatic nerve were significantly more sustained than those recorded in the Ci and elicited from the normal paw. The proportion of neurones driven by mechanical stimulation which gave rise to nociceptive reactions in freely moving animals, i.e. "nociceptive" neurones, was comparable in each cortex. However, half of the Cc neurones exhibited paroxysmal discharges occurring without intentional stimulation and of long duration (1 min to several minutes). Only 66% of Cc but 93% of Ci "nociceptive" neurones were exclusively activated by pinch. The remaining Cc neurones were also activated by applying moderate pressure to the paw with the ligated nerve. Pinch responses from the paw with the ligated nerve were often more intense and of longer duration than responses elicited from the intact paw. The "nociceptive" Cc neurones were especially sensitive to thermal stimuli of 39-44 degrees C when the stimuli were applied to the paw with the ligated nerve. They also responded vigorously to a 10 degrees C stimulus applied to this paw.(ABSTRACT TRUNCATED AT 400 WORDS)

Micromanipulation and cloning studies on buffalo oocytes and embryos using nucleus transfer. An investigation for testing the viability of production of cloned buffalo embryos through nucleus transfer has been made. Matured buffalo oocytes, after zona cutting to an extent of 60 degrees near polar body, were enucleated using a new approach. Instead of aspirating the cytoplasm contents in a pipette, the half of cytoplasm of oocyte was pushed out, thereby also taking away the nuclear material of the oocyte, leaving the demi-oocyte with the zona pellucida enucleated. The absence of fluorescence confirmed the success of the enucleating process. For enucleating, the oocytes which had intact plasma membrane were eligible for bisectioning. There was no significant difference in oocytes having intact membrane among grade I (33.9%) and grade II (31.4%) oocytes, whereas lower percentage of grade III oocytes had a very low percentage having intact plasma membranes (8.5%). The hours of maturation for 32, 37 and 42 did not influence the per cent oocytes which had intact membranes. All the bisected or demi-oocytes tested with fluorescence screening yielded successful enucleation in 88.2% demi-oocytes. The temporal effect of three maturation hours of 32, 37, and 42 hr; two electrical pulse numbers of 2 and 3 pulses and two magnitudes of electric pulses of 15 and 20 V were studied for their effect on the percentage of successful fusion of demi-oocyte blastomere complexes and the rate of complexes undergoing cleavages. The time period for which the oocytes were subjected to the process of maturation significantly affected the per cent fusions and per cent cleavage of the demi-oocyte blastomere complexes and 32 hr maturation yielded less fusions (38.5%) compared to maturation for 37 and 42 h (53.2 and 57.8%, respectively). The treatment of either 2 or 3 electrical pulse numbers resulted in significantly different fusion (45.6 and 54.1%) as well as cleavage rates (18.2 and 26.1%) of demi-oocyte-blastomere complexes electrofused. The treatment of two levels of magnitude of 15 and 20 V of an electric current resulted in similar per cent fusion (48.0 and 51.6%) and cleavage rates (21.0 and 23.2%). Fortified TCM with either 10 or 20% FBS for culturing freshly electrofused complexes for 1 hr did not differ significantly with respect to per cent complexes fused and cleaved, giving a fusion rate of 46.2 and 53.8% and cleavage rate of 21.2 and 23.2% for 10% and 20% FBS, respectively. Production of cloned embryos through the process of nuclear transfer has been accomplished. The successful cleavages of the nuclear transferred oocytes demonstrated the viability of enucleation procedures of the oocytes and technology implementation of electrofusion in buffalo oocytes.

Patterns of drug treatment for manic episode in the clinical practice. Outcomes of the Spanish sample in the EMBLEM Study. Although treatment for mania has been studied extensively in randomized clinical trials, there are few data that address how these patients are truly managed in clinical, functional, and economic terms in the psychiatric practice in Spain. To determine prescribing patterns in Spain on the basis of the Spanish sample of bipolar patients in manic or mixed phase included as part of the pan-European EMBLEM Study. The EMBLEM Study recruited 3,681 patients, 312 of whom (8.47%) were included in Spain. Patients had to be adults with a diagnosis of bipolar disorder who were initiating treatment for a manic phase. They underwent evaluation using the Spanish versions of scales that measure severity of mania (the Young Mania Rating Scale, CGI-BP and the Hamilton Scale) and functional level (LCM, SLICE of LIFE). Information was collected regarding drug and treatment adherence variables. Prior to being admitted into the study, 42% of the patients were receiving polytherapy, 35% were on monotherapy, and 23% were not taking any medication whatsoever. Forty percent of the patients presented partial or total non-compliance with the treatment prescribed. During the first stage of the study, in the case of single-drug treatment, acute management for mania consisted of mean daily doses of 25 mg of olanzapine, 6.6 mg of risperidone, 9.5 mg of haloperidol, 165 mg of lamotrigine, 938.5 mg of valproate, and 909 mg of lithium, whereas when combined therapy was used, the following doses were used: olanzapine, 22.1 mg; risperidone, 7.3 mg; haloperidol, 12.3 mg; lamotrigine, 1,75.1 mg; valproate, 1,038.4 mg, and lithium, 1012.6 mg. Of those patients who were on monotherapy at the beginning of the study 51% were treated with a single drug, whereas 48% were receiving polytherapy. Among the participants who were receiving combined treatment when they began the study, almost all of them, 94%, were prescribed combined treatment. In the case of the hospitalized patients who made up 88% of the sample, the vast majority, 92%, had improved by the time the study was completed. Mean time to release from hospital was 24 days. In Spain, treatment for mania is essentially based on combined treatments, hospitalization, and antimania drugs that are prescribed at somewhat higher doses than those recommended in the corresponding prescribing information documents, which indicates that the clinical reality of this entity is far more complex than clinical trials conducted in experimental conditions suggest.

