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FEDML 10

Is lymphocyte inhibition compromised in mesenchymal stem cells from psoriatic skin?

Psoriasis is a chronic inflammatory skin disorder associated with a host of immune abnormalities. Mesenchymal stem cells (MSCs) have immunosuppressive properties and, in earlier studies, we found that the bone marrow MSCs of patients with psoriasis exhibit abnormal cytokine secretion. Since MSCs can be isolated from skin, we hypothesized that the biological characteristics of MSCs in psoriatic skin lesions might reflect the pathogenesis of psoriasis. To investigate the effects of MSCs from psoriatic skin lesions on T-cell proliferation. MSCs obtained from psoriatic skin lesions and healthy human skin were examined by flow cytometry and cell differentiation assays. MSCs were co-cultured with normal peripheral blood T cells to assess changes in T-cell proliferation. Concentrations of interleukin (IL)-6, IL-11, hepatocyte growth factor (HGF), and transforming growth factor (TGF)-β1 in the MSC culture supernatants were measured by enzyme-linked immunosorbent assays. Surface markers and differentiation capacity were similar in MSCs from both sources. MSCs in psoriatic skin lesions were weaker inhibitors of T-cell proliferation (p<0.05) and exhibited increased secretion of IL-11 and reduced secretion of IL-6 and HGF (p<0.05). Secretion of TGF-β1 was unchanged (p > 0.05).

This study demonstrated abnormalities in MSCs derived from psoriatic skin lesions. We suggest that the attenuated inhibitory effect on T-cell proliferation might be one of the pathogenic mechanisms of psoriasis.

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Does learning trajectories of children with special health care need across the severity spectrum?

A significant proportion of school-aged children experience special health care needs (SCHN) and seek care from pediatricians with a wide range of condition types and severity levels. This study examines the learning pathways of children with established (already diagnosed at school entry) and emerging (teacher identified) SHCN from school entry through the elementary school years. The Longitudinal Study of Australian Children (LSAC) is a nationally representative clustered cross-sequential sample of 2 cohorts of Australian children which commenced in May 2004. Data were analyzed from the LSAC kindergarten cohort (n = 4,983), as well as a subsample of 720 children for whom teachers also completed the Australian Early Development Index checklist, a measure of early childhood development at school entry that includes SHCN. Latent class analysis was utilized to establish 3 academic trajectories from 4-5 to 10-11 years: high (24.3%), average (49.8%), and low (23.6%). Descriptive statistics revealed a trend for both children with established and emerging SHCN to fall into weaker performing learning pathways. Multinomial logistic regression focusing on those children with emerging SHCN confirmed this pattern of results, even after adjustment for covariates (relative risk 3.06, 95% confidence interval 1.03-9.10). Children who additionally had low socioeconomic standing were particularly at risk.

Even children with less complex SCHN are at risk for academic failure. Early identification, together with integrated health and educational support, may promote stronger pathways of educational attainment for these children. Achieving these better outcomes will require the involvement of both educational and health practitioners.

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Does deep Sequencing the microRNA profile in rhabdomyosarcoma reveal down-regulation of miR-378 family members?

Rhabdomyosarcoma (RMS) is a highly malignant tumour accounting for nearly half of soft tissue sarcomas in children. MicroRNAs (miRNAs) represent a class of short, non-coding, regulatory RNAs which play a critical role in different cellular processes. Altered miRNA levels have been reported in human cancers, including RMS. Using deep sequencing technology, a total of 685 miRNAs were investigated in a group of alveolar RMSs (ARMSs), embryonal RMSs (ERMSs) as well as in normal skeletal muscle (NSM). Q-PCR, MTT, cytofluorimetry, migration assay, western blot and immunofluorescence experiments were carried out to determine the role of miR-378a-3p in cancer cell growth, apoptosis, migration and differentiation. Bioinformatics pipelines were used for miRNA target prediction and clustering analysis. Ninety-seven miRNAs were significantly deregulated in ARMS and ERMS when compared to NSM. MiR-378 family members were dramatically decreased in RMS tumour tissue and cell lines. Interestingly, members of the miR-378 family presented as a possible target the insulin-like growth factor receptor 1 (IGF1R), a key signalling molecule in RMS. MiR-378a-3p over-expression in an RMS-derived cell line suppressed IGF1R expression and affected phosphorylated-Akt protein levels. Ectopic expression of miR-378a-3p caused significant changes in apoptosis, cell migration, cytoskeleton organization as well as a modulation of the muscular markers MyoD1, MyoR, desmin and MyHC. In addition, DNA demethylation by 5-aza-2'-deoxycytidine (5-aza-dC) was able to up-regulate miR-378a-3p levels with a concomitant induction of apoptosis, decrease in cell viability and cell cycle arrest in G2-phase. Cells treated with 5-aza-dC clearly changed their morphology and expressed moderate levels of MyHC.

MiR-378a-3p may function as a tumour suppressor in RMS and the restoration of its expression would be of therapeutic benefit in RMS. Furthermore, the role of epigenetic modifications in RMS deserves further investigations.

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Does health indicators associated with fall among middle-aged and older women enrolled in an evidence-based program?

Evidence-based fall prevention programs primarily attract older women, who are increasingly burdened by fall-related injuries. However, little is known about the relationship between older female participants' baseline health status and self-reported falls over the course of fall prevention interventions. Using data from A Matter of Balance/Volunteer Lay Leader Model (AMOB/VLL) workshops, this study examines female participants' sociodemographics and health indicators associated with self-reported falls at baseline and postintervention. Data were analyzed from 837 older women (M = 76.2 years) collected during the statewide AMOB/VLL dissemination in Texas. Longitudinal Poisson regression models, using the generalized estimating equation method, were used to investigate the associations of personal characteristics and health indicators with and reductions in the number of self-reported falls from baseline to postintervention. Approximately 21% of participants reported falling at baseline, and the number of reported falls significantly decreased from baseline to postintervention (β = -0.443). At baseline, more unhealthy physical days (β = 0.022), more unhealthy mental days (β = 0.018), and lower Falls Efficacy Scale scores (β = -0.052) were significantly associated with more falls reported at baseline. More falls at baseline was also associated with worse program attendance (β = -0.069). Greater improvements in Falls Efficacy Scale Scores (β = -0.069) and decreases in unhealthy physical health days (β = 0.026) over the course of the intervention were significantly associated with greater reductions in reported falls at postintervention, respectively.

Findings have implications for identifying at-risk older women upon enrollment, expanding the reach of AMOB/VLL, and leveraging AMOB/VLL to refer participants to other evidence-based exercise, disease management, and mental health interventions.

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Do women know best -- findings from a thematic analysis of 5,214 surveys of abortion care experience?

Patient experience is an essential component of quality care. Few studies have comprehensively evaluated patient experiences of abortion care. The objectives of this study were to describe women's experiences of abortion care in their own words, and to determine themes across patient experiences. Data for this thematic analysis, a qualitative method that allows for the identification, analysis, and report of patterns or themes within data, come from a larger study of safety and quality of aspiration abortion care across 22 clinical sites. Participants completed an abortion experience survey including fixed choice questions and an open-ended question: "Is there anything you would like to tell us about your experience?" The data were then categorized by responses to another survey question: "Overall, was your experience about, better, or worse than you expected?" A total of 5,214 responses were analyzed. Women reported positive abortion care experiences with the majority of women rating their experience as better than expected (n = 3,600). Two major themes that emerged from the data include clinic- and patient-level factors that impact how patients rate their experiences. Analysis of the responses categorized in the worse than expected group (n = 136) found that women primarily faulted clinic-level factors for their negative experiences, such as pain control and management, and wait time for appointments and in clinic.

This analysis highlights specific areas of abortion care that influence patients' experience. The few women who were disappointed by care in the clinic tended to fault readily modifiable clinical factors, and provided suggested areas of improvement to enhance positive experiences related to their abortion care.

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Does unit support protect against sexual harassment and assault among national guard soldiers?

Despite concerns about increased sexual harassment and assault after the 2013 legislation repealing the ban on women in combat, little research has examined military factors that could prevent sexual harassment and assault during deployment. This study examined whether unit support, which reflects the quality of service members' relationships within their unit, protects against sexual harassment and assault during deployment. Participants were 1,674 Ohio Army National Guard service members who reported at least one deployment during a telephone survey conducted in 2008 and 2009. Participants completed measures of sexual harassment/assault, unit support, and psychosocial support. Logistic regression was used to model odds of sexual harassment/assault. Approximately 13.2% of men (n = 198) and 43.5% of women (n = 74) reported sexual harassment, and 1.1% of men (n = 17) and 18.8% of women (n = 32) reported sexual assault during their most recent deployment. Greater unit support was associated with decreased odds of sexual harassment and assault.

A substantial proportion of men and women reported sexual harassment/assault. Greater unit support was associated with diminished odds of sexual harassment/assault during deployment. Programming designed to improve unit cohesion has the potential to reduce sexual harassment and assault.

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Does the T-box transcription factor Brachyury promote renal interstitial fibrosis by repressing E-cadherin expression?

Epithelial-to-mesenchymal transition (EMT) induced by TGF-β1 is one of well-recognized factors contributing to renal fibrosis. However, the underlying molecular mechanisms of EMT are not fully understood. Brachyury, an evolutionarily conserved transcription factor, was recently identified as an important factor promoting EMT in human carcinoma cell lines. There is no evidence that Brachyury is involved in renal tubular EMT. Our results demonstrated that Brachyury was prominently induced in TGF-β1-treated human proximal tubular epithelial (HK-2) cells and that this induction was accompanied by changes characteristic of EMT. Blockage of Brachyury expression by short interfering RNA (siRNA) in HK-2 cells effectively reversed the TGF-β1-induced EMT phenotype. Brachyury induction repressed E-cadherin transcription; the E-cadherin promoter contains a Brachyury binding site, and decreased expression of E-cadherin occurred in Brachyury-overexpressing cells when they were transfected with reporter constructs using the promoter. This effect was partially mediated by Slug and Snail, as knockdown of Snail and Slug by siRNA effectively reversed Brachyury-mediated EMT and partially restored E-cadherin expression. The expression of Brachyury also presented in a rat model of obstructive nephropathy and in tubulointerstitial fibrosis tissues of IgA nephropathy, suggesting that it may have a role in EMT and renal fibrosis in vivo.

Our results demonstrate for the first time that Brachyury plays an important role in regulating TGF-β1-mediated renal EMT and could be an attractive target for progression of renal disease therapies.

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Does pneumonia Pathogen Characterization be an Independent Determinant of Hospital Readmission?

Hospital readmissions for pneumonia occur often and are difficult to predict. For fiscal year 2013, the Centers for Medicare & Medicaid Services readmission penalties have been applied to acute myocardial infarction, heart failure, and pneumonia. However, the overall impact of pneumonia pathogen characterization on hospital readmission is undefined. This was a retrospective 6-year cohort study (August 2007 to September 2013). We evaluated 9,624 patients with a discharge diagnosis of pneumonia. Among these patients, 4,432 (46.1%) were classified as having culture-negative pneumonia, 1,940 (20.2%) as having pneumonia caused by antibiotic-susceptible bacteria, 2,991 (31.1%) as having pneumonia caused by potentially antibiotic-resistant bacteria, and 261 (2.7%) as having viral pneumonia. The 90-day hospital readmission rate for survivors (n = 7,637, 79.4%) was greatest for patients with pneumonia attributed to potentially antibiotic-resistant bacteria (11.4%) followed by viral pneumonia (8.3%), pneumonia attributed to antibiotic-susceptible bacteria (6.6%), and culture-negative pneumonia (5.8%) (P < .001). Multiple logistic regression analysis identified pneumonia attributed to potentially antibiotic-resistant bacteria to be independently associated with 90-day readmission (OR, 1.75; 95% CI, 1.56-1.97; P < .001). Other independent predictors of 90-day readmission were Charlson comorbidity score > 4, cirrhosis, and chronic kidney disease. Culture-negative pneumonia was independently associated with lower risk for 90-day readmission.

Readmission after hospitalization for pneumonia is relatively common and is related to pneumonia pathogen characterization. Pneumonia attributed to potentially antibiotic-resistant bacteria is associated with an increased risk for 90-day readmission, whereas culture-negative pneumonia is associated with lower risk for 90-day readmission.

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Does anemia on admission predict short- and long-term outcomes in patients with acute ischemic stroke?

It is still debatable whether anemia predicts stroke outcome. To describe the characteristics of patients with acute ischemic stroke (AIS) and anemia and identify whether hemoglobin status on admission is a prognostic factor of AIS outcome. All 2439 patients of the Acute Stroke Registry and Analysis of Lausanne (ASTRAL) between January 2003 and June 2011 were selected. Demographics, risk factors, prestroke treatment, clinical, radiological and metabolic variables in patients with and without anemia according to the definition of the World Health Organization were compared. Functional disability and mortality were recorded up to 12 months from admission. Anemic patients (17.5%) were older, had lower body mass index, higher rates of coronary artery disease (CAD), atrial fibrillation, diabetes mellitus and peripheral artery disease. Anemia was associated with more severe stroke manifestations, lower systolic and diastolic blood pressure measurements, worse estimated glomerular filtration rate and elevated C-reactive protein concentrations upon admission and with increased modified Rankin scores during the follow-up. Anemic patients had higher 7-day, 3-month and 12-month mortality, which was associated with hemoglobin status and other factors, including age, CAD, stroke severity, and baseline C-reactive levels. Hemoglobin levels were inversely associated with recurrent stroke and mortality throughout the 12-month follow-up.

Anemia is common among AIS patients and is associated with cardiovascular comorbidities. Low hemoglobin status independently predicts short and long-term mortality.

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Does obstructive sleep apnea syndrome increase pedestrian injury risk in children?

To evaluate pedestrian behavior, including reaction time, impulsivity, risk-taking, attention, and decision-making, in children with obstructive sleep apnea syndrome (OSAS) compared with healthy controls. Using a case control design, 8- to 16-year-olds (n = 60) with newly diagnosed and untreated OSAS engaged in a virtual reality pedestrian environment. Sixty-one healthy children matched using a yoke-control procedure by age, race, sex, and household income served as controls. Children with OSAS were riskier pedestrians than healthy children of the same age, race, and sex. Children with OSAS waited less time to cross (P < .01). The groups did not differ in looking at oncoming traffic or taking longer to decide to cross.

Results suggest OSAS may have significant consequences on children's daytime functioning in a critical domain of personal safety, pedestrian skills. Children with OSAS appeared to have greater impulsivity when crossing streets. Results highlight the need for heightened awareness of the consequences of untreated sleep disorders and identify a possible target for pediatric injury prevention.

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Is implementation of continuous capnography associated with a decreased utilization of blood gases?

Capnography provides a continuous, non-invasive monitoring of the CO2 to assess adequacy of ventilation and provide added safety features in mechanically ventilated patients by allowing for quick identification of unplanned extubation. These monitors may allow for decreased utilization of blood gases. The objective was to determine if implementation of continuous capnography monitoring decreases the utilization of blood gases resulting in decreased charges. This is a retrospective review of a quality improvement project that compares the utilization of blood gases before and after the implementation of standard continuous capnography. The time period of April 2010 to September 2010 was compared to April 2011 to September 2011. Parameters collected included total number of blood gases analyzed, cost of blood gas analysis, ventilator and patient days. The total number of blood gases after the institution of end tidal CO2 monitoring decreased from 12,937 in 2009 and 13,171 in 2010 to 8,070 in 2011. The average number of blood gases per encounter decreased from 20.8 in 2009 and 21.6 in 2010 to 13.8 post intervention. The blood gases per ventilator day decreased from 4.94 in 2009 and 4.76 in 2010 to 3.30 post intervention. The total charge savings over a 6-month period was $880,496.

Continuous capnography resulted in a significant savings over a 6-month period by decreasing the utilization of blood gas measurements.

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Does blood PGC-1α Concentration predict Myocardial Salvage and Ventricular Remodeling After ST-segment Elevation Acute Myocardial Infarction?

Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is a metabolic regulator induced during ischemia that prevents cardiac remodeling in animal models. The activity of PGC-1α can be estimated in patients with ST-segment elevation acute myocardial infarction. The aim of the present study was to evaluate the value of blood PGC-1α levels in predicting the extent of necrosis and ventricular remodeling after infarction. In this prospective study of 31 patients with a first myocardial infarction in an anterior location and successful reperfusion, PGC-1α expression in peripheral blood on admission and at 72 hours was correlated with myocardial injury, ventricular volume, and systolic function at 6 months. Edema and myocardial necrosis were estimated using cardiac magnetic resonance imaging during the first week. At 6 months, infarct size and ventricular remodeling, defined as an increase > 10% of the left ventricular end-diastolic volume, was evaluated by follow-up magnetic resonance imaging. Myocardial salvage was defined as the difference between the edema and necrosis areas. Greater myocardial salvage was seen in patients with detectable PGC-1α levels at admission (mean [standard deviation (SD)], 18.3% [5.3%] vs 4.5% [3.9%]; P = .04). Induction of PGC-1α at 72 hours correlated with greater ventricular remodeling (change in left ventricular end-diastolic volume at 6 months, 29.7% [11.2%] vs 1.2% [5.8%]; P = .04).

Baseline PGC-1α expression and an attenuated systemic response after acute myocardial infarction are associated with greater myocardial salvage and predict less ventricular remodeling.

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Does endoscopic medial orbital fat decompression for proptosis in type 1 grave orbitopathy?

To describe the surgical technique for endoscopic medial orbital fat decompression in type 1 (lipogenic) Graves orbitopathy and report outcomes. Retrospective interventional case review. We reviewed 108 patients (206 orbits) with inactive, type 1 Graves orbitopathy without diplopia, who underwent endoscopic medial orbital fat decompression solely for proptosis reduction. Following endoscopic transethmoid medial orbital wall decompression, extraconal and intraconal orbital fat was removed with a low-suction cutting instrument. All patients were followed up for at least 12 months. Surgical time, preoperative and postoperative Hertel exophthalmometry, incidence of postoperative diplopia within 30-degree visual field in the primary gaze, and other complications were analyzed. The mean surgical time was 97.7 ± 16.7 minutes (67-136 minutes). The mean follow-up was 16.0 ± 4.2 months (12-24 months). Preoperative and postoperative proptosis values at final review were 21.1 ± 2.3 mm (17-26 mm) and 13.0 ± 0.9 mm (12-15 mm), respectively (P < .001). Median reduction in proptosis was 8.0 mm with mean of 8.2 ± 1.8 mm (4-11 mm). Symmetry to within 2 mm was achieved in 106 of 108 patients (98.1%). Twenty-five of 108 patients (23.1%) had diplopia within 30-degree visual field of the gaze, and 23 of these had complete resolution within 3 months, while the remaining 2 patients required squint surgery.

Endoscopic medial orbital fat decompression may be an effective technique for proptosis in selected patients with type 1 Graves orbitopathy and is associated with a low rate of surgically induced diplopia.

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Does lidocaine potentiate the deleterious effects of triamcinolone acetonide on tenocytes?

Local anesthetics are commonly used for the treatment of a variety of tendinopathies in combination with corticosteroids injection. The goal of this study was to evaluate the effects of lidocaine and triamcinolone acetonide (TA) on cultured rat tenocytes and to determine whether there is a synergistic effect. Rat patellar tendon-derived tenocytes were cultured with or without TA and lidocaine, and the culture without any additive served as the control. Cell morphology and cell viability were evaluated. Expressions of tenocyte-related genes were measured by qRT-PCR. TA, when exposed to tenocytes in vitro, significantly decreased cell viability. The cells cultured with TA had a flattened shape. Moreover, the expressions of tenocyte-related genes in tenocytes were markedly decreased in the TA-treated group. We found that 1% lidocaine synergistically increased the deleterious effects of TA.

Our data provide evidence of the detrimental effects of these drugs on tendon tissues. Injection of TA in combination with 1% lidocaine should be used with caution.

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Is pKCε a negative regulator of PVAT-derived vessel formation?

Vessel formation is a crucial event in tissue repair after injury. Thus, one assumption of innovative therapeutic approaches is the understanding of its molecular mechanisms. Notwithstanding our knowledge of the role of Protein Kinase C epsilon (PKCε) in cardio-protection and vascular restenosis, its role in vessel progenitor differentiation remains elusive. Given the availability of PKCε pharmacological modulators already tested in clinical trials, the specific aim of this study is to unravel the role of PKCε in vessel progenitor differentiation, with implications in vascular pathology and vasculogenesis. Mouse Peri-Vascular Adipose Tissue (PVAT) was used as source of mesenchymal vessel progenitors. VEGF-induced differentiation of PVAT cells down-regulates both PKCε and p-PAK1 protein expression levels. PKCε overexpression and activation: i) reduced the expression levels of SMA and PECAM in endothelial differentiation of PVAT cells; ii) completely abrogated tubules formation in collagen gel assays; iii) increased the expression of p-PAK1.

PKCε negatively interferes with vessel progenitor differentiation via interaction with PAK-1.

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Does topical bFGF improve Secondary Lymphedema through Lymphangiogenesis in a Rat Tail Model?

Secondary lymphedema is a common complication of cancer therapy, but options for treating lymphedema are essentially ineffective and limited. On the contrary, lymphangiogenic growth factors accelerate lymphangiogenesis and improve lymphedema. Rat tail models of lymphedema were assigned to groups that received either daily topical basic fibroblast growth factor (bFGF) or saline (control) groups. Tail volume was measured, and the function of the lymphatic system was evaluated as the fluorescence intensity of indocyanine green every 3 days. The mRNA levels of vascular endothelial growth factor (VEGF)-C and VEGF-D and the protein levels of VEGF-C were evaluated at postoperative days (PODs) 7, 14, and 28. The subcutaneous and deep areas and lymphatic vessel density were histologically determined at PODs 7, 14, and 28. Tail volume was significantly larger in the control than in the bFGF group (P < 0.05). The intensity of indocyanine green fluorescence significantly decreased earlier in the bFGF group (P < 0.05). The mRNA and protein levels of VEGF-C were upregulated in the bFGF group at POD 14 (P < 0.01). Both subcutaneous and deep tissues gradually withered in both groups but more rapidly in the bFGF, than in the control group, reaching statistically significant differences in the subcutaneous and deeper areas at POD 14 (P < 0.05). Lymphatic vessel density was significantly higher in the bFGF than in the control group at POD 14 (P < 0.05).

Topical bFGF induces lymphangiogenesis and improves lymphedema in the rat tail model.

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Is elevated serum creatine phosphokinase associated with mortality and inotropic requirement in critically injured adults?

Hemeproteins such as free myoglobin can undergo autoxidation and catalyse lipid peroxidation, increasing oxidative stress. Creatine phosphokinase (CPK) elevation is a marker for free myoglobin after myocyte damage. Since oxidative injury is a key mechanism of injury-related organ dysfunction, we hypothesised that serum CPK levels correlate with mortality and need for inotropic medication and duration of inotropic support, i.e. shock, among critically injured patients. We conducted a retrospective review of 17,847 patients admitted to a single Trauma Intensive Care Unit over 9 years. 2583 patients with serum CPK levels were included in the analysis. Patient data were collected continuously into an electronic ICU repository. Univariate analysis was accomplished using Spearman correlation and the Mann–Whitney U test. Propensity score adjustment models accounting for potential confounders were used to assess the independent effect of CPK level on mortality, need for inotropic support, and duration of inotropic support. Median CPK was significantly higher in patients who died (916 [IQR 332, 2472] vs. 711 [253, 1971], p = 0.004) and in those who required inotropic medications (950 [353, 2525] vs. 469 [188, 1220], p < 0.001). After adjusting for propensity score and potential confounders the odds of mortality increased by 1.10 (95% CI 1.02–1.19, p = 0.020) and the odds of inotropic medication use increased by 1.30 (95% CI 1.22–1.38, p < 0.001) per natural log unit increase in CPK. There was a significant association between CPK level and duration of inotropic support (Spearman's rho .237, p < 0.001) that remained significant in a propensity score-adjusted model.

In critically injured patients, elevated serum CPK level is independently associated with mortality, need for inotropic medication, and duration of inotropic support. This study is the first to evaluate the relationship of CPK level and mortality in addition to surrogate measures of shock in a population of critically injured patients. If these associations are verified prospectively, there may be a role for treatment with hemeprotein reductants, such as paracetamol, to mitigate the effects of shock and end-organ dysfunction.

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Does thalidomide control adipose tissue inflammation associated with high-fat diet-induced obesity in mice?

Immunosuppressant agents modulate the activity of the immune system and control adipose tissue inflammatory responses associated with obesity. Controlling adipose tissue inflammation represents an interesting option for inhibiting the low-grade inflammatory state in obese subjects and for preventing obesity-associated pathologies. In this work, we assessed the effects of thalidomide on the inflammatory response in adipose tissue as well as on systemic inflammatory marker expression in the well-established high-fat diet-induced obesity mouse model. Swiss male mice were fed a high-fat diet (60% kcal from fat) for 12 weeks and received thalidomide for the last 10 days (100 mg.kg-1). Adipokine levels were measured in serum and adipose tissue by EIA and real-time quantitative PCR, respectively. Adipose tissue infiltrating macrophages were identified by immunohistochemistry and western blot analysis of F4/80 marker expression. Other inflammatory markers, such as c-Jun N-terminal kinase (JNK) phosphorylation and monocyte chemoattractant protein-1 (MCP-1) production, were also evaluated by western blot analysis. In vitro assays using 3T3-L1 adipocytes were also conducted to evaluated adipokine release. In obese mice, thalidomide administration induced a reduction in adiposity accompanied by a reduction of tumor necrosis factor-α (TNF-α), leptin and MCP-1 adipose tissue production, macrophage infiltration and JNK activation. TNF-α and leptin serum levels were also reduced by thalidomide treatment in obese mice. In vitro, the release of basal TNF-α and lipopolysaccharide (LPS)-induced MCP-1 was inhibited in 3T3-L1 cells.

Our results suggest that drugs that can modulate the inflammatory status as well as control adipose tissue expansion could represent an interesting approach in the management of obesity, highlighting the need for further development of such compounds.

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Does mild-to-moderate intensity exercise improve cardiac autonomic drive in type 2 diabetes?

The aim of the present study was to determine the effect of moderate aerobic exercise on cardiac autonomic function in type 2 diabetic patients. Heart rate variability of 20 patients with type 2 diabetes was assessed. Resting electrocardiogram for the heart rate variability analysis at spontaneous respiration was recorded for 5 min in the supine position before and after 6 months of supervised aerobic training given three times per week. In time domain measures, the square root of the mean of the sum of the squares of differences between adjacent R-R intervals (RMSSD; 29.7 [26-34.5] vs 46.4 [29.8-52.2] ms, P = 0.023) and the percentage of consecutive RR intervals that differ by more than 50 ms (pNN50; 10.7 [5.5-12.7] vs 26.1 [6.6-37.2]%, P = 0.025] were significantly increased after exercise. In frequency domain measures, low frequency (62.4 [59.1-79.2] vs 37 [31.3-43.3] nu, P = 0.003) and low frequency/high frequency (1.67 [1.44-3.8] vs 0.58 [0.46-0.59]%, P = 0.009) were significantly decreased, whereas high frequency (95 [67-149] vs 229 [98-427] ms(2), P = 0.006) and high frequency (37.6 [20.8-40.9] vs 63 [56.7-68.7] normalized units, P = 0.003) were significantly increased after exercise. In a Poincaré plot, standard deviation perpendicular to the line of the Poincaré plot (SD1; 21.3 [18.5-24.8]-33.1 [21.5-37.2] ms, P = 0.027) was significantly increased after exercise.

These data suggest that three times per week moderate intensity aerobic exercise for 6 months improves cardiac rhythm regulation as measured by heart rate variability in type 2 diabetic patients.

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Is severity of hearing impairment positively associated with urine albumin excretion rate in patients with type 2 diabetes?

To identify risk factors for hearing impairment among patients with type 2 diabetes mellitus. A total of 68 patients with type 2 diabetes were enrolled between March and September of 2011. Pure-tone auditory tests were carried out for each patient at the following speech frequencies: 250; 500; 1,000; 2,000; 4,000 and 8,000 Hz. Participants were classified as having hearing impairment if the average of the pure-tone thresholds measured at 500, 1000 and 2000 Hz in either ear exceeded 25 dBHL. Demographic, anthropometric, clinical, and laboratory parameters and diabetes-associated complications were analyzed. Patients were divided into those with (n = 32) and without (n = 36) hearing impairment. Hearing impaired participants had a higher urine albumin-to-creatinine ratio than those without (223.1 vs 56.5 mg/g, respectively). After adjustment for age, sex and other risk factors, the urine albumin-to-creatinine ratio remained significantly associated with hearing impairment (odds ratio 9.07, 95% confidence interval 1.73-47.43, P = 0.009). There were no significant differences in oxidative stress between the two groups.

The present study showed increased albuminuria was positively associated with the severity of hearing impairment among patients with type 2 diabetes. Screening for hearing impairment in diabetic patients who develop albuminuria might provide early detection of hearing impairment.

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Are in Rasmussen encephalitis , hemichannels associated with microglial activation linked to cortical pyramidal neuron coupling : a possible mechanism for cellular hyperexcitability?

Rasmussen encephalitis (RE) is a rare but devastating condition, mainly in children, characterized by sustained brain inflammation, atrophy of one cerebral hemisphere, epilepsy, and progressive cognitive deterioration. The etiology of RE-induced seizures associated with the inflammatory process remains unknown. Cortical tissue samples from children undergoing surgical resections for the treatment of RE (n = 16) and non-RE (n = 12) were compared using electrophysiological, morphological, and immunohistochemical techniques to examine neuronal properties and the relationship with microglial activation using the specific microglia/macrophage calcium-binding protein, IBA1 in conjunction with connexins and pannexin expression. Compared with non-RE cases, pyramidal neurons from RE cases displayed increased cell capacitance and reduced input resistance. However, neuronal somatic areas were not increased in size. Instead, intracellular injection of biocytin led to increased dye coupling between neurons from RE cases. By Western blot, expression of IBA1 and pannexin was increased while connexin 32 was decreased in RE cases compared with non-RE cases. IBA1 immunostaining overlapped with pannexin and connexin 36 in RE cases.

In RE, these results support the notion that a possible mechanism for cellular hyperexcitability may be related to increased intercellular coupling from pannexin linked to increased microglial activation. Such findings suggest that a possible antiseizure treatment for RE may involve the use of gap junction blockers.

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Do genome-wide ancestry patterns in Rapanui suggest pre-European admixture with Native Americans?

Rapa Nui (Easter Island), located in the easternmost corner of the Polynesian Triangle, is one of the most isolated locations on the planet inhabited by humans. Archaeological and genetic evidence suggests that the island was first colonized by Polynesians around AD 1200, during their eastward expansion. Although it remains contentious whether Polynesians reached South America, suggestive evidence has been brought forward supporting the possibility of Native American contact prior to the European "discovery" of the island in AD 1722. We generated genome-wide data for 27 Rapanui. We found a mostly Polynesian ancestry among Rapanui and detected genome-wide patterns consistent with Native American and European admixture. By considering the distribution of local ancestry tracts of eight unrelated Rapanui, we found statistical support for Native American admixture dating to AD 1280-1495 and European admixture dating to AD 1850-1895.

These genetic results can be explained by one or more pre-European trans-Pacific contacts.

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Are serum neutrophil gelatinase-associated lipocalin levels correlated with the complexity and the severity of atherosclerosis in acute coronary syndrome?

Neutrophil gelatinase-associated lipocalin (NGAL) is a novel inflammatory marker that is released from neutrophils. In this study, we evaluated the correlation between serum NGAL level and clinical and angiographic risk scores in patients diagnosed with non-ST elevation acute coronary syndrome (NSTE-ACS). Forty-seven random NSTE-ACS patients and 45 patients with normal coronary arteries (NCA) who underwent coronary angiography were enrolled in the study. GRACE risk score and SYNTAX and Gensini risk scores were used, respectively, for the purpose of clinical risk assessment and angiographic risk scoring. Serum NGAL level was measured via ELISA in peripheral blood samples obtained from the patients at the time of admission. Serum NGAL level was significantly higher in the NSTE-ACS group compared to the control group (112.3±49.6 ng/mL vs. 58.1±24.3 ng/mL, p<0.001). There was a significant positive correlation between serum NGAL levels and the GRACE (r=0.533 and p<0.001), SYNTAX (r=0.395 and p=0.006), and Gensini risk scores (r=0.575 and p<0.001). The intermediate-high SYNTAX (>22) group had statistically significantly higher serum NGAL levels compared to the low SYNTAX (≤22) group (143±29.5 ng/mL vs. 98.7±43.2 ng/mL, p=0.001).

NGAL level was positively correlated with lesion complexity and severity of coronary artery disease in patients with NSTE-ACS. Serum NGAL levels on admission are associated with increased burden of atherosclerosis in patients with NSTE-ACS.

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Does early tracheostomy in trauma patients save time and money?