Pathophysiological Abnormalities in Functional Dyspepsia Subgroups According to the Rome III Criteria. The Rome III criteria proposed to subdivide functional dyspepsia (FD) into a postprandial distress syndrome (PDS) group, characterized by the presence of postprandial fullness and/or early satiety, and an epigastric pain syndrome (EPS) group, characterized by the presence of epigastric pain and/or epigastric burning. It has been suggested that different pathophysiological mechanisms underlie the symptom presentations in these subgroups that might determine treatment choices. The aim of this study was to investigate the prevalence of gastric sensorimotor dysfunction in the PDS, EPS, and overlap groups and to evaluate potential differential associations with dyspeptic symptom scores. Consecutive FD patients fulfilling Rome III criteria were recruited and they scored frequency of dyspeptic symptoms (postprandial fullness, early satiety, nausea, bloating, epigastric pain, and epigastric burning) over the past 3 months (0-5; 1=once a month or less, 2=two or three times a month, 3=once a week, 4=several times a week, 5=every day). The cumulative symptom score was calculated by adding up the score of these dyspeptic symptoms. Based on these symptom scores, the patients were subdivided into subgroups according to the Rome III consensus: (i) PDS, characterized by postprandial fullness and/or early satiety at least several times a week, (ii) EPS, characterized by epigastric pain and/or epigastric burning at least once a week, and (iii) overlap, fulfilling the criteria for both PDS and EPS. Gastric sensitivity and gastric accommodation were measured using barostat testing, and solid gastric emptying was determined using the [14C]octanoate breath test. A total of 560 FD patients (165 men, age 41.8±0.7 years) were classified into PDS (n=131), EPS (n=50), and overlap (n=379) groups. The prevalence of gastric hypersensitivity, impaired gastric accommodation, and delayed gastric emptying were 37%, 37%, and 23%, respectively, without any differential distribution in Rome III subgroups (P=0.16, P=0.27, and P=0.39 respectively). Comparing the physiological parameters for these gastric sensorimotor functions, there was only a significant difference in the gastric half emptying time between subgroups, with the overlap group having a higher t1/2 (P<0.05) compared with the EPS group. In the overlap group, gastric hypersensitivity was associated with the severity of PDS symptoms (P=0.03), EPS symptoms (P=0.02), and the cumulative symptom score (P=0.02), whereas delayed gastric emptying was associated with nausea (P=0.02) and the cumulative symptom score (P=0.02). Except for gastric emptying in the overlap group, FD subgroups as defined by the Rome III criteria are not differentially associated with putative pathophysiological mechanisms. These observations question the utility of this classification for guiding therapeutic choices in clinical practice.

Erythema gyratum repens-like psoriasis. A 28-year-old man was admitted to our department for investigation in 1992. He presented with a red, scaly, centrifugally spreading eruption, which had appeared in 1990, beginning on the neck and thorax, and later extending to the trunk and limbs. The cutaneous lesions, located mainly on the trunk and proximal upper limbs, were arranged in rings, with a slightly raised prominent scaling edge (Fig. 1a). The characteristic feature was the presence of rings or waves within already existing rings, whereas the central part was flattened, with the texture of normal skin. The concentric figurate lesions resembled a wood grain pattern (Fig. 1b). The clinical picture was strikingly similar to tinea imbricata; there was, however, no itching, and repeated mycologic studies did not disclose Trichophyton concentricum. The histology was not characteristic. The epidermis, which was slightly edematous, was covered with a heavy crust. In the dermis, a sparse inflammatory infiltrate, somewhat more pronounced in the subpapillary areas, was composed of lymphocytes with some eosinophils. Periodic acid-Schiff (PAS) and other stains for mycotic infection were negative. The general condition was not affected and laboratory studies did not show any abnormalities, except for low serum protein (5.1 g/L) and decreased gamma globulins (10.5%). Cell-mediated immunity was preserved. Immunofluorescence studies (direct and indirect) were negative. In spite of repeatedly negative mycotic examinations and due to the striking similarity to tinea imbricata, we applied various antimycotic therapies (terbinafine, itraconazole), with no effect. The figurate pattern, with normal skin in between, altered from day to day, while new concentric rings appeared within the cleared skin. The migrating rate was about 2-3 cm per 2 weeks. The patient had undergone a thorough search for internal malignancy. During the follow-up period of 1992-98, cutaneous involvement slowly became almost generalized (1996), and the confluent lesions formed large plaques, but still with pronounced concentric rings. Transitional blood eosinophilia (27% in 1993 and 11% in 1996) regressed with no therapy. Since 1995, antibodies to HBs and HBc have been present with no clinical symptoms of liver disease. The blood proteins increased to 7.0 g/L, and gamma globulins to 17.2% (normal). The histology, studied repeatedly, started to display some signs of psoriasis from 1996 and, in 1998, was already consistent with the disease (Fig. 2). RE-PUVA (0.8 mg/kg acitretin and UVA 0.8 J/cm2 ) was applied for 2 weeks before the patient interrupted the therapy. In spite of this, there was further improvement and, in 1999, the patient was almost free of lesions with some abortive rings left. From time to time, single vesicles appeared within the elevated borders of the rings. The histology of such vesicles was consistent with abortive pustular psoriasis (Fig. 3).

Seasonal variation in the composition and melting behavior of milk fat. Dairy bulk tank milk was sampled during 1yr from 2 conventional (C1 and C2) and 1 organic dairy (O1) for studying the seasonal variation as well as the variation between dairies in the composition and properties of milk fat. The composition of fatty acids (FA) as well as triglycerides (TAG) in milk fat was analyzed, and the melting properties of milk fat were analyzed by use of differential scanning calorimetry. The main differences in fat content and composition of FA in milk fat between dairies included a higher fat content, greater proportion of C18:0, and smaller proportion of C16:0 in milk from dairy C2, which could be associated with a higher frequency of Jersey herds supplying milk to this dairy. The organic milk was characterized by a higher proportion of C18:3n-3, C18:2 cis-9,trans-11, C6 to C14, a lower proportion of C18:1 cis-9, and a higher melting point of the low-melting fraction. The TAG composition showed a greater proportion of C24 to C38 TAG in milk fat from dairy O1 and a greater proportion of C52 to C54 TAG in milk fat from dairy C2, which was in accordance with the differences in FA composition. Melting point of the low-melting fraction was higher for milk fat from dairy O1 compared with dairies C1 and C2, whereas no differences between dairies were observed with respect to melting points of the medium- and high-melting fractions. The seasonal variation in FA composition was most pronounced for dairy O1 although similar patterns were observed for all dairies. During the summer, the content of C18:0 and C18:1 cis-9 in milk fat was greater, whereas the content of C14:0 and C16:0 was lower. In addition, the content of C18:2 cis-9,trans-11 and C18:1 trans-11 increased in late summer for dairy O1. The differential scanning calorimetry thermograms of individual milk fat samples could be divided into 3 groups by principal component analysis. For dairy O1, summer samples belonged to group 1, spring and autumn samples to group 2, and winter samples to group 3. For dairy C1 winter samples (group 2), were separated from other samples (group 1), and for dairy C2 all samples were in group 1. Individual melting points were related to FA composition, and the melting point of the low-melting fraction was positively correlated to the content of C14:0 and C16:0 in milk fat and negatively correlated to the content of C18:1 cis-9 and C18:0.