Patients suffering traumatic brain and chest wall injuries are often difficult to liberate from the ventilator yet best timing of tracheostomy remains ill-defined. While prior studies have addressed early versus late tracheostomy, they generally suffer from the use of historical controls, which cannot account for variations in management over time. Propensity scoring can be utilized to identify controls from the same patient population, minimizing impact of confounding variables. The purpose of this study was to determine outcomes associated with early versus late tracheostomy by application of propensity scoring. Patients requiring intubation within 48h and receiving tracheostomy from January 2010 to June 2012 were identified. Early tracheostomy (ET) was a tracheostomy performed by the fifth hospital day. ET patients were matched to late tracheostomy patients (LT, tracheostomy after day 5) using propensity scoring and compared for multiple outcomes. Cost for services was calculated using average daily billing rates at our institution. One hundred and six patients were included, 53 each in the ET (mean day tracheostomy=4) and the LT (mean day tracheostomy=10) cohorts. The average age was 47 years and 94% suffered blunt injury, with an average NISS of 23.7. Patients in the ET group had significantly shorter TICU LOS (21.4 days vs. 28.6 days, p<0.0001) and significantly fewer ventilator days (16.7 days vs. 21.9, p<0.0001) compared to the LT group. ET patients also had significantly less VAP (34% vs. 64.2%, p=0.0019).

In the current era of increased health-care costs, early tracheostomy significantly decreased both pulmonary morbidity and critical care resource utilization. This translates to an appreciable cost savings, at minimum $52,173 per patient and a potential total savings of $2.8million/year for the entire LT cohort. For trauma patients requiring prolonged ventilator support, early tracheostomy should be performed.

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Is troponin-I a predictor of a delayed diagnosis of atrial fibrillation in acute ischemic stroke and transient ischemic attack?

Prolonged cardiac monitoring detects higher rates of atrial fibrillation (AF) in ischemic stroke and transient ischemic attack (TIA) but is costly and has practical implications. The use of admission troponin-I (TnI) level to identify patients at high risk of delayed AF detection was investigated. Consecutive ischemic stroke and TIA cases presenting to our institute over a 13-month period were identified from the Irish Stroke and TIA Register. Electronic databases and case notes were examined. "Delayed" AF was diagnosed after a sinus rhythm admission electrocardiogram and no documented history. Group comparisons were made by AF status. The association between TnI and AF was investigated using a multivariate regression model. A total of 185 cases (130 ischemic stroke) were analyzed. Mean age (standard deviation) was 73.3 (13.9) years, 47% female. Sixty-two cases (33.5%) had AF. The first documented presentation of AF was found in 21 cases, on admission electrocardiogram (n = 11) or inpatient telemetry (delayed, n = 10). TnI was higher in those with delayed AF than in those without AF (W = 194; P = .036). A higher proportion of those with an elevated TnI (30%) than those with a normal TnI (6.1%) had delayed diagnosis of AF (χ(2) = 6.41, P = .011). Having an abnormal TnI was a significant independent predictor of delayed AF detection (odds ratio, 5.8; P = .037).

TnI elevation is associated with a higher likelihood of subsequent AF diagnosis. Identification of these higher risk stroke and TIA cases for more intensive cardiac monitoring may improve stroke secondary prevention practices.

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Does borax partially prevent neurologic disability and oxidative stress in experimental spinal cord ischemia/reperfusion injury?

The aim of this study is to investigate the potential effects of borax on ischemia/reperfusion injury of the rat spinal cord. Twenty-one Wistar albino rats were divided into 3 groups: sham (no ischemia/reperfusion), ischemia/reperfusion, and borax (ischemia/reperfusion + borax); each group was consist of 7 animals. Infrarenal aortic cross clamp was applied for 30 minutes to generate spinal cord ischemia. Animals were evaluated functionally with the Basso, Beattie, and Bresnahan scoring system and inclined-plane test. The spinal cord tissue samples were harvested to analyze tissue concentrations of nitric oxide, nitric oxide synthase activity, xanthine oxidase activity, total antioxidant capacity, and total oxidant status and to perform histopathological examination. At the 72nd hour after ischemia, the borax group had significantly higher Basso, Beattie, and Bresnahan and inclined-plane scores than those of ischemia/reperfusion group. Histopathological examination of spinal cord tissues in borax group showed that treatment with borax significantly reduced the degree of spinal cord edema, inflammation, and tissue injury disclosed by light microscopy. Xanthine oxidase activity and total oxidant status levels of the ischemia/reperfusion group were significantly higher than those of the sham and borax groups (P < .05), and total antioxidant capacity levels of borax group were significantly higher than those of the ischemia/reperfusion group (P < .05). There was not a significantly difference between the sham and borax groups in terms of total antioxidant capacity levels (P > .05). The nitric oxide levels and nitric oxide synthase activity of all groups were similar (P > .05).

Borax treatment seems to protect the spinal cord against injury in a rat ischemia/reperfusion model and improve neurological outcome.

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Does proteinuria predict postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate?

Acute kidney injury is a common and serious problem after cardiac surgery. Postoperative acute kidney injury is independently associated with in-hospital mortality and long-term morbidity, even after adjustment for comorbid diseases. Chronic kidney disease has been recognized as a strong risk factor of acute kidney injury after cardiac surgery. The association between proteinuria and postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate remains uncertain. Patients with an estimated glomerular filtration rate greater than 60 mL/min/1.73 m(2) who underwent cardiac surgery between January 2003 and December 2007 in a tertiary medical center were retrospectively analyzed. Dipstick urinalysis was performed before surgery. Proteinuria was categorized into negative, trace, 1+, 2+, or 3+. Postoperative acute kidney injury was defined by the Acute Kidney Injury Network criteria. Multinomial logistic regression was used to clarify whether proteinuria is an independent risk factor of postoperative acute kidney injury. A total of 1246 patients were included in this study, with a mean estimated glomerular filtration rate of 80 ± 13 mL/min/1.73 m(2). Proteinuria was present in 290 patients (23.4%). Postoperative acute kidney injury developed in 434 patients (34.8%), and 36 patients (2.9%) required renal replacement therapy. Proteinuria was independently associated with all stages of postcardiotomy acute kidney injury and dialysis-requiring acute kidney injury. The crude risk of acute kidney injury was greater in patients with a higher grade of proteinuria. In subgroup analysis for gender, diabetes, and surgical type, preoperative proteinuria remains a strong risk factor of acute kidney injury after cardiac surgery.

Urine analysis is usually neglected before cardiac surgery despite the fact that proteinuria is the earliest manifestation of kidney dysfunction. In the current study, we show that urine protein is strongly and independently associated with postoperative acute kidney injury in subjects with preserved estimated glomerular filtration rate. These data suggest that such a relatively simple and clinically easy to use tool as a urinary dipstick may be useful to identify patients at high risk of acute kidney injury before cardiac surgery.

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Does ultrasound shear wave elastography help discriminate low-grade from high-grade bowel wall fibrosis in ex vivo human intestinal specimens?

To determine whether bowel wall fibrosis can be detected in freshly resected human intestinal specimens based on ultrasound-derived shear wave speed. Seventeen intact (>3-cm) bowel segments (15 small and 2 large intestine) from 12 patients with known or suspected inflammatory bowel disease were procured immediately after surgical resection. Ultrasound shear wave elastography of the bowel wall was performed by two methods (Virtual Touch Quantification [VTQ] and Virtual Touch-IQ [VT-IQ]; Siemens Medical Solutions USA, Inc, Mountain View, CA). Eighteen short-axis shear wave speed measurements were acquired from each specimen: 3 from the 9-, 12-, and 3-o'clock locations for each method. Imaging was performed in two areas for specimens greater than 10 cm in length (separated by ≥5 cm). A gastrointestinal pathologist scored correlative histologic slides for inflammation and fibrosis. Differences in mean shear wave speed between bowel segments with low and high inflammation/fibrosis scores were assessed by a Student t test. Receiver operating characteristic curve analysis was performed. High-fibrosis score (n = 11) bowel segments had a significantly greater mean shear wave speed than low-fibrosis score (n = 6) bowel segments (mean ± SD: VTQ, 1.59 ± 0.37 versus 1.18 ± 0.08 m/s; P= .004; VT-IQ, 1.87 ± 0.44 versus 1.50 ± 0.26 m/s; P= .049). There was no significant difference in mean shear wave speed between high-and low-inflammation score bowel segments (P > .05 for both VTQ and VT-IQ). Receiver operating characteristic curves showed areas under the curve of 0.91 (95% confidence interval, 0.67-0.99) for VTQ and 0.77 (95% confidence interval, 0.51-0.94) for VT-IQ in distinguishing low-from high-fibrosis score bowel segments.

Ex vivo bowel wall shear wave speed measurements increase when transmural intestinal fibrosis is present.

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Do b-type natriuretic peptides improve cardiovascular disease risk prediction in a cohort of women?

Although N-terminal pro-B-type natriuretic peptide (NT-proBNP) has a strong relationship with incident cardiovascular disease (CVD), few studies have examined whether NT-proBNP adds to risk prediction algorithms, particularly in women. This study sought to evaluate the relationship between NT-proBNP and incident CVD in women. Using a prospective case-cohort within the WHI (Women's Health Initiative) observational study, we selected 1,821 incident cases of CVD (746 myocardial infarctions, 754 ischemic strokes, 160 hemorrhagic strokes, and 161 other cardiovascular [CV] deaths) and a randomly selected reference cohort of 1,992 women without CVD at baseline. Median levels of NT-proBNP were higher at study entry among incident cases (120.3 ng/l [interquartile range (IQR): 68.1 to 219.5 ng/l]) than among control subjects (100.4 ng/l [IQR: 59.7 to 172.6 ng/l]; p < 0.0001). Women in the highest quartile of NT-proBNP (≥140.8 ng/l) were at 53% increased risk of CVD versus those in the lowest quartile after adjusting for traditional risk factors (1.53 [95% confidence interval (CI): 1.21 to 1.94]; p for trend <0.0001). Similar associations were observed after adjustment for Reynolds Risk Score covariables (1.53 [95% CI: 1.20 to 1.95]; p for trend <0.0001); the association remained in separate analyses of CV death (2.66 [95% CI: 1.48 to 4.81]; p for trend <0.0001), myocardial infarction (1.39 [95% CI: 1.02 to 1.88]; p for trend = 0.008), and stroke (1.60 [95% CI: 1.22 to 2.11]; p for trend <0.0001). When added to traditional risk covariables, NT-proBNP improved the c-statistic (0.765 to 0.774; p = 0.0003), categorical net reclassification (0.08; p < 0.0001), and integrated discrimination (0.0105; p < 0.0001). Similar results were observed when NT-proBNP was added to the Reynolds Risk Score.

In this multiethnic cohort of women with numerous CV events, NT-proBNP modestly improved measures of CVD risk prediction.

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Do novel markers predict death and organ failure following hemorrhagic shock?

ADAMTS 13, sP-Selectin and HSP27 have been investigated as potential prognostic markers in patients with hemorrhagic shock. This study was part of a double-blind, randomized, parallel-group, controlled trial and included seventeen trauma patients presented to ED with severe hemorrhagic. The sera for testing were collected from these patients at the time of admission. Investigators and laboratory personnel performing testing were blinded to the patients' identity and clinical course. The prognostic value of ADAMTS13, sP-Selectin, and HSP27 was compared to prognostic value of systolic blood pressure (SBP), base deficit estimation (BD), heart rate (HR), shock index (SI) and tissue oxygen saturation (StO2) by constructing the receiver operation characteristics (ROC). The area under the curve (AUC) of the ROC for HSP27 (0.92) was greater than for SBP (0.45), BD (0.89), HR (0.61), SI (0.45) and StO2 (0.46). AUC for sP-Selectin (0.86) and for ADAMTS13 antigen (0.74) were comparable with BD one, but greater than for the rest of currently used tests.

Serum concentrations of ADAMTS13, HSP27 and sP-Selectin measured during the admission, appear to be comparable to or better than SBP, BD, SI, HR and StO2 in predicting MODS and death after hemorrhage from trauma. These potential new markers deserve further investigation.

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Is the diagnosis of inflammatory bowel disease often unsupported in clinical practice?

The diagnosis of inflammatory bowel disease can be challenging and requires the efforts of a multidisciplinary team. We performed a retrospective analysis with the aim of evaluating the adequacy of the prerequisites for arriving at an accurate histological diagnosis. The following parameters were considered as prerequisites for a diagnosis of inflammatory bowel disease: clinical and endoscopic data; proper sampling and handling of biopsies; and elementary microscopic lesions. We collected 345 cases from 13 centres. The date of onset and treatment were available for 13% and 16% of the cases, respectively. Endoscopy information was accessible for 77% of the cases. Endoscopic mapping was completed in 13% of the cases. In no cases were the biopsies oriented on acetate strips. The diagnosis was conclusive in 47% of the cases. Activity, epithelial disruption and crypt distortion were described in 35% of the reports with a conclusive diagnosis.

Our study showed that the diagnostic prerequisites were widely unfulfilled, although approximately half of the diagnoses were conclusive for inflammatory bowel disease. Thus, in our assessment of clinical practice: (1) clinicians seldom provide suitable clinical and/or endoscopic information for a histological diagnosis and (2) histopathological diagnoses of inflammatory bowel disease are often not supported by morphology.

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Does transjugular intrahepatic portosystemic shunt placement increase feasibility of colorectal surgery in cirrhotic patients with severe portal hypertension?

Colorectal resection in cirrhotic patients is associated with high mortality and morbidity related to portal hypertension and liver insufficiency. This retrospective study evaluated the clinical outcomes of cirrhotic patients who underwent transjugular intrahepatic porto-systemic shunt (TIPS) placement before colorectal resection for cancer. Main outcomes measures were postoperative morbidity and mortality rates. TIPS placement was successful in all eight patients and significantly decreased the mean hepatic venous pressure gradient from 15.5 ± 2.9 to 7.5 ± 1.9 mmHg (p = 0.02). Surgical procedures included right colectomy (n = 3), left colectomy (n = 2), and proctectomy with total mesorectal excision (n=3). Post-operatively, two patients (25%) died of multiple organ failure. The overall postoperative morbidity rate was 75%, and major complications were seen in 25%.

Portal decompression via TIPS placement may enable selected cirrhotic patients with severe portal hypertension to undergo colorectal resection for cancer.

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Does pentoxifylline associated to hypertonic saline solution attenuate inflammatory process and apoptosis after intestinal ischemia/reperfusion in rats?

To evaluate intestinal inflammatory and apoptotic processes after intestinal ischemia/reperfusion injury, modulated by pentoxifylline and hypertonic saline. It was allocated into four groups (n=6), 24 male Wistar rats (200 to 250 g) and submitted to intestinal ischemia for 40 min and reperfusion for 80 min: IR (did not receive any treatment); HS group (Hypertonic Saline, 4 ml/kg-IV); PTX group (Pentoxifylline, 30 mg/kg-IV); HS+PTX group (Hypertonic Saline and Pentoxifylline). All animals were heparinized (100 U/kg). At the end of reperfusion, ileal fragments were removed and stained on hematoxylin-eosin and histochemical studies for COX-2, Bcl-2 and cleaved caspase-3. The values of sO2 were higher on treated groups at 40 minutes of reperfusion (p=0.0081) and 80 minutes of reperfusion (p=0.0072). Serum lactate values were lower on treated groups after 40 minutes of reperfusion (p=0.0003) and 80 minutes of reperfusion (p=0.0098). Morphologic tissue injuries showed higher grades on IR group versus other groups: HS (p=0.0006), PTX (p=0.0433) and HS+PTX (p=0.0040). The histochemical study showed lesser expression of COX-2 (p=0.0015) and Bcl-2 (p=0.0012) on HS+PTX group. A lower expression of cleaved caspase-3 was demonstrated in PTX (p=0.0090; PTXvsIR).

The combined use of pentoxifylline and hypertonic saline offers best results on inflammatory and apoptotic inhibitory aspects after intestinal ischemia/reperfusion.

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Is pattern of first recurrent lesions in pancreatic cancer : hepatic relapse associated with dismal prognosis and portal vein invasion?

The aim of this study was to evaluate patterns of the initial recurrence after pancreatectomy for pancreatic cancer and risk factors in each pattern. This study included 209 pancreatic cancer patients who underwent pancreatectomy and of whom the detailed information on the first recurrent lesions detected by imaging during postoperative followup were available. Relapse patterns were classified into 4 groups: liver, peritoneal, local and extra-abdominal recurrences. We evaluated their associations with prognosis and various clinicopathological factors to identify relevant risk factors. Cumulative numbers of patients with liver, peritoneal, local, and extra-abdominal recurrences were 81, 70, 98 and 22, respectively, for the first recurrences. Hepatic relapse was associated with significantly shorter overall survival than other sites (p<0.001) and was an independent prognostic factor in multivariate analysis (p<0.001). Pathological portal vein invasion was the only independent risk factor for hepatic relapse (p=0.045). There was no significant correlation between the depth of invasion and prevalence of hepatic relapse.

Hepatic relapse was associated with a dismal prognosis and with pathological portal vein invasion. Novel therapeutic strategies are therefore required to reduce the incidence of hepatic relapse, especially in patients with portal vein invasion.

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Does first registry result from the newly approved ACURATE TA™ TAVI system†?

The novel ACURATE TA™ transcatheter aortic valve (Symetis, Ecublens, Switzerland) is composed of a self-expanding nitinol stent covered by an anti-paravalvular leak skirt designed for transapical implantation. Since Conformite Europeenne (CE)-mark approval, the first 250 patients implanted with the newly approved device have been included in this post-market, multicentre registry. The registry was conducted at 17 sites in Germany, Italy, Switzerland and Argentina to treat 250 high-risk elderly patients. This all-comers population presented preoperatively with a mean aortic gradient of 43.2 ± 17.4 mmHg, mean age of 80.9 ± 6.3 years, mean society of thoracic surgeons risk score of 8.0 ± 5.9% and mean logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 22.3 ± 12.7%. The majority of patients (93%) were in New York Heart Association (NYHA) class III/IV. All patients were treated within a multidisciplinary Heart Team. The procedural success rate was 98% (n = 245) with two valve-in-valve procedures and three conversions to conventional surgery. The 30-day mortality rate was 6.8%. Postimplant echocardiography revealed a relevant paravalvular leak (moderate 2+) in 2.3% of patients, with all other patients demonstrating either none/trace or a 1+ leak. The 30-day stroke rate was 2.8% and the mean transvalvular gradient was 12.4 ± 5.8 mmHg. A new pacemaker implantation was required in 10.0% of patients and 85% of patients returning for the follow-up presented in NYHA class I/II.

The short-term result of the registry shows a safety and efficacy profile comparable, if not improved in some aspects, with previously approved transcatheter aortic valve implantation devices. These 'real-world' data highlight an excellent functional outcome, especially in regard to a low rate of relevant paravalvular leak.

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Does phosphorylation of BK channels modulate the sensitivity to hydrogen sulfide ( H2S )?

Gases, such as nitric oxide (NO), carbon monoxide (CO), or hydrogen sulfide (H2S), termed gasotransmitters, play an increasingly important role in understanding of how electrical signaling of cells is modulated. H2S is well-known to act on various ion channels and receptors. In a previous study we reported that H2S increased calcium-activated potassium (BK) channel activity. The goal of the present study is to investigate the modulatory effect of BK channel phosphorylation on the action of H2S on the channel as well as to recalculate and determine the H2S concentrations in aqueous sodium hydrogen sulfide (NaHS) solutions. Single channel recordings of GH3, GH4, and GH4 STREX cells were used to analyze channel open probability, amplitude, and open dwell times. H2S was measured with an anion selective electrode. The concentration of H2S produced from NaHS was recalculated taking pH, temperature salinity of the perfusate, and evaporation of H2S into account. The results indicate that from a concentration of 300 μM NaHS, only 11-13%, i.e., 34-41 μM is effective as H2S in solution. GH3, GH4, and GH4 STREX cells respond differently to phosphorylation. BK channel open probability (Po) of all cells lines used was increased by H2S in ATP-containing solutions. PKA prevented the action of H2S on channel Po in GH4 and GH4 STREX, but not in GH3 cells. H2S, high significantly increased Po of all PKG pretreated cells. In the presence of PKC, which lowers channel activity, H2S increased channel Po of GH4 and GH4 STREX, but not those of GH3 cells. H2S increased open dwell times of GH3 cells in the absence of ATP significantly. A significant increase of dwell times with H2S was also observed in the presence of okadaic acid.

Our results suggest that phosphorylation by PKG primes the channels for H2S activation and indicate that channel phosphorylation plays an important role in the response to H2S.

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Is cognitive reserve a determinant of health-related quality of life in patients with cirrhosis , independent of covert hepatic encephalopathy and model for end-stage liver disease score?

Covert hepatic encephalopathy (CHE) is associated with cognitive dysfunction, which affects daily function and health-related quality of life (HRQOL) in patients with cirrhosis. The effects of CHE and liver disease are determined by cognitive reserve—the ability of the brain to cope with increasing damage while continuing to function—and are assessed by composite intelligence quotient (IQ) scores. We examined cognitive reserve as a determinant of HRQOL in patients with cirrhosis. We performed a prospective study of 118 outpatients with cirrhosis without overt HE (age, 56 y). We studied cognition using the standard paper-pencil battery; patients with below-normal results for more than 2 tests were considered to have CHE. We also assessed HRQOL (using the sickness impact profile [SIP]), psychosocial and physical scores (a high score indicates reduced HRQOL), model for end-stage liver disease (MELD) scores, and cognitive reserve (using the Barona Index, a validated IQ analysis, based on age, race, education, residence area, and occupation). Cognitive reserve was divided into average and high groups (<109 or >109), and MELD and SIP scores were compared. We performed regression analyses, using total SIP score and psychosocial and physical dimensions as outcomes, with cognitive reserve, CHE, and MELD score as predictors. Study participants had average MELD scores of 9, and 14 years of education; 81% were white, 63% were urban residents, their mean IQ was 108 ± 8, and 54% had average cognitive reserve (the remaining 46% had high reserves). CHE was diagnosed in 49% of patients. Cognitive reserve was lower in patients with CHE (109) than without (105; P = .02). Cognitive reserve correlated with total SIP and psychosocial score (both r = -0.4; P < .001) and physical score (r = -0.3; P = .01), but not MELD score (P = .8). Patients with high cognitive reserve had a better HRQOL, despite similar MELD scores. In regression analyses, cognitive reserve was a significant predictor of total SIP (P < .001), psychosocial (P < .001), and physical scores (P < .03), independent of CHE, MELD, or psychiatric disorders.

A higher cognitive reserve is associated with a better HRQOL in patients with cirrhosis, despite similar disease severity and prevalence. This indicates that patients with good cognitive reserve are better able to withstand the demands of cirrhosis progression and CHE, leading to a better HRQOL. Patients with lower cognitive reserve may need more dedicated and earlier measures to improve HRQOL. Cognitive reserve should be considered when interpreting HRQOL and cognitive tests to evaluate patients with cirrhosis.

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Does use of PET-CT for the assessment of treatment result in patients with sarcoidosis?

Sarcoidosis is a multisystem disease of unknown origin. Determining the involvement and the response to the treatment is important. The aim of this study was to identify the effects of methylprednisolone and indomethacine on metabolic activity and pulmonary function test parameters in patients with sarcoidosis. A total of 24 pulmonary sarcoidosis patients were enrolled in the study. All the patients underwent spirometry and [(18)F]fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) scan before treatment and were divided into two groups according to the necessity of corticosteroid treatment or not. Patients who did not have corticosteroid indication were treated with indomethacine. Symptomatic patients and patients who did not respond to indomethacine treatment received methylprednisolone. Patients were followed up on a monthly basis to determine the response. FDG uptakes as the disease activity were re-evaluated before ending the treatment at the sixth month. Mean age of patients (16 male, 8 female) was 39.79 (9.3) years. Besides mediastinum and pulmonary parenchyma, extrapulmonary sites were also involved in patients with pulmonary sarcoidosis (distant lymph nodes (upper abdominal, supraclavicular, inguinal, and axillary), liver, and spleen). Although maximum standard uptake values of methylprednisolone group regressed significantly (p < 0.001) after treatment, indomethacine group did not have significant regression (p = 0.345). Despite metabolic regressions, spirometry values of patients did not significantly increase (p > 0.005).

FDG PET-CT may be useful for determining activity and the efficacy of treatments. Methylprednisolone is effective in reducing metabolic activity but does not lead to improvement in functional parameters.

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Does energy replacement using glucose increase postprandial lipemia after moderate intensity exercise?

Aerobic exercise can decrease postprandial triglyceride (TG) concentrations but the relationship between exercise-induced energy deficits and postprandial lipemia is still unclear. The aim of the present study was to examine the effect of a single bout of aerobic exercise, with and without energy replacement, on postprandial lipemia and on peripheral blood mononuclear cell (PBMC) mRNA expression of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) receptors and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Nine healthy male humans completed three two-day trials in a random order. On day 1, volunteers rested (CON), completed 60 minutes of treadmill walking at 50% of VO2peak (EX) or completed the same bout of walking but with the energy replaced afterwards with a glucose solution (EXG). On day 2, volunteers rested and consumed a high fat test meal in the morning. Total and incremental TG AUC were significantly lower on the EXG (P < 0.05) and EX (P < 0.05) trials than the CON trial with no difference between the two exercise trials. No significant difference was observed in VLDL or LDL receptor mRNA expression among the trials (P > 0.05).

In conclusion, energy replacement by glucose did not affect the decrease in postprandial TG concentrations observed after moderate intensity exercise and exercise does not affect changes in PBMC HMGCR, VLDL and LDL receptor mRNA expression.

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Is circulating retinol binding protein 4 associated with coronary lesion severity of patients with coronary artery disease?

This study was to examine the association between plasma retinol binding protein 4 (RBP4) levels and the complexity of angiographic coronary lesion in patients with coronary artery disease (CAD). A cross-sectional and prospective study was carried out in Guangzhou Chinese population. 672 persons were evaluated by medical history, clinical examination, coronary angiography, and fasting plasma samples, and were followed prospectively for 3 years. We measured the plasma RBP4 levels in 447 women (201 with stable CAD and 246 with acute coronary syndrome [ACS]). Coronary lesions were classified as having a simple or complex appearance based on the visual estimation of the coronary angiograms. Median plasma RBP4 levels were significantly higher in stable CAD patients with complex coronary lesions (n = 84) than in those with simple lesions (n = 117) (38.78[range 32.65-46.91] vs. 30.78 [range 24.48-36.08] μg/ml, P < 0.001). Multiple logistic regression analysis demonstrated that higher RBP4 levels were independently associated with a 23% higher risk for complex lesions (odds ratio 1.228, 95% confidence interval [CI] 1.061 to 1.358; P = 0.031). Among the ACS patients, who had higher RBP4 levels than the stable CAD patients, those with multiple complex lesions had significantly higher median RBP4 levels than those with a single complex lesion (46.47 μg/ml [range 37.68-53.29] vs. 38.15 μg/ml [range 32.26-44.56], P < 0.001). Total plasma RBP4 levels were predictors of cardiac death (hazard ratio [HR]: 1.102; 95% CI: 1.086 to 1.191; P = 0.012) after adjustment for traditional risk factors for CAD.

Plasma RBP4 levels are significantly associated with coronary lesion complexity in women with stable CAD and ACS and predict incident cardiovascular events.

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Is a high quality diet associated with reduced systemic inflammation in middle-aged individuals?

To examine if overall diet quality is associated with cellular and soluble biomarkers of systemic inflammation in middle-aged individuals. A group of 667 individuals, aged 63-68 years, selected from the cardiovascular arm of the Malmö Diet and Cancer cohort, participated in this study. Baseline examinations consisted of an extensive socio-demographic questionnaire, anthropometric measurements, blood sampling and detailed dietary data. Mononuclear leukocytes frozen at baseline were thawed and analysed with flow cytometry to quantify monocyte subsets based on CD14 and CD16 expression. Plasma cytokines were measured using multiplexed immune assays. A diet quality index consisting of six components (saturated fatty acids, polyunsaturated fatty acids, fish and shellfish, dietary fibre, fruit and vegetables, and sucrose) was constructed to measure adherence to the Swedish Nutrition Recommendations/Dietary Guidelines. General linear models were used to investigate associations between index scores and several biomarkers of inflammation. A higher percentage of women reported adherence to the nutritional recommendations and had better overall diet quality than men. Participants with higher diet quality were more likely to have a healthier lifestyle. The levels of high-sensitive CRP, S100A8/A9, TNF-α, white blood cells, neutrophils, lymphocytes and CD14(+)CD16(++) were lower in participants with higher index scores. The associations remained significant after adjustment for potential confounders.

In this cross-sectional study, we found that a high diet quality is associated with lower systemic inflammation. As the incidence of cardiovascular disease and cancer is directly correlated with the levels of inflammation, our findings might indicate a protective role of high-quality diet.

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Does pseudoaneurysm of head and neck vessels have been frequently observed in road side bomb blast victims?

Due to recent war situation in neighboring country we have witnessed large number of victims with post-traumatic false (pseudo) aneurysms of head and neck in roadside bomb blast victims in Pakistan. Thus through this observational retrospective study we aim to share our experience of managing these patients. 5 years patients' case records, from June 2008-June 2013, were reviewed from the hospital's records. 14 cases of roadside bomb blast victims, developing false aneurysms of major or minor vessels of head and neck, were studied. We excluded the post-traumatic pseudoaneurysms involving other sites and vessels of the body. We observed the mechanism, the duration of presentation, symptoms/signs, vessels involved, complications and the management done. All 14 cases presented with a localized pulsatile swelling with tenderness in the course of a known artery and with an overlying entry site wound from bomb blast sharp nails. Men were affected more as compared to women. All (14) cases had 2-12 weeks of duration between the injury and presentation. Temporal artery (4) was involved in most cases followed by common carotid artery (3). Open surgery was treatment of choice in 12 (85.7%) of cases; however 2 (14.3%) patients had endovascular intervention to correct the pathology. Post-operatively all patients recovered completely, without any major or minor complications.

Surgical intervention remains the management of choice for post-traumatic false aneurysms of head and neck in Pakistan. Despite the benefits of endovascular procedures, improvements must be weighed against the added costs on the patients.

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Is altered perineal microbiome associated with vulvovaginitis and urinary tract infection in preadolescent girls?

Vulvovaginitis has a known association with urinary tract infections (UTIs) in girls. We hypothesize that vulvovaginitis is a major contributor to UTIs in prepubertal girls by increasing periurethral colonization with uropathogens. Periurethral swabs and urine specimens were obtained from a total of 101 girls (58 with vulvovaginitis and 43 without vulvovaginitis). Specimens were cultured for bacterial growth. The dominant organism in the periurethral swabs and urine cultures was recorded and antibiotic sensitivity profiles were compared. Periurethral swabs from children with vulvovaginitis were associated with a statistically significant increase in uropathogenic bacteria (79% Enterococcus species or Escherichia coli) as the dominant culture compared with swabs from girls without vaginitis (18%) (p < 0.05). In children with vulvovaginitis, 52% of the urine cultures were positive for UTIs, and the dominant organism in the urine cultures matched the species and antibiotic sensitivity profile of the corresponding periurethral swab. Only 11% of the urine cultures from girls without vulvovaginitis were positive for UTIs.

Vulvovaginitis may cause UTIs by altering the perineal biome such that there is increased colonization of uropathogens.

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Does cystamine improve functional recovery via axon remodeling and neuroprotection after stroke in mice?

Stroke is a leading cause of disability. However, there is no pharmacological therapy available for promoting recovery. Although treatment of stroke with cystamine has gained increasing interest, the detailed mechanisms underlying this process remain elusive. Thus, our aim is to examine the effect of cystamine on the function recovery after stroke and investigate further cystamine mechanisms. Adult male C57BL/6J mice were subjected to photothrombotic model of focal stroke or sham operation. Cystamine or saline was administered intraperitoneally at 24 h after stroke. Functional recovery was analyzed using behavioral tests; axon remodeling was analyzed using magnetic resonance diffusion tensor imaging (DTI) and histological assessment. ANA-12, an antagonist of tropomyosin-related kinase B (TrkB), was administrated to examine the mechanisms underlying the neuroprotection mediated by cystamine. Treatment with cystamine resulted in amelioration of impaired function with concomitant enhancement of axonal remodeling. Cystamine treatment significantly increased brain-derived neurotrophic factor (BDNF) levels and phosphorylation of TrkB in brain after stroke. Cystamine significantly enhanced neuronal progenitor cell proliferation, neuronal survival, and plasticity through BDNF/TrkB pathway.

These data provide evidence to investigate the promising utility of cystamine for therapy of stroke in a variety of ways, acting principally through BDNF/TrkB pathway.

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Does anti-IGF-1R monoclonal antibody inhibit the carcinogenicity activity of acquired trastuzumab-resistant SKOV3?