Assessment of nonlinear heart rate dynamics after beating-heart revascularization. Advanced nonlinear methods of measuring heart rate variability (HRV) derived from the mathematics of complex dynamics and fractal geometry have provided new insights into the abnormalities of heart rate behavior in various pathologic conditions. These methods have provided additional prognostic information compared with traditional HRV measures and clearly have complemented the conventional linear methods. Knowledge about the behavior of complex cardiac dynamics indices after different cardiac procedures is very limited, however. We aimed to clarify how nonlinear heart rate dynamics are affected by beating-heart revascularization (off-pump coronary artery bypass graft [CABG] surgery) within the first week after the procedure. Included in the study were 66 patients who had isolated stable multivessel coronary artery disease and were in normal sinus rhythm. The patients were on chronic beta-blocker therapy and were scheduled for off-pump CABG. We performed 15-minute high-resolution electrocardiographic recordings preoperatively and on the third and seventh postoperative days to assess linear and nonlinear heart rate dynamics. Frequency-domain measurements, detrended fluctuation analysis (DFA) with short-term (<or=11 beats, alpha1) and long-term (>11 beats, alpha2) correlation properties of RR-intervals, and fractal dimension (FD) measurements (average, high, and low) were made. Arrhythmia was monitored preoperatively with 24-hour Holter recordings, postoperatively by continuous monitoring for the first 4 days after the procedure, and subsequently by clinical monitoring; 24-hour Holter recordings were obtained again on the seventh postoperative day. We used the paired-samples Student t test, the Mann-Whitney U test, and the Fisher exact test for statistical analyses. Differences in arrhythmia occurrence before and after the procedure were tested with the Wilcoxon signed rank test and the McNemar test. A P level < .05 was considered statistically significant. Values for all frequency-domain parameters decreased significantly after off-pump CABG (P< .001). Values for the alpha1 and high FD parameters decreased significantly after the procedure (P= .028 and .001, respectively), whereas alpha2 increased significantly (P= .023). DFA alpha1 was significantly lower in patients with postoperative atrial fibrillation than in patients remaining in sinus rhythm (mean +/- SD, 0.79+/-0.32 versus 1.13+/-0.45 [P= .003] on the third postoperative day; 0.89+/-0.31 versus 1.22+/-0.34 [P< .001] on the seventh postoperative day), whereas low and average FDs were significantly higher (1.84+/-0.16 versus 1.68+/-0.19 [P= .003] on the third postoperative day and 1.77+/-0.18 versus 1.66+/-0.17 [P= .01] on the seventh postoperative day for the low FD; 1.83+/-0.09 versus 1.76+/-0.10 [P= .011] on the third postoperative day and 1.80+/-0.11 versus 1.73+/-0.10 [P= .014] on the seventh postoperative day for the average FD). The low FD was significantly higher on the third postoperative day in patients with postoperative deterioration of ventricular ectopy than in patients with improved ventricular ectopy (1.74+/-0.17 versus 1.48+/-0.08, [P= .03]). The decreases in alpha1, average FD, and high FD indicate that a profound decay of cardiac complexity and fractal correlation can be observed after off-pump CABG. Furthermore, a more extensive impairment of nonlinear indices was observed in patients who developed postoperative arrhythmias than in those who remained in stable sinus rhythm. Our findings suggest that the postoperative hyperadrenergic setting acts as a preliminary condition in which both reduced and enhanced vagal activity may predispose patients to arrhythmia, indicating that postoperative rhythm disturbances are an end point associated with divergent autonomic substrates.

Clinical case of the month. A 29-year-old man with acute onset blurry vision, weakness, and gait abnormality. Stroke. A 29-year-old man, with no significant past medical history, was in his usual state of health until the afternoon of admission. The patient was seated at work eating lunch when he suddenly noticed that his vision became blurry. He covered his right eye and had no visual difficulty but noted blurry vision upon covering his left eye. At this point, the patient tried to stand up, but had difficulty walking and noticed he was "falling toward his left." Facial asymmetry when smiling was also appreciated. The patient denied any alteration in mental status, confusion, antecedent or current headaches, aura, chest pains, or shortness of breath. He was not taking any prescribed medications and had no known allergies. The patient denied any prior hospitalization or surgery. He denied use of tobacco, alcohol, or illicit drugs, and worked as a maintenance worker in a hotel. His family history is remarkable for his father who died of pancreatic cancer in his 50s and his mother who died of an unknown heart condition in her late 40s. Vital signs on presentation to the emergency department included temperature of 97.6 degrees F; respiratory rate of 18 per minute; pulse of 68 per minute; blood pressure of 124/84 mmHg; pulse oximetry of 99% on ambient air. His body mass index was 24 and he was complaining of no pain. The patient had no carotid bruits and no significant jugular venous distention. Cardiovascular exam revealed a regular rate and rhythm with no murmurs. Neurological exam revealed left-sided facial weakness, dysarthria, and preserved visual fields. He was able to furrow his brow. Gait deviation to the left was present, and Romberg sign was negative. Deep tendon reflexes were 2+ throughout, and no other focal neurological deficit was present. The patient was admitted to the hospital with a diagnosis of stroke. Electrocardiogram, fasting lipid profile, computed tomography (CT) scan of head, magnetic resonance imaging (MRI) of head and neck, and transthoracic echo with bubble study were ordered. The initial head CT did not reveal bleeding. He was started on aspirin (ASA). On the second hospital day, the symptoms improved with resolution of dysarthria. His ataxia had also improved. Fasting lipid profile revealed mildly elevated low-density lipoprotein and total cholesterol. His head MRI revealed an acute right thalamic stroke. Echocardiography was significant only for a patent foramen ovale (PFO) with transit of agitated saline "bubbles" from right atrium to left heart within three cardiac cycles (Figure). Doppler ultrasound of extremities revealed no evidence of deep venous thrombosis. A complete resolution of symptoms occurred by the third hospital day. The patient was discharged on full dose aspirin and a statin and was referred for consideration of enrollment in a PFO closure versus medical management trial.