Antibody resistance, not only de novo but also acquired cases, usually exists and is related with lower survival rate and high risk of recurrence. Reversing the resistance often results in better clinical therapeutic effect. Previously, we established a trastuzumab-resistant ovarian cancer cell line, named as SKOV3-T, with lower HER2 and induced higher IGF-1R expression level to keep cell survival. IGF-1R was identified important for SKOV3-T growth. Then, a novel anti-IGF-1R monoclonal antibody, named as LMAb1, was used to inhibit SKOV3-T in cell growth/proliferation, migration, clone formation and in vivo carcinogenicity. In both in vitro and in vivo assays, LMAb1 showed effective anti-tumor function, especially when being used in combination with trastuzumab, which was beneficial to longer survival time of mice as well as smaller tumor. It was also confirmed preliminarily that the mechanism of antibody might be to inhibit the activation of IGF-1R and downstream MAPK, AKT pathway transduction.

We achieved satisfactory anti-tumor activity using trastuzumab plus LMAb1 in trastuzumab-resistant ovarian cancer model. In similar cases, not only acquired but also de novo, good curative effect might be achieved using combined antibody therapy strategies.

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Does metabolic efficiency promote protection from pressure overload in hearts expressing slow skeletal troponin I?

The failing heart displays increased glycolytic flux that is not matched by a commensurate increase in glucose oxidation. This mismatch induces increased anaplerotic flux and inefficient glucose metabolism. We previously found adult transgenic mouse hearts expressing the fetal troponin I isoform, (ssTnI) to be protected from ischemia by increased glycolysis. In this study, we investigated the metabolic response of adult mouse hearts expressing ssTnI to chronic pressure overload. At 2 to 3 months of age, ssTnI mice or their nontransgenic littermates underwent aortic constriction (TAC). TAC induced a 25% increase in nontransgenic heart size but only a 7% increase in ssTnI hearts (P<0.05). Nontransgenic TAC developed diastolic dysfunction (65% increase in E/A ratio), whereas the E/A ratio actually decreased in ssTnI TAC. Isolated perfused hearts from nontransgenic TAC mice showed reduced cardiac function and reduced creatine phosphate:ATP (16% reduction), but ssTnI TAC hearts maintained cardiac function and energy charge. Contrasting nontransgenic TAC, ssTnI TAC significantly increased glucose oxidation at the expense of palmitate oxidation, preventing the increase in anaplerosis observed in nontransgenic TAC hearts. Elevated glucose oxidation was mediated by a reduction in pyruvate dehydrogenase kinase 4 expression, enabling pyruvate dehydrogenase to compete against anaplerotic enzymes for pyruvate carboxylation.

Expression of a single fetal myofilament protein into adulthood in the ssTnI-transgenic mouse heart induced downregulation of the gene expression response for pyruvate dehydrogenase kinase to pressure overload. The consequence of elevated pyruvate oxidation in ssTnI during TAC reduced anaplerotic flux, ameliorating inefficiencies in glucose oxidation, with energetic and functional protection against cardiac decompensation.

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Does preoperative neutrophil-to-lymphocyte ratio predict response to first-line platinum-based chemotherapy and prognosis in serous ovarian cancer?

To investigate the role of preoperative neutrophil-to-lymphocyte ratio (NLR) in prediction of response to first-line platinum-based chemotherapy and survival outcome in serous ovarian cancer (SOC) patients. Clinicopathologic data were reviewed for patients with SOC treated with primary cytoreduction followed by platinum-based chemotherapy. The correlations of NLR value with clinicopathological features, clinical response to chemotherapy, and survival outcome were further explored. High preoperative NLR was significantly associated with advanced FIGO stage, histological grade, increased serum CA-125 level, and positive lymph node metastasis (P < 0.05, respectively). SOC patients in the third and fourth NLR quartile had significantly lower complete response rates compared to those in the first NLR quartile. In addition, survival analysis identified NLR as an independent prognostic factor for both PFS (HR 2.262, 95% CI 1.342-3.811; P = 0.002) and OS (HR 3.254, 95% CI 1.741-6.084; P < 0.001) in SOC patients.

Our findings indicated that high levels of preoperative NLR might be a potential biomarker of worse response to first-line platinum-based chemotherapy and poor clinical outcomes in patients with SOC. Further validation of this easily available parameter as a potential stratification tool in prospective studies should be encouraged.

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Are alcohol mixed with energy drinks robustly associated with patterns of problematic alcohol consumption among young adult college students?

Young adults are a population at great risk for problematic health behaviors. Alcohol mixed with energy drink (AmED) consumption is a relatively popular health risk behavior among young adults. AmED consumption continues to illustrate negative outcomes in the research literature, having been linked with other substance use, high-risk sexual behavior, and sexual victimization. Limited research to date has examined associations between AmED consumption and patterns of alcohol dependence. Undergraduate college students (n=757) filled out an online survey which assessed their drinking habits in the past week and month, including their consumption of AmED beverages, personality characteristics, substance use, and problematic alcohol consumption via the Alcohol Use Disorders Identification Test (AUDIT). A minority of participants reported AmED consumption in both the past month (11.6%) and past week (9.7%). Compared to their alcohol-only drinking counterparts, AmED consumers scored significantly higher on measures of impulsivity, and lower on anxiety sensitivity when compared to their alcohol-only drinking counterparts. In multivariate analyses, AmED consumption was robustly associated with patterns of alcohol dependence (AUDIT score≥8) among young adult college students, while controlling for energy drink use, alcohol use, personality factors, substance use, and demographic variables.

AmED consumption in the past month is robustly associated with problematic alcohol consumption. The present study describes harmful outcomes associated with AmED consumption, and extends the literature on the combined effects of alcohol and energy drinks on young adult risk behaviors. Further research needs to address causal mechanisms for the AmED and problematic alcohol consumption relation.

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Does home and workplace built environment support for physical activity?

Physical inactivity has been associated with obesity and related chronic diseases. Understanding built environment (BE) influences on specific domains of physical activity (PA) around homes and workplaces is important for public health interventions to increase population PA. To examine the association of home and workplace BE features with PA occurring across specific life domains (work, leisure, and travel). Between 2012 and 2013, telephone interviews were conducted with participants in four Missouri metropolitan areas. Questions included sociodemographic characteristics, home and workplace supports for PA, and dietary behaviors. Data analysis was conducted in 2013; logistic regression was used to examine associations between BE features and domain-specific PA. In home neighborhoods, seven of 12 BE features (availability of fruits and vegetables, presence of shops and stores, bike facilities, recreation facilities, crime rate, seeing others active, and interesting things) were associated with leisure PA. The global average score of home neighborhood BE features was associated with greater odds of travel PA (AOR=1.99, 95% CI=1.46, 2.72); leisure PA (AOR=1.84, 95% CI=1.44, 2.34); and total PA (AOR=1.41, 95% CI=1.04, 1.92). Associations between workplace neighborhoods' BE features and workplace PA were small but in the expected direction.

This study offers empirical evidence on BE supports for domain-specific PA. Findings suggest that diverse, attractive, and walkable neighborhoods around workplaces support walking, bicycling, and use of public transit. Public health practitioners, researchers, and worksite leaders could benefit by utilizing worksite domains and measures from this study for future BE assessments.

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Do young low-income ethnic minority children watch less television when their mothers regulate what they are viewing?

Parenting practices can reduce how much television (TV) children watch. This study evaluated the longitudinal association between maternal regulation of TV content and the amount of TV watched by low-income ethnic minority children. This was a secondary data analysis of the Welfare, Children & Families: A Three City Study. Data were used from ethnic minority mothers with a child from birth to 4 years old, collected over two waves approximately 16 months apart. The dependent variable was the amount of TV watched by the child (wave two). The main independent variable was the maternal regulation of TV content (wave one). Using multiple linear regression, we evaluated the relationship between maternal regulation of TV content and the amount of TV watched by the child, adjusting for covariates. Of the 835 mothers, 71% were high content regulators and 8% reported no content regulation. Children whose mothers reported no regulation watched more TV approximately 16 months later than those whose mothers reported high regulation of content (β = 0.91, 95% CI: 0.09-1.73).

Our findings suggest that regulating content influences viewing amounts in young children approximately 16 months later. Interventions focused on heightening parental regulation of content may improve content and diminish viewing amounts.

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Is clinically recognizable error rate after the transfer of comprehensive chromosomal screened euploid embryos low?

To determine the clinically recognizable error rate with the use of quantitative polymerase chain reaction (qPCR)-based comprehensive chromosomal screening (CCS). Retrospective study. Multiple fertility centers. All patients receiving euploid designated embryos. Trophectoderm biopsy for CCS. Evaluation of the pregnancy outcomes following the transfer of qPCR-designated euploid embryos. Calculation of the clinically recognizable error rate. A total of 3,168 transfers led to 2,354 pregnancies (74.3%). Of 4,794 CCS euploid embryos transferred, 2,976 gestational sacs developed, reflecting a clinical implantation rate of 62.1%. In the cases where a miscarriage occurred and products of conception were available for analysis, ten were ultimately found to be aneuploid. Seven were identified in the products of conception following clinical losses and three in ongoing pregnancies. The clinically recognizable error rate per embryo designated as euploid was 0.21% (95% confidence interval [CI] 0.10-0.37). The clinically recognizable error rate per transfer was 0.32% (95% CI 0.16-0.56). The clinically recognizable error rate per ongoing pregnancy was 0.13% (95% CI 0.03-0.37). Three products of conception from aneuploid losses were available to the molecular laboratory for detailed examination, and all of them demonstrated fetal mosaicism.

The clinically recognizable error rate with qPCR-based CCS is real but quite low. Although evaluated in only a limited number of specimens, mosaicism appears to play a prominent role in misdiagnoses. Mosaic errors present a genuine limit to the effectiveness of aneuploidy screening, because they are not attributable to technical issues in the embryology or analytic laboratories.

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Do human adenovirus Ad36 and its E4orf1 gene enhance cellular glucose uptake even in the presence of inflammatory cytokines?

Aging and obesity are associated with elevated pro-inflammatory cytokines such as monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)α, which are linked to insulin resistance. Anti-inflammatory agents have marginal effect in improving insulin resistance. Hence, agents are needed to improve glycemic control despite the inflammation. Ad36, a human adenovirus, increases TNFα and MCP1 mRNA in adipose tissue, yet improves glycemic control in mice. Ad36 via its E4orf1 gene, up-regulates AKT/glucose transporter (Glut)-4 signaling to enhance cellular glucose uptake. Directly test a role of Ad36, or E4orf1 in enhancing cellular glucose uptake in presence of inflammatory cytokines. Experiment 1: 3T3-L1 preadipocytes were treated with 0, 10 or 100 ng/mL lipopolysaccharides (LPS), and infected with 0 or 5 plaque forming units (PFU) of Ad36/cell. 3T3-L1 cells that stably and inducibly express E4orf1 or a null vector (pTRE-E4orf1 or pTRE-null cells), were similarly treated with LPS and then with doxycycline, to induce E4orf1. Experiment 2: 3T3L1 preadipocytes were treated with 25 nM MCP1 or 20 nM TNFα for 16 h, followed by infection with 0 or 5 PFU of Ad36/cell. Experiment 3: pTRE-E4orf1 or -null cells were similarly treated with MCP1 or TNFα followed by doxycycline to induce E4orf1. Cellular glucose uptake and cellular signaling were determined 72 h post-Ad36 infection or E4orf1-induction, in continued presence of MCP1 or TNFα. In 3T3-L1 preadipocytes, Ad36, but not E4orf1, increased MCP1 and TNFα mRNA, in presence of LPS stimulation. Ad36 or E4orf1 up-regulated AKT-phosphorylation and Glut4 and increased glucose uptake (P < 0.05) in the presence of MCP1 or TNFα.

Unlike Ad36, E4orf1 does not appear to stimulate inflammatory response. Ad36 and E4orf1 both enhance cellular glucose uptake even in presence of inflammation. Further research is needed to harness this novel and beneficial property of E4orf1 to improve hyperglycemia despite chronic inflammation that is commonly present in aging and obesity.

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Does femoral insufficiency fractures in the elderly - excessive medial femoral bowing complicate intramedullary nailing?

The aim of this study was to evaluate the characteristics of low-energy femoral insufficiency fractures in elderly patients. The study retrospectively evaluated the clinical course of 4 patients with low-energy femoral shaft and subtrochanteric fractures admitted to our department between 2009 and 2011. Three patients had prior long-term alendronate therapy and one had prior glucocorticoid therapy. There were 5 femoral shaft fractures, 2 incomplete shaft fractures, 2 subtrochanteric and 1 intertrochanteric fractures. All femoral shaft fractures had characteristic fracture patterns with thickened lateral cortices at the proximal fragment. Six femurs had excessive medial femoral bowing, which complicated intramedullary nailing. Additional fractures were seen on both femurs of one patient who had been primarily treated with short implants. A bifocal femoral fracture was seen in one femur. Union was achieved in all patients. Two patients were able to walk independently, one with a cane and one with double crutches.

We suggest the addition of another radiographic pattern of 'excessive medial femoral bowing' in low-energy femoral shaft fractures in elderly patients. This bowing complicates intramedullary nailing. Moreover, these insufficiency fractures should be fixed with long cephalomedullary nails.

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Do mutations in the Arabidopsis homoserine kinase gene DMR1 confer enhanced resistance to Fusarium culmorum and F. graminearum?

Mutation of Arabidopsis DMR1, encoding homoserine kinase, leads to elevation in homoserine and foliar resistance to the biotrophic pathogens Hyaloperonospora arabidopsidis and Oidium neolycopersici through activation of an unidentified defence mechanism. This study investigates the effect of mutation of dmr1 on resistance to the ascomycete pathogens Fusarium graminearum and F. culmorum, which cause Fusarium Ear Blight (FEB) disease on small grain cereals. We initially found that the dmr1-2 mutant allele confers increased resistance to F. culmorum and F. graminearum silique infection, and decreased colonisation of rosette leaves. Meanwhile the dmr1-1 allele supports less rosette leaf colonisation but has wild type silique resistance. Three additional dmr1 alleles were subsequently examined for altered F. culmorum susceptibility and all showed increased silique resistance, while leaf colonisation was reduced in two (dmr1-3 and dmr1-4). Amino acid analysis of dmr1 siliques revealed homoserine accumulation, which is undetectable in wild type plants. Exogenous application of L-homoserine reduced bud infection in both dmr1 and wild type plants, whilst D-homoserine application did not. Delayed leaf senescence was also observed in dmr1 plants compared to wild type and correlated with reduced Fusarium leaf colonisation.

These findings suggest that common Arabidopsis DMR1 mediated susceptibility mechanisms occur during infection by both obligate biotrophic oomycete and hemi-biotrophic fungal pathogens, not only in vegetative but also in reproductive plant tissues. This has the potential to aid the development of cereal crops with enhanced resistance to FEB.

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Does ultrasound elastography correlate treatment response by antiviral therapy in patients with chronic hepatitis C?

To investigate the relationship between tissue elasticity before and after antiviral therapy and shear wave as well as strain elastography. FibroScan and real-time tissue elastography were performed before and after antiviral therapy for chronic hepatitis C, and treatment efficacy and elastographic findings were comparatively analyzed. Elasticity was evaluated by measuring liver stiffness (LS) in kilopascals using FibroScan, and the liver fibrosis index (LFI) was assessed by real-time tissue elastography. LS and LFI correlated well before and after therapy (r = 0.567, p = 0.003 and r = 0.576, p = 0.002, respectively). In the group without a sustained virological response (SVR), LS increased in 4 of 5 patients. Patients with an increase in both LS and LFI were all in the non-SVR group (3/3, 100%). In addition, LS increased in all patients except 1 in the non-SVR group (4/5, 80%). In the SVR group, both LS and LFI decreased in all patients except 1 (18/19, 94.7%). In the patient with an increase in LS despite achieving SVR, LS decreased quickly after alcohol cessation.

With a few exceptions, SVR improved LS. All patients with an increase in LFI were in the non-SVR group, even though LFI decreased in 2 patients. Our findings suggest that an LFI increase indicates lack of treatment efficacy with antiviral therapy. LFI may be useful for the assessment of treatment efficacy in patients with worsening of LS despite achieving SVR with antiviral therapy.

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Does very urgent carotid endarterectomy increase the procedural risk?

The timing of CEA for symptomatic internal carotid artery (ICA) stenosis remains a matter of controversy. Recent registry data showed a significantly increased risk, especially in the very early days after the onset of symptoms. In this study the outcome of CEA in the hyperacute phase has been investigated. The outcome of CEA for symptomatic ICA stenosis between January 2004 and December 2013 has been retrospectively analyzed. Patients were divided into four timing groups: surgery within 0 and 2 days, between 3 and 7 days, 8 and 14 days, and thereafter. The post-operative 30 day stroke and death rates were assessed. A total of 761 symptomatic patients (40.1% with transient ischemic attack [TIA], 21.3% with amaurosis fugax, and 38.6% with ischemic stroke) were included, with an overall peri-operative stroke and death rate of 3.3%. A stroke and death rate of 4.4% (9/206) for surgery within 0 and 2 days, 1.8% (4/219) between 3 and 7 days, 4.4% (6/136) between 8 and 14 days, and 2.5% (5/200) in the period thereafter (p = .25 for the difference between the groups) was observed. The timing of surgery did not influence the peri-operative outcome in a multivariate regression analysis (OR 0.93 [0.63-1.36], p = .71).