Hyperbaric oxygen therapy for late radiation tissue injury. Cancer is a significant global health problem. Radiotherapy is a treatment for many cancers and about 50% of patients having radiotherapy with be long-term survivors. Some will experience LRTI developing months or years later. HBOT has been suggested for LRTI based upon the ability to improve the blood supply to these tissues. It is postulated that HBOT may result in both healing of tissues and the prevention of problems following surgery. To assess the benefits and harms of HBOT for treating or preventing LRTI. We searched The Cochrane Central Register of Controlled Trials (CENTRAL) Issue 3, 2004, MEDLINE, EMBASE, CINAHL and DORCTHIM (hyperbaric RCT register) in September 2004. Randomised controlled trials (RCTs) comparing the effect of HBOT versus no HBOT on LRTI prevention or healing. Three reviewers independently evaluated the quality of the relevant trials using the guidelines of the Cochrane Handbook Clarke 2003) and extracted the data from the included trials. Six trials contributed to this review (447 participants). For pooled analyses, investigation of heterogeneity suggested important variability between trials. From single studies there was a significantly improved chance of healing following HBOT for radiation proctitis (relative risk (RR) 2.7, 95% confidence Interval (CI) 1.2 to 6.0, P = 0.02, numbers needed to treat (NNT) = 3), and following both surgical flaps (RR 8.7, 95% CI 2.7 to 27.5, P = 0.0002, NNT = 4) and hemimandibulectomy (RR 1.4, 95% CI 1.1 to 1.8, P = 0.001, NNT = 5). There was also a significantly improved probability of healing irradiated tooth sockets following dental extraction (RR 1.4, 95% CI 1.1 to 1.7, P = 0.009, NNT = 4). There was no evidence of benefit in clinical outcomes with established radiation injury to neural tissue, and no data reported on the use of HBOT to treat other manifestations of LRTI. These trials did not report adverse effects. These small trials suggest that for people with LRTI affecting tissues of the head, neck, anus and rectum, HBOT is associated with improved outcome. HBOT also appears to reduce the chance of osteoradionecrosis following tooth extraction in an irradiated field. There was no such evidence of any important clinical effect on neurological tissues. The application of HBOT to selected patients and tissues may be justified. Further research is required to establish the optimum patient selection and timing of any therapy. An economic evaluation should be also be undertaken. There is no useful information from this review regarding the efficacy or effectiveness of HBOT for other tissues.

Ventricular arrhythmias in aortic valve stenosis before and after transcatheter aortic valve implantation. Transcatheter aortic valve implantation (TAVI) is a therapeutic treatment for patients with severe aortic stenosis (AS) at high surgical risk. Although the procedure is associated with a reduction in total mortality, there are no data regarding changing in the incidence of premature ventricular contractions (PVCs) and ventricular arrhythmias (VAs) after TAVI. The aim of this study was to assess the incidence of VAs before and after TAVI. We enrolled 237 patients who underwent TAVI at our centre. Ninety-one patients were excluded for the following reasons: presence of prior permanent pacemaker (PPM) (n = 20), new PPM implant after TAVI (n = 48), death during the follow-up period (n = 16), and lost at follow-up (n = 7). Finally, 146 patients were included in our analysis. The presence of VAs was evaluated in all patients recording a 24 h Holter monitoring before the procedure and after 1 and 12 months. Ventricular arrhythmias were classified according to a modified Lown grading system. Before the procedure, isolates PVCs (grade 1-2 of Lown grading system) were present in 34.9% of patients (n = 51). Complex PVCs (grade 3-4a-4b of Lown grading system) were present in 48.6% of the population (multifocal PVCs in 32 patients, 21.9%; pairs in 25 patients, 17.1%; ventricular tachycardia in 14 patients, 9.6%). One month after the procedure, we observed statistically significant incidence decrease of arrhythmias of grade 3 (from 21.9 to 17.1%) and grade 4 (pairs from 17.1 to 12.3%; ventricular tachycardia from 9.6 to 4.8%). After 12 months, there was a further significant reduction in the frequency and severity of PVCs. In particular, 45.8% of patients had isolates PVCs (<30 in all given hours of monitoring in 45 patients, 30.8%; higher than 30 in any hour of monitoring in 22 patients, 15%) while the frequency of complex arrhythmias was reduced to 16.4% (multifocal PVCs in 13 patients, 9%; couplets 8 patients, 5.5% and ventricular tachycardia in 3 patients, 2.0%). The difference was statistically significant (P < 0.01). This study indicates that VAs are common in patients with AS. We observed a significant decrease in the incidence and severity of PVCs since the first month after TAVI. Furthermore, after 1 year follow-up there was a further and significant reduction in the frequency of complex PVCs. This may be related to the benefits determined by valve replacement on left ventricular function.