These data show that very urgent surgery in symptomatic patients can be performed without increased procedural risk. Given the fact that ruptured plaques with neurological symptoms carry the highest risk of a recurrent ischemic event in the first 2 days, treating patients as soon as possible to offer the highest benefit in stroke prevention is recommended.

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Does b7-H4 overexpression impair the immune response of T cells in human cervical carcinomas?

To investigate B7-H4 expression and its correlation with the number of infiltrating T lymphocytes and cytokine production by those lymphocytes in human cervical cancer and to determine the effect of recombinant B7-H4 on the active peripheral blood T cells of the patients in vitro. B7-H4 expression was detected in 67 cases of cervical cancer using immunohistochemical staining. Tumor-infiltrating CD8(+)T, CD4(+)T, and FOXP3(+) (Forkhead Box P3) T lymphocytes and their levels of IFN-γ and TGF-β₁ production were determined by immunofluorescent double-staining. After the peripheral blood T lymphocytes of patients were co-cultured with B7-H4, proliferation, apoptosis, and cell subtypes were analyzed using flow cytometry. Cytokines in the supernatant were detected by ELISA. B7-H4 was expressed in 46% (31/67) of the cases of cervical cancer. The number of infiltrating CD8(+)T lymphocytes and their IFN-γ production in positive B7-H4 expression cervical cancers was significantly lower than in negative B7-H4 cases (P<0.01, P<0.05), but there was no significant difference between cases positive and negative for B7-H4 with respect to infiltrating FOXP3(+)T and CD4(+)T cells or TGF-β1 production. After co-culture with B7-H4 for 48 h, the patients' activated T lymphocytes were arrested at G1/G2 phase. The Ki67 positive rates of CD4(+)T and CD8(+)T cells were 2.13 ± 0.13% and 1.03 ± 1.33%, and they were lower than in the blank group. The proportion of CD4(+)T and CD8(+)T cells decreased, but CD4(+)T/CD8(+)T and the proportion of CD4(+)CD25(+)Foxp3(+)T cells increased. In addition, concentrations of IL-10 and TGF-β1 in the supernatant of co-cultured T cells increased significantly (P<0.05, P<0.05), but that of IFN-γ decreased. B7-H4 had no significant effect on apoptosis of the T cells.

B7-H4 is overexpressed in human cervical cancers, and it is associated with lower numbers of tumor-infiltrating CD8(+)T lymphocytes and therefore less IFN-γ production. In vitro, B7-H4 inhibits the proliferation of CD4(+)T and CD8(+)T but promotes the proliferation of Tregs and the secretion of IL-10 and TGF-β1. B7-H4 plays an important role in depressing the anti-tumor immunity of CD8(+)T cell in microenvironments of cervical cancer.

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Does preoperative mp-MRI of the prostate provide little information about staging of prostate carcinoma in daily clinical practice?

To evaluate the staging accuracy of preoperative multiparametric MRI (mp-MRI), its influence on the technique of radical retropubic prostatectomy (RRP), and its value for daily clinical practice. A total of 106 patients underwent RRP (January 2011-June 2012) and had preoperative MRI staging data available for review. Staging results acquired by mp-MRI were correlated to both biopsy and histopathology results. Surgical reports were reviewed for intraoperative aspect of tumor extension, technique of RRP (nerve sparing or extended), and extent of lymphadenectomy. The accuracy of diagnosing extracapsular extension (ECE) was 72.2 %, with an overall sensitivity and specificity of 30.0 and 93.3 %, respectively. The negative predictive value was 72.7 %. The sensitivity and specificity to diagnose positive seminal vesical invasion (SVI) were 63.6 and 92.9 %, respectively. Neither higher field force nor the use of an endorectal coil could enhance the accuracy of mp-MRI. In case of awareness of an existing MRI, there was a significantly higher percentage of nerve protection (left: 93 %; right: 89 % vs. left 75 %; right: 75 %). The higher percentage of nerve sparing surgery did not result in a higher level of positive resection margins.

In routine clinical practice, mp-MRI at non-academic centers has very limited clinical value in predicting ECE and SVI. Our data support the current recommendations against the widespread preoperative use of mp-MRI because it is not adding reliable predictive information on the extent of prostate cancer.

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Do gene expression and genetic analysis reveal diverse causes of recessive self-compatibility in Brassica napus L?

Brassica napus (AACC) is self-compatible, although its ancestor species Brassica rapa (AA) and Brassica oleracea (CC) are self-incompatible. Most B.napus accessions have dominant self-compatibility (SC) resulting from an insertion of 3.6 kb in the promoter region of BnSCR-1 on the A genome, while recessive SC in B.napus has rarely been observed. Expression and cloning of SRK and SCR genes and genetic analysis were carried out to dissect bases of recessive SC in B.napus. Eleven accessions were screened to identify stable recessive SC and had the S genotype BnS-7 on the A genome and BnS-6 on the C genome similarly to BrS-29 and BoS-15, respectively. In eight SC accessions, BnSCR-7 and BnSCR-6 were nearly undetectable and harbored no structural mutations in the promoters, while SRK genes were expressed at normal levels and contained intact CDS, with the exception of BnSRK-7 in line C32. SRK and SCR genes were expressed normally but their CDSs had no mutations in three SC accessions. In self-incompatible S-1300 and 11 F1 hybrids, SRK genes and BnSCR-1300 transcripts were present at high levels, while expression of the BnSCR-7 and BnSCR-6 were absent. Plants of S genotype S1300S1300 were completely SI, while SI phenotypes of SBnS-7SBnS-7 and S1300SBnS-7 plants were segregated in BC1 and F2 populations.

The recessive SC in eight accessions is caused by the loss of function of BnSCR-7 and BnSCR-6 in pollen. Translational repression contributes to the recessive SC in three accessions, whose SRK and SCR genes were expressed normally and had identical CDSs to BrS-29 or BoS-15. SI in 11 F1 hybrids relies on the expression of BnSCR-1300 rather than SRK genes. Other factor(s) independent of the S locus are involved in recessive SC. Therefore, diverse causes underlie recessive SC in B. napus, yielding insight into these complex mechanisms.

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Do prostaglandin D2 and leukotriene E4 synergize to stimulate diverse TH2 functions and TH2 cell/neutrophil crosstalk?

Prostaglandin D2 (PGD2) and cysteinyl leukotrienes (cysLTs) are lipid mediators derived from mast cells, which activate TH2 cells. The combination of PGD2 and cysLTs (notably cysteinyl leukotriene E4 [LTE4]) enhances TH2 cytokine production. However, the synergistic interaction of cysLTs with PGD2 in promoting TH2 cell activation is still poorly understood. The receptors for these mediators are drug targets in the treatment of allergic diseases, and hence understanding their interaction is likely to have clinical implications. We aimed to comprehensively define the roles of PGD2, LTE4, and their combination in activating human TH2 cells and how such activation might allow the TH2 cells to engage downstream effectors, such as neutrophils, which contribute to the pathology of allergic responses. The effects of PGD2, LTE4, and their combination on human TH2 cell gene expression were defined by using a microarray, and changes in specific inflammatory pathways were confirmed by means of PCR array, quantitative RT-PCR, ELISA, Luminex, flow cytometry, and functional assays, including analysis of downstream neutrophil activation. Blockade of PGD2 and LTE4 was tested by using TM30089, an antagonist of chemoattractant receptor-homologous molecule expressed on TH2 cells, and montelukast, an antagonist of cysteinyl leukotriene receptor 1. PGD2 and LTE4 altered the transcription of a wide range of genes and induced diverse functional responses in TH2 cells, including cell adhesion, migration, and survival and cytokine production. The combination of these lipids synergistically or additively enhanced TH2 responses and, strikingly, induced marked production of diverse nonclassical TH2 inflammatory mediators, including IL-22, IL-8, and GM-CSF, at concentrations sufficient to affect neutrophil activation.

PGD2 and LTE4 activate TH2 cells through different pathways but act synergistically to promote multiple downstream effector functions, including neutrophil migration and survival. Combined inhibition of both PGD2 and LTE4 pathways might provide an effective therapeutic strategy for allergic responses, particularly those involving interaction between TH2 cells and neutrophils, such as in patients with severe asthma.

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Does consumption of unprocessed cow 's milk protect infants from common respiratory infections?

Breast-feeding is protective against respiratory infections in early life. Given the co-evolutionary adaptations of humans and cattle, bovine milk might exert similar anti-infective effects in human infants. To study effects of consumption of raw and processed cow's milk on common infections in infants. The PASTURE birth cohort followed 983 infants from rural areas in Austria, Finland, France, Germany, and Switzerland, for the first year of life, covering 37,306 person-weeks. Consumption of different types of cow's milk and occurrence of rhinitis, respiratory tract infections, otitis, and fever were assessed by weekly health diaries. C-reactive protein levels were assessed using blood samples taken at 12 months. When contrasted with ultra-heat treated milk, raw milk consumption was inversely associated with occurrence of rhinitis (adjusted odds ratio from longitudinal models [95% CI]: 0.71 [0.54-0.94]), respiratory tract infections (0.77 [0.59-0.99]), otitis (0.14 [0.05-0.42]), and fever (0.69 [0.47-1.01]). Boiled farm milk showed similar but weaker associations. Industrially processed pasteurized milk was inversely associated with fever. Raw farm milk consumption was inversely associated with C-reactive protein levels at 12 months (geometric means ratio [95% CI]: 0.66 [0.45-0.98]).

Early life consumption of raw cow's milk reduced the risk of manifest respiratory infections and fever by about 30%. If the health hazards of raw milk could be overcome, the public health impact of minimally processed but pathogen-free milk might be enormous, given the high prevalence of respiratory infections in the first year of life and the associated direct and indirect costs.

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Does melatonin-sulforaphane hybrid ITH12674 induce neuroprotection in oxidative stress conditions by a 'drug-prodrug ' mechanism of action?

Neurodegenerative diseases are a major problem afflicting ageing populations; however, there are no effective treatments to stop their progression. Oxidative stress and neuroinflammation are common factors in their pathogenesis. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the master regulator of oxidative stress, and melatonin is an endogenous hormone with antioxidative properties that reduces its levels with ageing. We have designed a new compound that combines the effects of melatonin with Nrf2 induction properties, with the idea of achieving improved neuroprotective properties. Compound ITH12674 is a hybrid of melatonin and sulforaphane designed to exert a dual drug-prodrug mechanism of action. We obtained the proposed hybrid in a single step. To test its neuroprotective properties, we used different in vitro models of oxidative stress related to neurodegenerative diseases and brain ischaemia. ITH12674 showed an improved neuroprotective profile compared to that of melatonin and sulforaphane. ITH12674 (i) mediated a concentration-dependent protective effect in cortical neurons subjected to oxidative stress; (ii) decreased reactive oxygen species production; (iii) augmented GSH concentrations in cortical neurons; (iv) enhanced the Nrf2-antioxidant response element transcriptional response in transfected HEK293T cells; and (v) protected organotypic cultures of hippocampal slices subjected to oxygen and glucose deprivation and re-oxygenation from stress by increasing the expression of haem oxygenase-1 and reducing free radical production.

ITH12674 combines the signalling pathways of the parent compounds to improve its neuroprotective properties. This opens a new line of research for such hybrid compounds to treat neurodegenerative diseases.

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Does comprehensive analysis suggest simple processes underlying EEG/ERP - demonstration with the go/no-go paradigm in ADHD?

Current basic or more advanced methods for analysis of averaged EEG/ERP are based on assumptions on the underlying processes, which are not necessarily precise. In this work we present the findings of a method which obviates such assumptions and aims at a comprehensive analysis of the averaged EEG/ERP signal. For the sake of demonstration we chose the established go/no-go paradigm in the context of ADHD. Our analysis method characterized two spatiotemporally distinct neurophysiologic processes which underlie the sampled signal: one which may be related to attention and the other which may be more related to perception.

We show how these processes accord with and provide insight on the waveforms reported in the literature.

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Does endometriosis also affect the decidua in contact with the fetal membranes during pregnancy?

Are the fetal membranes of women affected with endometriosis similar to those from disease-free women?

Decidua of women with endometriosis is able to generate endometriotic-like lesions in contact with the fetal membranes.

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Do endometriotic ovarian cysts negatively affect the rate of spontaneous ovulation?

Do endometriotic ovarian cysts influence the rate of spontaneous ovulation?

Endometriotic cysts, no matter what their volume, do not influence the rate of spontaneous ovulation in the affected ovary.

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Do song characteristics track bill morphology along a gradient of urbanization in house finches ( Haemorhous mexicanus )?

Urbanization can considerably impact animal ecology, evolution, and behavior. Among the new conditions that animals experience in cities is anthropogenic noise, which can limit the sound space available for animals to communicate using acoustic signals. Some urban bird species increase their song frequencies so that they can be heard above low-frequency background city noise. However, the ability to make such song modifications may be constrained by several morphological factors, including bill gape, size, and shape, thereby limiting the degree to which certain species can vocally adapt to urban settings. We examined the relationship between song characteristics and bill morphology in a species (the house finch, Haemorhous mexicanus) where both vocal performance and bill size are known to differ between city and rural animals. We found that bills were longer and narrower in more disturbed, urban areas. We observed an increase in minimum song frequency of urban birds, and we also found that the upper frequency limit of songs decreased in direct relation to bill morphology.

These findings are consistent with the hypothesis that birds with longer beaks and therefore longer vocal tracts sing songs with lower maximum frequencies because longer tubes have lower-frequency resonances. Thus, for the first time, we reveal dual constraints (one biotic, one abiotic) on the song frequency range of urban animals. Urban foraging pressures may additionally interact with the acoustic environment to shape bill traits and vocal performance.

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Do the effects of ifenprodil on the activity of antidepressant drugs in the forced swim test in mice?

According to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2-4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10mg/kg) on the activity of antidepressant agents from diverse pharmacological groups. The antidepressant-like effect was assessed by the forced swim test in mice. Ifenprodil potentiated the antidepressant-like effect of imipramine (15mg/kg) and fluoxetine (5mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5mg/kg) or tianeptine (15mg/kg).

The concomitant administration of certain commonly prescribed antidepressant drugs that affect the serotonergic neurotransmission (i.e., typical tricyclic antidepressants and selective serotonin reuptake inhibitors) with a negative modulator selectively binding to the GluN1/N2B subunits of the NMDA receptor complex (i.e., ifenprodil) may induce a more pronounced antidepressant-like effect than monotherapy. However, these findings still need to be confirmed in further experiments.

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Does pulmonary morbidity improve after autologous stem cell transplantation in POEMS syndrome?

POEMS syndrome is a plasma cell disorder manifested by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes. Pulmonary morbidity includes restriction, decreased diffusing capacity for carbon monoxide (DLCO), respiratory muscle weakness, abnormal imaging, and pulmonary hypertension. Autologous peripheral blood stem cell transplantation (aPBSCT) is an effective treatment for POEMS syndrome. It is unknown if aPBSCT improves pulmonary morbidity. We hypothesize pulmonary morbidity will improve following aPBSCT. Retrospective cohort study of POEMS syndrome aPBSCT recipients from 2000 to 2010. Demographic, pulmonary function test (PFT), echocardiogram, cytokine, and imaging data at baseline and after aPBSCT were abstracted. Pre- and post-transplant data were compared using Wilcoxon signed-rank and McNemar's tests. 53 patients met criteria. Median improvements in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and total lung capacity (TLC) after transplant were 180, 315 and 350 ml respectively (median follow-up of 1.1 years). DLCO, maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) improved by a median of 11, 12.5 and 10% predicted respectively. RVSP and chest imaging also improved. Vascular endothelial growth factor and IL-6 decreased by a median of 334 and 2 pg/ml respectively. All comparisons were statistically significant. Longitudinal data demonstrated stability in FEV1, MEP, and TLC and continued improvement in FVC, MIP and DLCO on subsequent PFTs (median follow-up 26.5 months).

Patients with POEMS syndrome treated with aPBSCT have significant improvement in PFTs, respiratory muscle strength, imaging, and post-transplant IL-6. The improvement in PFTs persists during long-term follow-up.

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Do nitric oxide and cGMP induce COX-2 expression and PGE2 production in human granulosa cells through CREB signaling pathway?