Cancer incidence and mortality in France over the period 1978-2000. Monitoring cancer incidence and mortality time trends is essential for cancer research and health-care planning. French cancer registries do not cover the entire population and do not provide a representative sample of the national population. Our study aimed at estimating national cancer incidence and mortality trends over the longest period available. Incidence and mortality data were collected over the period 1978-1997. Twenty-seven cancer sites were selected and age, sex and site specific incidence and mortality rates were estimated for each year from 1978 up to 2000. Observed incidence and mortality data in the population covered by cancer registries were modelled using age-cohort methods. An estimation of the incidence/mortality ratio was obtained from these models and applied to the mortality rates predicted from an age-cohort model for the entire French population. The person-years of observation were calculated cohort-wise from census data provided by the national institute of statistics Cancer incidence increased by 63% throughout the study period, from 170,000 new cases in 1980 to 278,000 in 2000. This evolution was due to demographic changes but also to an increase in the risk of cancer which was estimated to more than 35% during the same period. In men, this change is largely explain by the increase of prostate cancer incidence. Among women, the increase was dominated by the continuing increase in breast cancer incidence. Large increases were also seen for non-Hodgkin lymphoma, melanoma, and thyroid cancer in both genders and for lung cancer in women. Cancer mortality increased by 20% from 125,000 deaths in 1980 to 150,000 in 2000. This increase is less than that predicted from changes in demographic factors and corresponds in fact to a decrease in the risk of death estimated to about 8%, slightly greater for women than for men. This decrease is associated with a decreasing incidence for stomach cancers for both sexes, alcohol-related cancer for men and cervical cancer for women. Colo-rectal cancer decreasing mortality contributes to this improvement despite an incidence increase. Between 1980 and 2000, the study showed a large change in the cancer burden both quantitatively and qualitatively. Decrease in exposure, earlier diagnosis and therapeutic improvement explained part of this change, but overall the distribution of cancer cases shifted toward a distribution including less aggressive cancers. A striking divergence between incidence and mortality trends is observed for a great number of cancers. Prostate cancer shares with breast cancer the same pattern of a severe increasing incidence and a stable mortality. This points to important changes in medical practice and needs further analysis. The trend of lung cancer mortality among women should be emphasised since the situation will inevitably worsen in the coming years. It is already the third cause of cancer death among women.

Green techniques in comparison to conventional ones in the extraction of Amaryllidaceae alkaloids: Best solvents selection and parameters optimization. An undisputed trend in sample preparation at present is to meet the requirements of green chemistry especially in the field of natural products. Green technology continuously pursues new solvents to replace common organic solvents that possess inherent toxicity. Over the past two decades, non-ionic surfactants have gained enormous attention from the scientific community. The micelle-mediated extraction and cloud-point preconcentration (CPE) methods offer a convenient alternative to the conventional extraction systems. Recently, natural deep eutectic solvents (NDESs) have emerged as green and sustainable solvents for efficient extraction of bioactive compounds or drugs. They are generally composed of neutral, acidic or basic compounds that form liquids of high viscosity when mixed in certain molar ratio. The presented work aimed to comprehensively compare and evaluate the potential and effectiveness of NDES as well as non-ionic surfactants (Genapol X-080, Triton X-100 and Triton X-114) for extraction of Amaryllidaceae alkaloids from Crinum powellii bulbs as representative example of plant material, in comparison to the conventional solvents (methanol, ethanol and water).A new validated high-performance thin-layer chromatographic (HPTLC) method has been developed for the simultaneous quantitation of three alkaloids markers, lycorine, crinine and crinamine, in the bulbs of C. powellii. Extraction efficiency of the targeted alkaloids from the bulb matrix with organic and ecofriendly (green) solvents were studied. Results revealed that NDES and surfactants were significantly more efficient in alkaloid extraction than previous methods requiring the consumption of organic solvents and water. Genapol X-80 demonstrated 138%, 149% and 145%, while choline chloride: fructose (5:2): H2O (35%) NDES mixture demonstrated 243%, 225% and 238% of the total alkaloidal extraction capacity of ethanol, methanol and water, respectively at 50 °C for extraction time 1 h using ultrasonication for all experiments. Furthermore, Box-Behnken response surface design combined with the overall desirability value were successfully employed to optimize and study the individual and interactive effect of process variables such as extraction temperature, time and surfactant %, for Genapol X-80, and sonication extraction temperature, time and water concentration, for choline chloride: fructose: H2O NDES mixture, on the alkaloidal yield from C. powellii. It was evident that parameters interacting together can act in synergism if adjusted properly according to the optimized conditions to obtain maximum alkaloids extractability. It is for the first time that the efficiency of micelle-mediated extraction has been compared to that of natural deep eutectic solvents for the extraction of alkaloids and the results thoroughly discussed.

Strategies for increasing the efficiency of heterojunction organic solar cells: material selection and device architecture. Thin-film blends or bilayers of donor- and acceptor-type organic semiconductors form the core of heterojunction organic photovoltaic cells. Researchers measure the quality of photovoltaic cells based on their power conversion efficiency, the ratio of the electrical power that can be generated versus the power of incident solar radiation. The efficiency of organic solar cells has increased steadily in the last decade, currently reaching up to 6%. Understanding and combating the various loss mechanisms that occur in processes from optical excitation to charge collection should lead to efficiencies on the order of 10% in the near future. In organic heterojunction solar cells, the generation of photocurrent is a cascade of four steps: generation of excitons (electrically neutral bound electron-hole pairs) by photon absorption, diffusion of excitons to the heterojunction, dissociation of the excitons into free charge carriers, and transport of these carriers to the contacts. In this Account, we review our recent contributions to the understanding of the mechanisms that govern these steps. Starting from archetype donor-acceptor systems of planar small-molecule heterojunctions and solution-processed bulk heterojunctions, we outline our search for alternative materials and device architectures. We show that non-planar phthalocynanines have appealing absorption characteristics but also have reduced charge carrier transport. As a result, the donor layer needs to be ultrathin, and all layers of the device have to be tuned to account for optical interference effects. Using these optimization techniques, we illustrate cells with 3.1% efficiency for the non-planar chloroboron subphthalocyanine donor. Molecules offering a better compromise between absorption and carrier mobility should allow for further improvements. We also propose a method for increasing the exciton diffusion length by converting singlet excitons into long-lived triplets. By doping a polymer with a phosphorescent molecule, we demonstrate an increase in the exciton diffusion length of a polymer from 4 to 9 nm. If researchers can identify suitable phosphorescent dopants, this method could be employed with other materials. The carrier transport from the junction to the contacts is markedly different for a bulk heterojunction cell than for planar junction cells. Unlike for bulk heterojunction cells, the open-circuit voltage of planar-junction cells is independent of the contact work functions, as a consequence of the balance of drift and diffusion currents in these systems. This understanding helps to guide the development of new materials (particularly donor materials) that can further boost the efficiency of single-junction cells to 10%. With multijunction architectures, we expect that efficiencies of 12-16% could be attained, at which point organic photovoltaic cells could become an important renewable energy source.

[Indirect effects of school volunteering by senior citizens on parents through the "REPRINTS" intergenerational health promotion program]. We have launched a new intervention study, called "REPRINTS" (Research of productivity by intergenerational sympathy), in which senior volunteers aged 60 years and over are engaged in reading picture books to school children, regularly visiting public elementary schools since 2004. So far, no repeated cross-sectional studies to demonstrate indirect effects on parents have been reported, although reciprocal effects on senior volunteers and children have been demonstrated. The purpose of this study was to examine the changes of evaluation of "REPRINTS" program by parents of school children during the 2 years. Four to six volunteers as a group visited an elementary school in a suburb of Kawasaki city twice a week to read picture books. A baseline survey was conducted one month after launching the volunteer activity. First to fourth follow-up surveys were conducted every 6 months after baseline surver. Of 368 parents, 230 whose children were in 1st-4th grade were analyzed. School grade of children, gender, emotional image scale of older adults by the SD (Semantic Differential) method (13 items), parents' evaluation of activity of "REPRINTS" volunteers such as promotion of reading for children, or children's respect for older adults, appreciation, familiarity with older adults, indirect effects on promotion of safety in the community, and reducing parent's physical and psychological burdens of volunteer service for school. Repeated cross-sectional analyses by ANCOVA, adjusted for confounding factors, were conducted in order to compare changes in responses between parents of 1st-2nd grade children (lower-grade children) with those of 3rd-4th grade-children (middle-grade children). We examined experiences of being read with picture books, greeting and having conversations with volunteers among all of 330 students of 1st-4th grade. These three items were examined using Chi-squared test to compare longitudinal change between parents of lower-grade and middle-grade children. Evaluation of children's familiarity with older adults significantly declined among parents of middle-grade children, but was maintained among those of lower-grade children during the 2 years. Physical burdens of volunteer service for school were lower among parents' of lower-grade children at baseline, and were significantly reduced among parents' of all grades. Promotion of reading for children, indirect effects on promotion of safety in the community, and frequency of hearing episodes of "REPRINTS" volunteers from children were higher among parents' of lower-grade children at baseline. Psychological burdens were reduced and level of knowledge of "REPRINTS" volunteers was increased among parents' of all grades. In terms of parents' emotional image scale of older adults in general, no significant difference was found among the grades of school children and number of surveys for all the subscales of 'socialization', 'activity', and 'cheerfulness'. The level of knowledge and a number of items of evaluation of "REPRINTS" volunteers were significantly increased among parents of both lower-grade and middle-grade children during the 2-year intervention. This study indicates that the "REPRINTS" program can contribute to establishing trust and reliance between generations of older adults and parents of school children with the children as mediators.

Evaluation of tropically adapted straightbred and crossbred beef cattle: heifer age and size at first conception and characteristics of their first calves. The objectives of this work were to estimate genetic effects for age and size at estimated time of first conception, and temperament in straightbred and crossbred heifers (n = 554) produced from Romosinuano, Brahman, and Angus cattle, and to evaluate first-parturition performance of heifers, including calf birth weight, occurrence of calving difficulty, occurrence of poor vigor in their newborn calves, and calf mortality. At approximately 7 mo of age, weaned heifers were pastured with Mashona or Tuli bulls until confirmed pregnant. Body weight, hip height, exit velocity (m/s), and chute temperament score (1 = calm, no movement; 5 = continuous movement, struggling) were recorded at 28-d intervals until heifers averaged 19 mo of age. Age at first conception was estimated as age at calving minus 285 d. Regression analyses were used to estimate BW and hip height at age of first conception. Brahman heifers were older, heavier, and had greater hip height than other straightbred groups (P < 0.05) and most crossbred groups. Brahman and reciprocal Brahman-Angus heifers had greater (P < 0.05) exit velocity than Romosinuano and Angus heifers. Brahman sire and dam breed chute temperament scores were greater (P < 0.05) than those of all other breed groups. Estimates of heterosis for age at first conception were -53.7 ± 9.5 (-11%), -56 ± 10.1 (-11%), and -92.9 ± 11 d (-18%) for Romosinuano-Brahman, Romosinuano-Angus, and Brahman-Angus, respectively (P < 0.01). Heterosis was detected (P < 0.04) for Romosinuano-Brahman for BW (12 ± 4.3 kg, 3.7%) and hip height (1.3 ± 0.6 cm, 1%) at first conception. Maternal heterosis for calf birth weight was 3.6 ± 0.5 (12%) and 2.4 ± 0.6 kg (8.6%) for Romosinuano-Angus and Brahman-Angus. In Romosinuano-Brahman and Brahman-Angus, heterosis for exit velocity was 0.23 ± 0.09 (10%) and 0.5 ± 0.1 m/s (21%). The direct breed effect of Romosinuano was to reduce age (-58.2 ± 18.9 d), BW (-57.6 ± 10.5 kg), and hip height (-2.6 ± 1.1 cm) at the time of first conception (P < 0.01), and the direct Brahman effects (P < 0.001) were large and numerically positive for these traits (169.8 ± 20.8 d, 93.3 ± 11.6 kg, and 14 ± 1.2 cm). Use of Romosinuano in crossbreeding programs with Brahman may be useful for decreasing the age at first conception. The larger birth weights of calves born to Romosinuano-Angus cross heifers would not be desirable in southern cow-calf operations.