It is well known that cyclooxygenase-2 (COX-2) and its major derivative product prostaglandin E2 (PGE2) play key regulatory roles in the ovulation process. Animal studies have demonstrated that the inhibition of nitric oxide (NO) suppresses ovarian PGE2 production and ovulation. Although the expression of NO synthases has been detected in human granulosa cells, the effect of NO on COX-2 expression and PGE2 production in these cells remains unknown. The purpose of this article was to investigate the effects of NO on COX-2 expression and PGE2 production in human granulosa cells. SVOG cells are human granulosa cells that were obtained from women undergoing in vitro fertilization and immortalized with simian virus 40 large T antigen. SVOG cells were used to investigate the effects of NO on COX-2 expression and PGE2 production. The study was conducted in an academic research center. The levels of mRNA and protein were examined by RT-quantitative real-time PCR and Western blotting, respectively. The accumulation levels of PGE2 were measured by ELISA. Treatment with the NO donor S-nitroso-N-acetyl-DL-penicillamine (SNAP) induced COX-2 expression and PGE2 production. In addition, the stimulatory effect of SNAP on COX-2 and PGE2 was mimicked by treatment with the cGMP analog 8-bromo-cGMP (8-Br-cGMP). Interestingly, neither SNAP nor 8-Br-cGMP affected the expression of COX-1. Moreover, our results showed that either SNAP or 8-Br-cGMP activated cAMP response element-binding protein (CREB) signaling and that the knockdown of CREB attenuated SNAP- and 8-Br-cGMP-induced COX-2 expression and PGE2 production.

CREB mediates NO and cGMP-induced COX-2 expression and PGE2 production, which subsequently contribute to NO-regulated ovulation in human granulosa cells.

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Does miR-219-5p modulate cell growth of papillary thyroid carcinoma by targeting estrogen receptor α?

Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. It has been demonstrated that micro-RNAs (miRNAs) are involved in the development of PTC. The miRNA-chromatin immunoprecipitation microarray assay revealed down-regulation of miR-219-5p; however, the effect of miR-219-5p on PTC cell growth remains unknown. This result implied the critical role of miR-219-5p in the development of PTC. We investigated the association between miR-219-5p and PTC development. Expression of miR-219-5p was monitored in 30 PTC tissue specimens and compared with that in 30 normal thyroid tissue specimens. The effect of miR-219-5p on PTC development was studied by cell proliferation, migration, and apoptosis assays. The underlying mechanism was clarified by a reporter assay and rescue experiment. The current study confirmed that miR-219-5p expression was inhibited in PTC tissue samples. There were statistically significant differences in the expression of miR-219-5p with regard to sex, tumor size, and lymph node metastasis in patients with PTC. Forced expression of miR-219-5p suppressed PTC cell proliferation and migration and promoted apoptosis. Further study showed that estrogen receptor (ER) α was the direct target of miR-219-5p and mediated the effect of miR-219-5p on PTC occurrence. Expression of miR-219-5p was inversely correlated with that of ERα. Importantly, ERα overexpression in PTC cells rescued the inhibitory effect of miR-219-5p on PTC cell proliferation and migration. Thus, our results indicated that miR-219-5p played a critical role in PTC growth by inhibiting ERα.

Our investigation identified miR-219-5p as a negative regulator of PTC development through targeting of ERα.

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Is hypothalamic damage associated with inflammatory markers and worse cognitive performance in obese subjects?

Growing evidence implicates hypothalamic inflammation in the pathogenesis of diet-induced obesity and cognitive dysfunction in rodent models. Few studies have addressed the association between obesity and hypothalamic damage in humans and its relevance. This study aimed to determine markers of obesity-associated hypothalamic damage on diffusion tensor imaging (DTI) and to determine whether DTI metrics are associated with performance on cognitive testing. This cross-sectional study analyzed DTI metrics (primary [λ(1)], secondary [λ(2)], and tertiary [λ(3)] eigenvalues; fractional anisotropy; and mean diffusivity) in the hypothalamus of 24 consecutive middle-age obese subjects (13 women; 49.8 ± 8.1 y; body mass index [BMI], 43.9 ± 0.92 kg/m(2)) and 20 healthy volunteers (10 women; 48.8 ± 9.5 y; BMI, 24.3 ± 0.79 kg/m(2)). measures: Hypothalamic damage assessed by DTI metrics and cognitive performance evaluated by neuropsychological test battery. λ(1) values in the hypothalamus were significantly lower in obese subjects (P < .0001). The sensitivity, specificity, and positive and negative predictive values for obesity-associated hypothalamic damage by λ(1) < 1.072 were 75, 87.5, 83.3, and 80.7%, respectively. Patients with hypothalamic λ(1) < 1.072 had higher values of BMI, fat mass, inflammatory markers, carotid-intima media thickness, and hepatic steatosis and lower scores on cognitive tests. Combined BMI and alanine aminotransferase had the strongest association with hypothalamic damage reflected by λ(1) < 1.072 (area under the curve = 0.89).

DTI detects obesity-associated hypothalamic damage associated with inflammatory markers and worse cognitive performance. This study highlights the potential utility of λ(1) as a surrogate marker of obesity-associated hypothalamic damage.

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Is s100A8 a novel therapeutic target for anaplastic thyroid carcinoma?

Anaplastic thyroid carcinoma (ATC) is one of the most deadly human malignancies. It is 99% lethal, and patients have a median survival of only 6 months after diagnosis. Despite these grim statistics, the mechanism underlying the tumorigenic capability of ATC cells is unclear. S100A8 and S100A9 proteins have emerged as critical mediators in cancer. The aim was to investigate the expression and function of S100A8 and S100A9 in ATC and the mechanisms involved. We determined the expression of S100A8 and S100A9 in human ATC by gene array analysis and immunohistochemistry. Using RNAi-mediated stable gene knockdown in human ATC cell lines and bioluminescent imaging of orthotopic and lung metastasis mouse models of human ATC, we investigated the effects of S100A8 and S100A9 on tumorigenesis and metastasis. We demonstrated that S100A8 and S100A9 were overexpressed in ATC but not in other types of thyroid carcinomas. In vivo analysis in mice using ATC cells that had S100A8 knocked down revealed reduced tumor growth and lung metastasis, as well as significantly prolonged animal survival. Mechanistic investigations showed that S100A8 promotes ATC cell proliferation through an interaction with RAGE, which activates the p38, ERK1/2 and JNK signaling pathways in the tumor cells.

These findings establish a novel role for S100A8 in the promoting and enhancing of ATC progression. They further suggest that the inhibition of S100A8 could represent a relevant therapeutic target, with the potential of enabling a more effective treatment path for this deadly disease.

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Do associations of Heart Rate With Inflammatory Markers Are Modulated by Gender and Obesity in Older Adults?

Faster resting heart rate (HR), which is associated with inflammation and elevated cortisol levels, is a risk factor for excess cardiovascular morbidity and mortality. Obesity is associated with increased cardiovascular morbidity and mortality, inflammation, and elevated cortisol levels. The aim of the present study was to evaluate the interaction of Body Mass Index (BMI) with inflammation and cortisol in modulating HR in older subjects. We analyzed data of 895 participants aged 65+ enrolled in the "InCHIANTI" study, in sinus rhythm, and not taking beta blockers or digoxin. Linear regression was performed to assess the adjusted association between HR, IL-6, and cortisol levels. The model was also analyzed stratifying for BMI tertiles. Logistic regression was adopted for evaluating the association of HR exceeding the mean value with Il-6 and serum cortisol. According to multivariable linear regression, IL-6 and cortisol levels were associated with HR (B = 1.42, 95% CI = 0.43-2.42; p = .005 and B = .34, 95% CI = 0.17-.51; p < .0001, respectively). The association was significant only among women in the highest BMI tertile (B = 4.16, 95% CI = 1.40-6.91; p = .003 for IL-6 and B = .57, 95% CI = 0.14-1.01; p = .010 for cortisol). Logistic regression confirmed that IL-6 and cortisol levels were associated with HR above the mean value in the highest BMI tertile (OR = 2.13, 95% CI = 1.15-3.97; p = .009 and OR = 1.14, 95% CI = 1.03-1.25; p = .009, respectively).

Faster HR is associated with proinflammatory state in elderly patients; this association seems to be limited to women with higher BMI.

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Do plant traits respond to the competitive neighbourhood at different spatial and temporal scales?

Clonal plants can plastically modify their traits in response to competition, but little is known regarding the spatio-temporal scale at which a competitive neighbourhood determines the variability in species traits. This study tests the hypothesis that the local neighbourhood can be expected to influence the processes that are involved in competition tolerance and avoidance, and that this effect depends on organ lifespan. Fragments of the rhizomatous Elytrigia repens (Poaceae) were sampled in 2012 in experimental plant communities that varied in species identity and abundance. These communities had been cultivated since 2009 in mesocosms in a common garden. Fragment performance, shoot and clonal traits were measured, and the effects of past and present local neighbourhoods of five different radius sizes (5-25 cm) were examined. Past and present local neighbourhood compositions were assessed in 2011 and 2012, respectively. Most of the measured traits of E. repens responded to the local neighbourhood (5-10 cm radius), with an additional effect of the larger neighbourhood (20-25 cm radius) on ramet height, leaf dry matter content, maximal internode length and specific rhizome mass. Contrary to the expectation of the hypothesis, the temporal influence was not due to the organ lifespan. Indeed, five of the eight traits studied responded to both the past and present neighbourhoods. With the exception of specific rhizome mass, all trait responses were explained by the abundance of specific species.

This study demonstrates that the traits of a single clonal individual can respond to different competitive environments in space and time. The results thus contribute to the understanding of competition mechanisms.

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Are endoscopy and EUS key for effective surveillance and management of duodenal adenomas in familial adenomatous polyposis?

Patients with familial adenomatous polyposis (FAP) are prone to developing duodenal adenoma and cancer. Optimal surveillance and management of these adenomas are not well established. We assessed the outcome of FAP patients undergoing intense multimodal surveillance and subsequent endoscopic resection of advanced lesions. Eighty consecutive FAP patients enrolled during 2001 to 2011 from the Familial Cancer Clinic of a tertiary hospital as part of routine surveillance. Case series, prospective in years 2006 to 2011 and retrospective in years 2001 to 2006. Patients were followed by annual forward-view and/or side-view upper endoscopy. A biopsy sample was obtained from visible lesions and normal papillae. Ampullary adenomas were further assessed by EUS to determine dimensions and resectability. Advanced adenomas (size ≥ 10 mm, villous type, high-grade dysplasia) underwent endoscopic ampullectomy or polypectomy and continued surveillance. Detection of advanced adenomas by endoscopy and EUS, endoscopic maintenance of duodenum free of advanced adenoma and cancer. Patients (38 men and 42 women, mean age 32.68 ± 13.60) were followed 7.2 years and underwent 5.36 diagnostic studies on average. Thirty-eight patients had ampullary adenomas. Advanced adenoma was diagnosed by endoscopy in 10 patients. Importantly, EUS upstaged 9 additional patients to advanced adenoma and downstaged 1, thus altering the treatment course in 36% of patients performing EUS. Endoscopic ampullectomy was performed in 15 patients. Adenoma recurred in 10. Five remained nonadvanced and 5 in advanced stages: 3 were successfully retreated endoscopically and 2 ultimately required surgery for residual adenoma. Advanced nonampullary adenomas were successfully resected endoscopically in 23 patients. No patient had duodenal cancer during the study period.

Limited follow-up period, young age group, uncontrolled study.

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Are well differentiation and intact Smad4 expression specific features of groove pancreatic ductal adenocarcinomas?

We aimed to select true groove pancreatic ductal adenocarcinomas (GPDACs) and define their specific features. We performed histopathologic and immunohistochemical comparisons of 6 GPDACs with 6 duodenal adenocarcinomas (DACs) and 24 conventional pancreatic ductal adenocarcinomas (cPDACs). Both groups were adjusted to ensure similar mean tumor size. Representative loupe image showed prominent duodenal invasion and slight pancreatic invasion. Groove pancreatic ductal adenocarcinomas exhibited different mucins and cytokeratin profiles in DACs, but cPDACs and small branch pancreatic ducts had the same profiles. Histopathologic analysis of GPDACs showed a significantly higher incidence of duodenal invasion and well differentiation than cPDACs, although the incidences of lymph node metastasis, angiolymphatic invasion, and neural invasion were similar. Immunohistochemical analysis of GPDACs showed a significantly lower frequency of abnormal Smad4 immunolabeling, and fewer GPDAC samples exhibited abnormal immunolabeling for MUC1, p16, Smad4, and p53 than cPDACs.

These results suggest that GPDACs arise from small branch pancreatic ducts around accessory pancreatic duct penetrating the groove and duodenum and are distinguishable from DACs. Molecular immunohistochemistry suggests the accumulation of genetic abnormalities during tumor progression is slow in comparison with cPDACs. Thus, the site of PDAC occurrence, such as the border or inner area of the pancreas head, may determine genetic progressivity.

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Does peroxiredoxin 1 promote pancreatic cancer cell invasion by modulating p38 MAPK activity?

The aim of this study was to investigate the role of peroxiredoxin 1 (Prdx1) in the invasiveness of pancreatic ductal adenocarcinoma (PDAC) cells. Immunohistochemistry was used to determine overexpression of Prdx1 in human PDAC tissues. Immunoprecipitation and immunocytochemistry were used to determine the interaction and intracellular distribution of Prdx1 and a member of the mitogen-activated protein kinase (MAPK) family protein, p38 MAPK, in PDAC cells. Finally, immunocytochemistry and Matrigel invasion assay were used to examine the effects of Prdx1 and p38 MAPK on the formation of cell protrusions and PDAC cell invasion. Prdx1 is overexpressed in human PDAC tissues. Peroxiredoxin 1 interacts with active forms of p38 MAPK, and complexes of Prdx1 and phosphorylated p38 MAPK localize at the leading edges of migrating PDAC cells. Suppression of Prdx1 decreases active p38 MAPK localized in cell protrusions and inhibits the invasiveness of PDAC cells. Consequently, suppression of Prdx1 inhibits membrane ruffling and protrusions. The p38 MAPK inhibitor SB203580 also decreases the formation of membrane protrusions and inhibits invasiveness.

Prdx1 associates with the formation of membrane protrusions through modulation of the activity of p38 MAPK, which in turn promotes PDAC cell invasion.

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Do increased interleukin-23/17 axis and C-reactive protein are associated with severity of acute pancreatitis in patients?

The interleukin (IL)-23/IL-17 axis plays an important role in various inflammatory conditions but its function in acute pancreatitis (AP) is not well understood. The present study investigated the relationship between serum levels of IL-23, IL-17, and C-reactive protein (CRP) in patients and the severity of AP. Eighty-five patients with AP were categorized into mild group, moderately severe group, and severe group according to the revised Atlanta classification, 2012. Serum levels of IL-23 and IL-17 were measured by enzyme-linked immunosorbent assay in patients 48 hours after admission. The CRP levels of patients were also measured on admission and 48 hours after admission. The serum levels of CRP of patients on admission and 48 hours after admission and levels of IL-23 and IL-17 of patients 48 hours after admission increased alone with the severity of AP, respectively (P < 0.01). The serum levels of IL-23 and IL-17 in the patients were correlated with CRP levels (r = 0.234, r = 0.552, P < 0.001, respectively).

The serum levels of IL-17, IL-23, and CRP are correlated with the severity of AP and represent valuable prognostic factors in the assessment of disease severity of patients with AP.

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Does [ Waist-to-height ratio change with gender , age and pubertal stage in elementary school children ]?

Waist-to-height ratio (WHtR) is a cardiometabolic risk indicator in children. A value greater than or equal to 0.55 is an effective screening tool for identifying obese children with metabolic syndrome. However, it is unclear whether this cutoff can be applied equally to any age or gender. To analyze the variability of WHtR by age, gender and pubertal stage in elementary school children. Cross-sectional study in 2,980 school children (6-14 years old, 51% male) of Santiago, Chile. We measured weight, height and waist circumference and calculated body mass index and WHtR. Pubertal stage was assessed and classified as peripubertal (Tanner I and II) and pubertal (Tanner III, IV and V). The mean age was 9.9 ± 2.3 years, with no gender difference (p = 0.5). Eighty one percent of boys and 59.4% of girls were peripubertal (p < 0.001). The association between age-adjusted WHtR by gender and pubertal stage was not significant (p = 0.409). Therefore mean, standard deviation and percentiles of WHtR were calculated without sex and pubertal stage segmentations.

Since WHtR does not vary with age, gender and pubertal status in elementary school children, it is possible to use a single cutoff value, previously defined in this population, to identify children with cardiometabolic risk.

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Do maternal and childhood psychological factors predict chronic disabling fatigue at age 13 years?