Mechanisms of rice straw biochar effects on phosphorus sorption characteristics of acid upland red soils. An important pathway for biochar to alter the availability of soil phosphorus (P) is to change P sorption characteristics of the soil. The aim of this study was to understand the mechanisms of biochar effects on P sorption in acid upland red soils in the presence of different concentrations of exogenous P. Rice straw biochar (RSB) was prepared and applied at rates of 0, 1%, 3%, and 5% (w/w) to three red soils (MZ1, MZ2, and QY1) differing in initial pH (pH = 4.31, 4.82, and 5.68, respectively). The P sorption characteristics of these red soils were described using the Langmuir and Temkin equations and their relationships with soil basic physicochemical properties were analyzed. Furthermore, a representative red soil (MZ2) was selected to analyze the zeta potential of soil colloids and the chemical properties of sorption equilibrium solution, in order to understand their relationships with P sorption characteristics. Results showed that within a certain range of P concentration in the equilibrium solution, the amount of P sorbed by the three red soils decreased and the corresponding amount of P desorbed increased with increasing amendment rate of RSB. RSB showed the greatest effect on P desorption characteristics of MZ2 soil in the presence of higher exogenous P concentration. With increasing RSB amendment rate, the maximum P sorption of MZ1 soil decreased, while those of MZ2 and QY1 soils increased after an initial decrease. Phosphate sorption equilibrium constant and maximum P buffer capacity of each soil first increased and then decreased. However, a single physicochemical property could not interpret complex changes in multi-factors that jointly determine the P sorption characteristics of red soils. In the case of MZ2 soil, RSB amendment shifted the zeta potential of soil colloids to the negative direction; this decreased the positive charge and increased the negative charge on the soil surface, thus reducing P sorption in the MZ2 soil. In the presence of the same concentration of exogenous P, RSB amendment altered the pH, dissolved organic C (DOC), humification index (HIX), and maximum fluorescence intensity (Fmax) in the sorption equilibrium solution. In most cases, the amount of P sorbed by the MZ2 soil was negatively correlated with the pH value, DOC concentration, HIX value, and Fmax value of humic-like dissolved organic matter (DOM), and positively correlated with the Fmax value of protein-like DOM (P < 0.05 or P < 0.01). The relative fractional distribution of the contents for humic-like and protein-like DOM might determine the difference in the P sorption characteristics of MZ2 soil. In conclusion, different amendment rates of RSB affected the release of phosphate from soil surfaces into the solution by altering basic physicochemical and electrochemical properties of red soils and chemical properties of sorption equilibrium solution.

Metal concentrations in electronic cigarette aerosol: Effect of open-system and closed-system devices and power settings. Electronic cigarettes (E-cigarettes) generate aerosol containing metal contaminants. Our goals were to quantify aerosol metal concentrations and to compare the effects of power setting and device type (closed-system vs. open-system) on metal release. Aerosol samples were collected from two closed-system devices (a cigalike and pod) and two open-system devices (mods). Each open-system device was operated at three different power settings to examine the effect of device power on metal release. Concentrations of 14 metals in e-cigarette aerosol collected via droplet deposition were measured using inductively coupled plasma mass spectroscopy. Aerosol metal concentrations were reported as mass fractions (μg/kg) in the e-liquid. For open-system device 1 (OD1), median arsenic (As), chromium (Cr), copper (Cu), iron (Fe), manganese (Mn), nickel (Ni), lead (Pb), antimony (Sb), tin (Sn), and zinc (Zn) concentrations increased 14, 54, 17, 30, 41, 96, 14, 81, 631, and 7-fold when the device power was increased from low (20 W) to intermediate (40 W) setting. When the power was further increased from intermediate (40 W) to high (80 W) setting, concentrations of As, Cr, Cu, Mn, Ni, and Sb did not change significantly. For open-system device 2 (OD2), Cr and Mn concentrations increased significantly when device power was increased from low (40 W) to intermediate (120 W) setting, and then decreased significantly when power was further increased from intermediate (120 W) to high (200 W) setting. Among the four devices, aerosol metal concentrations were higher for the open-system than the closed-system devices, except for aluminum (Al) and uranium (U). For Cr, median (interquartile range) concentrations (μg/kg) from the open-system devices were 2.51 (1.55, 4.23) and 15.6 (7.88, 54.5) vs. 0.39 (0.05, 0.72) and 0.41 (0.34, 0.57) for the closed-system devices. For Ni, concentrations (μg/kg) from the open-system devices were 793 (508, 1169) and 2148 (851, 3397) vs. 1.32 (0.39, 3.35) and 11.9 (10.7, 22.7) from the closed-system devices. Inhalation of 0% and 100% of samples from OD1, 7.4% and 88.9% from OD2 by typical e-cigarette users would exceed chronic minimum risk levels (MRL) of Mn and Ni, respectively. No MRL exceedance was predicted for the closed-system devices. A large fraction of users of OD1 (100%) and OD2 (77.8%) would be exposed to Ni levels higher than those from reference tobacco cigarette 3R4F. Our findings suggest that power setting and device type affect metal release from devices to aerosol which would subsequently be inhaled by users. Metal concentrations from open-system devices first increased with device power, and then leveled off for most metals. Open-system devices generate aerosol with higher metal concentrations than closed-system devices. These findings inform tobacco regulatory science, policy makers and health professionals on potential metal health risks associated with e-cigarette use, design and manufacturing.

Chemical and biological investigations of beta-oligoarginines. In view of the important role arginine plays in living organisms as the free amino acid and, especially, as a residue in peptides and proteins, the homologous beta-homoarginines are central in our investigations of beta-peptides (Fig. 1). The preparation of beta2-homoarginine derivatives suitably protected for solution- or solid-phase peptide syntheses is described with full experimental detail (9 and 12 in Scheme 1). The readily available Fmoc-beta3 hArg(Boc)2-OH is used for manual solid-phase synthesis of beta3-oligoarginines (on Rink amide or Rink amide AM resin) either by single amino acid coupling (Scheme 3) or, much better, by dimer-fragment coupling (Scheme 4). In this way, beta3-oligoarginine amides composed of 4, 6, 7, 8, and 10 residues, both with and without fluorescein labelling, were synthesized (Schemes 2-4), purified by preparative HPLC and identified by high-resolution mass spectrometry. The free amino acids (R)- and (S)-H-beta2 hArg-OH and (S)-H-beta3 hArg-OH were tested for their ability to function as substrates for NO synthase (iNOS); the beta3-oligoarginine amides (5, 6, and 7 residues) were tested for antibacterial (against six pathogens) and hemolytic (against rat and human erythrocytes) activities. All test results were negative: none of the free beta-homoarginines induced NO formation (Fig. 3), and there was no lysis of erythrocytes (concentrations up to 100 microM; Table 1), and no significant antibiotic activity (MIC > or = 64 microg/ml; Table 2). Cell-penetration studies with the fluorescence-labelled, peptidase-resistant beta3-oligoarginine amides were carried out with HeLa cells and human foreskin keratinocytes (HFKs). The results obtained with fluorescence microscopy are: i) the longer-chain beta-oligoarginine amides (8 and 10 residues; Figs. 4-6) enter the cells and end up in the nuclei, especially in the nucleoli, irrespective of temperature (37 degrees and 4 degrees with HFKs) or pretreatment with NaN3 (with HFKs), indicating a non-endocytotic and non-energy-dependent uptake mechanism; ii) the beta-tetraarginine derivative occupies the cell surface but does not enter the cells (with HeLa); iii) the cell-growth rate of the HFKs is not affected by a 1-microM concentration of the fluorescence-labelled beta-octaarginine amide (Fig. 7), i.e., there is no antiproliferative effect. In vivo experiments with mouse skin and the beta-octaarginine derivative show migration of the beta-peptide throughout the epidermis (Fig. 8). As a contribution to understanding the mechanism, we have also studied the behavior of fluorescence-labelled beta-octa- and beta-decaarginine amides (TFA salts) towards giant unilamellar vesicles (GUVs) built of neutral (POPC) or anionic (POPC/POPG mixtures) phospholipids: the beta-oligoarginine amides bind tightly to the surface of anionic GUVs but do not penetrate the lipid bilayer (Fig. 9) as they do with living cells. In contrast, a beta-heptapeptide FL-22, which had been used as a negative control sample for the cell-penetration experiments, entered the GUVs of negative surface charge. Thus, the mechanisms of cell and GUV-model penetration appear to be different. Finally, the possible applications and implications of the 'protein transduction' by beta-oligoarginines are discussed.

Acephate resistance in populations of the tarnished plant bug (Heteroptera: Miridae) from the Mississippi River Delta. A monitoring program that used a glass-vial bioassay to detect acephate resistance in populations of the tarnished plant bug, Lygus lineolaris (Palisot de Beauvois) (Heteroptera: Miridae), was carried out with weed-collected populations from 20 sites in the delta of Arkansas, Louisiana, and Mississippi. Additional results from field tests using recommended rates of formulated acephate in cotton showed that plant bug populations with resistance ratio (RR50) values > 3.0 for acephate (from the glass-vial bioassay) would be difficult to control in the field. Over a 4-yr-period from 2001 through 2004, only one population tested with the glass-vial bioassay was found with an RR50 value > 3.0 for acephate, but six populations having RR50 values > 3.0 were found in the delta in 2005. In fall 2005, an additional 10 populations from the hill region (the cotton growing areas outside the delta) were tested and four of these populations had RR50 values > 3.0. The number of populations with RR50 values > 3.0 increased to five of 10 and 18 of 20 in the hills and delta, respectively, in fall 2006. Laboratory tests using resistant populations found that resistance to acephate was not sex-linked and the alleles controlling the resistance were semidominant in nature. Because of the large increase in resistant populations and the nature of the resistance found in this study, along with control problems experienced by growers in 2006, entomologists in the mid-South strongly recommended that alternation of insecticide classes in field treatments for plant bug control be used by growers in 2007. This control strategy probably helped control plant bugs in the hills of MS where plant bug pressure was low in 2007, and only one population was found in the fall with an RR50 value > 3.0. Plant bug pressure was very high in many parts of the delta in 2007, and 15 of the 20 populations tested in the fall had RR50 values > 3.0. In one field test in cotton, a population with multiple resistance was tested and not effectively controlled in treatments using recommended rates of carbamate, organophosphate, and pyrethroid insecticides. Alternation of insecticide classes may not work very well when populations are present that are resistant to three of the four main classes of cotton insecticides. New insecticides in different classes are badly needed for control of tarnished plant bugs in cotton in the mid-South.

Deficient in vitro megakaryocytopoiesis and decreased in vivo platelet turnover in children and young adults with chronic thrombocytopenia. Chronic thrombocytopenia is uncommon in children and frequently thought to be secondary to chronic idiopathic thrombocytopenic purpura (ITP), which is considered an immune disorder. However, not all children with chronic ITP respond to immunosuppressive therapy. Platelet survival and megakaryocyte growth were studied to determine if there is a failure of platelet production in children with chronic thrombocytopenia who carry a presumptive diagnosis of chronic ITP. In vitro megakaryocyte growth using a plasma clot system and in vivo survival of 111In-labeled autologous platelets were studied in seven patients (aged 2 days to 17 years at diagnosis; aged 2 to 28 years at time of megakaryocyte study) with chronic isolated thrombocytopenia (range 1,000 to 130,000/microl). All seven patients exhibited elevated platelet-associated immunoglobulin G early in the course of their disease and showed normal marrow morphology with normal numbers of morphologically typical megakaryocytes on initial marrow biopsy. Occasional dysplastic-appearing megakaryocytes were noted in three of the seven patients at diagnosis and all patients were noted to have dysplastic megakaryocytes, reduced megakaryocytes, or both during follow-up (range 5 to 16 years). Either morphologic or karyotypic abnormalities indicative of myelodysplasia subsequently developed in three patients. No patient exhibited any significant megakaryocyte colony growth under basal conditions. In one patient, megakaryocytic colonies significantly increased when grown in the presence of serum from aplastic patients and growth factors (granulocyte-macrophage colony-simulating factor, interleukin-3, and interleukin-6). Erythroid colony growth was markedly deficient in four of five patients studied and myeloid colonies were normal in two of three patients studied. Five of the seven patients underwent platelet survival studies. Platelet survival was < 6 days in the 4 patients with platelet counts < 100,000/microl (range 2 to 60,000/microl; survival range 92 to 137 hours) and was normal in the patient whose platelet count was > 100,000/microl (platelets 132,000/microl; survival 253 hours). All five patients had either overtly low or inappropriately low platelet turnovers (range 100 to 1423 platelets/microl per hour; normal range 1200 to 1600 platelets/microl per hour). The patient with the lowest platelet count and platelet turnover had previously undergone a splenectomy without benefit. Megakaryocyte dysfunction resulting in subnormal production of platelets may play a significant role in the thrombocytopenia noted in some patients who have an isolated thrombocytopenia and a clinical picture that suggests ITP. Determination of platelet turnover may help to identify these patients. These data suggest the presence of a stem cell defect which may progress to myelodysplasia or overt marrow failure in these patients.