To investigate whether premorbid maternal and childhood psychological problems are risk factors for chronic disabling fatigue at age 13 years among children in the Avon Longitudinal Study of Parents and Children birth cohort. Chronic disabling fatigue was defined as fatigue of at least 3-month, and up to 5-year, duration that prevented school attendance or hobbies/sport/leisure activities, and for which other causes were not identified. Maternal psychological factors were symptoms of anxiety and depression assessed up to eight times between pregnancy and age 6 years. We investigated critical periods for maternal effects and effects of paternal depression at three time points. Child psychological factors included internalizing and externalizing problems and upsetting life events occurring at age 7-8 years. Of 5,657 children, 110 (1.9%) had chronic disabling fatigue at age 13 years. Maternal anxiety (adjusted odds ratio [AOR], 1.19; 95% confidence interval [CI], 1.09-1.31 per episode), maternal depression (AOR, 1.24; CI, 1.11-1.39 per episode), child psychological problems (AOR, 1.19; CI, 1.00-1.41 per problem), and upsetting events (AOR, 1.22; CI, .99-1.58 per event) were associated with chronic disabling fatigue. Associations of child psychological problems and upsetting events were attenuated (AOR, 1.12; CI, .93-1.33 per problem; AOR, 1.19; CI, .94-1.52 per event) after further adjusting for maternal anxiety and depression.

Pediatricians need to be aware that children whose mothers experience anxiety and/or depression between pregnancy and child's age 6 years have an increased risk of developing chronic disabling fatigue in early adolescence. Conversely, clinicians need to be alert to fatigue in children whose mothers have longstanding anxiety and depression. These findings suggest the importance of family-based approaches to treatment.

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Is position-related injury uncommon in robotic gynecologic surgery?

To assess the rate and risk factors for position-related injury in robotic gynecologic surgery. A prospective database from 12/2006 to 1/2014 of all planned robotic gynecologic procedures was retrospectively reviewed for patients who experienced neurologic injury, musculoskeletal injury, or vascular compromise related to patient positioning in the operating room. Analysis was performed to determine risk-factors and incidence for position-related injury. Of the 831 patients who underwent robotic surgery during the study time period, only 7 (0.8%) experienced positioning-related injury. The injuries included minor head contusions (n=3), two lower extremity neuropathies (n=2), brachial plexus injury (n=1) and one large subcutaneous ecchymosis on the left flank and thigh (n=1). There were no long term sequelae from the positioning-related injuries. The only statistically significant risk factor for positioning-related injury was prior abdominal surgery (P=0.05). There were no significant associations between position-related injuries and operative time (P=0.232), body mass index (P=0.847), age (P=0.152), smoking history (P=0.161), or medical comorbidities (P=0.229-0.999).

The incidence of position-related injury among women undergoing robotic surgery was extremely low (0.8%). Due to the low incidence we were unable to identify modifiable risk factors for position-related injury following robotic surgery. A standardized, team-oriented approach may significantly decrease position-related injuries following robotic gynecologic surgery.

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Is increased alcohol consumption in urocortin 3 knockout mice unaffected by chronic inflammatory pain?

Stress neurocircuitry may modulate the relationship between alcohol drinking and chronic pain. The corticotropin-releasing factor (CRF) system is crucial for regulation of stress responses. The current study aimed to elucidate the role of the endogenous CRF ligand Urocortin 3 (Ucn3) in the relationship between alcohol drinking behavior and chronic pain using a genetic approach. Ucn3 (KO) and wildtype (WT) littermates were subjected to a 24-h access drinking procedure prior to and following induction of chronic inflammatory pain. Ucn3 KO mice displayed significantly increased ethanol intake and preference compared with WT across the time course. There were no long-term effects of chronic pain on alcohol drinking behavior, regardless of genotype, nor any evidence for alcohol-induced analgesia.

The increased drinking in Ucn3 KO supports a role for this peptide in alcohol-related behavior. These data suggest the necessity for more research exploring the relationship between alcohol drinking, chronic pain and the CRF system in rodent models.

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Does serum free light chain response after 2 courses of induction chemotherapy predict prognosis in myeloma patients?

The aim of this study was to investigate the prognostic effect of serum free light chain (sFLC) response after 2 cycles of first-line chemotherapy (CT) in multiple myeloma (MM) patients. The data of 78 newly diagnosed MM patients who had sFLC levels at diagnosis and after 2 cycles of first-line CT were included in the study. The prognostic effect of sFLCs were evaluated with normalization of sFLC κ/λ ratio after 2 cycles of CT and involved/uninvolved (i/u) sFLCs. At the end of follow-up the probability of overall survival (OS) was 95.7% versus 68.5% in patients with and without normalized sFLC κ/λ ratio, respectively (P = .072). The probability of OS with i/u sFLC assessment was 97.4% versus 55.8% with regard to i/u sFLC ≤ 10 and > 10, respectively (P = .001). In univariate and multivariate analysis including sFLC ratio, age, sex, and International Staging System, i/u sFLC ratio > 10 after 2 cycles of CT was identified as an independent risk factor for OS (P = .015; hazard ratio [HR], 13.2; 95% confidence interval [CI], 1.668-104.65 vs. P = .011; HR, 15.17; 95% CI, 1.85-123.89).

Early response assessment in terms of sFLC after 2 courses of induction CT seems to have a prognostic effect in MM patients. The methodology and timing of the evaluation based on sFLCs needs to be validated in prospective studies.

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Does protopine inhibit heterotypic cell adhesion in MDA-MB-231 cells through down-regulation of multi-adhesive factors?

A Chinese herb Corydalis yanhusuo W.T. Wang that showed anticancer and anti-angiogenesis effects in our previous studies was presented for further studies. In the present study, we studied the anticancer proliferation and adhesion effects of five alkaloids which were isolated from Corydalis yanhusuo. MTT dose response curves, cell migration assay, cell invasion assay, as well as three types of cell adhesive assay were performed on MDA-MB-231 human breast cancer cells. The mechanism of the compounds on inhibiting heterotypic cell adhesion were further explored by determining the expression of epidermal growth factor receptor (EGFR), Intercellular adhesion molecule 1 (ICAM-1), αv-integrin, β1-integrin and β5-integrin by western blotting assay. In five tested alkaloids, only protopine exhibited anti-adhesive and anti-invasion effects in MDA-MB-231 cells, which contributed to the anti-metastasis effect of Corydalis yanhusuo. The results showed that after treatment with protopine for 90 min, the expression of EGFR, ICAM-1, αv-integrin, β1-integrin and β5-integrin were remarkably reduced.

The present results suggest that protopine seems to inhibit the heterotypic cell adhesion between MDA-MB-231 cells, and human umbilical vein endothelial cells by changing the expression of adhesive factors.

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Does hydrogen sulfide protect testicular germ cells against heat-induced injury?

The present study was designed to investigate whether H2S can protect testicular germ cells against heat exposure induced injury and the underlying mechanisms. It was found that all three H2S generating enzymes, cystathionine β-synthase (CBS), cystathionine γ-lysase (CSE), and 3-mercaptopyruvate sulfurtransferase (3 MST), were expressed in mouse testicular tissue. Three episodes of heat exposure (42 °C, 30 min/day, 3 days) significantly decreased endogenous H2S production and down-regulated the expression of CBS and CSE in testes. In primary cultured testicular germ cells, exogenous application of NaHS (an H2S donor) attenuated heat stress (42 °C, 30 min) induced cell death and apoptosis. This was mediated by the inhibitory effects of H2S on cytochrome C release and the ratio of the Bax/Bcl-2. NaHS also improved mitochondrial function by decreasing oxygen consumption and increasing ATP production. NaHS treatment also stimulated SOD activity and reduced ROS production.

Our results revealed both physiological and pharmacological roles of H2S in testicular germ cells. Exogenous application of H2S may protect germ cells by preservation of mitochondrial function and stimulation of anti-oxidant activity.

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Is long noncoding RNA PCA3 gene promoter region related to the risk of prostate cancer on Chinese males?

Long noncoding RNA prostate cancer gene antigen 3 (PCA3) is one of the most prostate cancer-specific genes at present. Consequently, the prostate-specific expression and the sharp up-regulation of PCA3 RNA in prostate cancer suggest a unique transcriptional regulation, which possibly can be attributed to promoter polymorphism. In this study, we investigated a short tandem repeat (STR) polymorphism of TAAA in the promoter region of PCA3 gene found in our previous study in prostate cancer (PCa) patients and benign prostatic hypertrophy (BPH) patients, aiming to evaluate the association between the STR and increased risk for PCa. 120 PCa cases and 120 benign prostatic hypertrophy (BPH) cases were identified among participants. The region encompassing the TAAA repeat was amplified with a specific primer set we designed and screened by PCR-based cloning and sequencing in paired peripheral blood leukocytes and prostate tissues. Genotype-specific risks were estimated as odds ratios (ORs) associated with 95% confidence intervals (CIs) and adjusted for age by means of unconditional logistic regression. 5 PCA3 TAAA STR polymorphisms and 8 genotypes were found in both peripheral blood leukocytes and prostate tissues, the carriers with more TAAA repeats were associated with increased risk for PCa than individuals having less TAAA repeats. Interestingly, 18 (15.0%) of 120 PCa patients had more (TAAA)n repeats in prostate tissues than that in peripheral blood leukocytes, and 3 (2.5%) of 120 had less (TAAA)n repeats in prostate tissues.

The results of this study suggest that short tandem repeat polymorphism of TAAA in the promoter region of PCA3 gene is a risk-increasing factor for prostate cancer in the Chinese population. In addition to the hereditary factor, the insertion mutation of (TAAA)n in a local tissue maybe another mechanism of the onset of PCa.

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Does ski diminish TGF-β1-induced myofibroblast phenotype via up-regulating Meox2 expression?

The aim of the present work was to investigate the mechanism of transforming growth factor (TGF)-β1 and Sloan-Kettering Institute (Ski) in the pathogenesis of hypertrophic scars (HS). Wound healing is an inherent process, but the aberrant wound healing of skin injury may lead to HS. There has been growing evidence suggesting a role for TGF-β1 and Ski in the pathogenesis of fibrosis. The MTT assay was used to detect the cell proliferation induced by TGF-β1. The Ski gene was transduced into cells with an adenovirus, and then the function of Ski in cell proliferation and differentiation was observed. Ski mRNA levels were measured by RT-PCR. Western blotting was used to detect the protein expression of α-SMA, E-cadherin, Meox1, Meox2, Zeb1 and Zeb2. TGF-β1 can promote human skin fibroblast (HSF) cell proliferation in a time-dependent manner, but the promoting effect could be suppressed by Ski. TGF-β1 also induces the formation of the myofibroblast phenotype and the effect of TGF-β1 could be diminished by Ski. Also, Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by up-regulating the expression of Meox2.

Ski diminishes the myofibroblast phenotype induced by TGF-β1 through the suppression of Zeb2 by up-regulating the expression of Meox2.

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Does docosahexaenoic acid induce M2 macrophage polarization through peroxisome proliferator-activated receptor γ activation?

Impaired resolution of acute inflammation results in development of chronic inflammatory disorders such as atherosclerosis, asthma and arthritis. Clearance of apoptotic neutrophils by M2 macrophages, the process termed efferocytosis, is critical for complete resolution of inflammation as it prevents secondary necrosis caused by disgorgement of toxic contents from apoptotic cells in the inflamed site. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on efferocytosis. To determine the effect of DHA on efferocytosis, murine macrophage-like RAW264.7 cells were co-incubated with apoptotic Jurkat T cells, and efferocytosis was assessed by flow cytometry. The expression and production of M1 and M2 markers were determined by RT-PCR, ELISA and flow cytometry. To demonstrate the involvement of peroxisome proliferator-activated receptor γ (PPARγ) in DHA-mediated effects, siRNA against PPARγ was utilized. The expression of PPARγ was examined by semiquantitative reverse-transcription polymerase chain reaction (RT-PCR), Western blot analysis and immunocytochemistry. The PPARγ activation was measured by the electrophilic gel shift assay. DHA enhanced the efferocytic ability of RAW264.7 cells, and induced their M2 polarization. Notably, knockdown of PPARγ abolished the stimulatory effect of DHA on M2 polarization as well as efferocytosis. Furthermore, lipopolysaccharide-induced production of pro-inflammatory cytokines was significantly inhibited by DHA, suggesting that DHA alters the macrophage phenotype in favor of M2 while it suppresses M1 polarization.

These findings indicate that DHA can promote resolution of inflammation by facilitating efferocytosis through M2 macrophage polarization. Therefore, DHA may have a therapeutic potential in the management of inflammatory diseases which are related to impaired resolution of inflammation.

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Does different approaches for interpretation and reporting of immunohistochemistry analysis result in the bone tissue - a review?

Immunohistochemistry (IHC) is a well-established, widely accepted method in both clinical and experimental parts of medical science. It allows receiving valuable information about any process in any tissue, and especially in bone. Each year the amount of data, received by IHC, grows in geometric progression. But the lack of standardization, especially on the post-analytical stage (interpreting and reporting of results), makes the comparison of the results of different studies impossible. Comprehensive PubMED literature search with a combination of search words "immunohistochemistry" and "scoring system" was performed and 773 articles describing IHC results were identified. After further manual analysis 120 articles were selected for detailed evaluation of used approaches. Six major approaches to the interpretation and presentation of IHC analysis results were identified, analyzed and described.

The overview of the existing approaches in evaluation and interpretation of IHC data, which are provided in the article, can be used in bone tissue research and for either better understanding of existing scoring systems or developing a new one. Standard multiparametric, semiquantitative IHC scoring systems should simplify and clarify the process of interpretation and reporting of received data.

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Do survey of radiologist attitudes and perceptions regarding the incorporation of a departmental peer review system?

The aim of this study was to investigate the attitudes and perceptions of staff radiologists regarding the incorporation of a nonanonymous peer review system at an academic hospital. A questionnaire gauging knowledge of, attitudes toward, and perceptions regarding peer review was distributed to all staff radiologists at a large academic hospital. The survey was distributed before the implementation of a nonanonymous peer review system. Data were analyzed using descriptive statistics. Responses were cross-tabulated according to subspecialty and number of years in practice. The majority of respondents agreed that peer review is important for improving patient care (31 of 36 [86%]) and professional development (29 of 36 [81%]), but the vast majority (33 of 36 [92%]) believed that peer review should be anonymous. Twenty-six of 36 respondents (72%) believed that peer review will not be safe from malpractice issues, 24 of 36 (67%) agreed that it has the potential to damage interpersonal relationships within the department, and 15 of 36 (42%) believed that it may influence their job security or rankings within the department. Significant differences were identified between radiologists with more and fewer years of practice experience.

The incorporation of a nonanonymous peer review system generates anxiety and uncertainty within a radiology department. The investigation of physicians' attitudes toward and perceptions about peer review is important for understanding the potential impact not only on patient care but also on radiologists' relationships and psychology in the workplace.

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Does naringin ameliorate memory deficits in experimental paradigm of Alzheimer 's disease by attenuating mitochondrial dysfunction?

Mitochondrial dysfunction has been well documented in age related disorders like Alzheimer's disease. Alterations in mitochondrial membrane potential lead to neuronal death by excessive generation of free radicals, inflammatory cytokines, and excitotoxins. Intracerebroventricular (ICV) streptozotocin (STZ) induced-cognitive impairment has been widely used as an experimental model of Alzheimer's disease. Naringin is a potent antioxidant, which can cross the blood brain barrier protecting brain tissue and modulating brain chemistry. The present study was designed to evaluate the effect of naringin, in ICV STZ-induced mitochondrial dysfunction and memory loss in rats. Streptozotocin (3mg/kg, ICV) was injected bilaterally in two divided doses on first and third day followed by treatment with different doses of naringin (50, 100 and 200mg/kg; p.o.) for twenty one days. Behavioral alterations were monitored using Morris water maze paradigm and elevated plus maze test. Animals were sacrificed to evaluate various biochemical and mitochondrial parameters in brain. Rivastigmine was used as a standard drug. ICV-STZ administration produced significant cognitive deficits as assessed by both Morris water maze and elevated plus maze task which is accompanied by significantly enhanced oxidative-nitrosative stress, altered acetylcholinesterase and mitochondrial enzyme activities in cerebral cortex and hippocampus of rats brain along with significantly increased brain TNF-α and IL-1β levels. Chronic treatment with naringin dose dependently restored cognitive deficits in ICV-STZ rat along with mitigation of mitochondrial dysfunction mediated oxido-nitrosative stress and cytokine release.

Our findings demonstrate that naringin ameliorates mitochondrial dysfunction mediated oxido-nitrosative stress and inflammatory surge in ICV-STZ rats.

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Does tanshinone IIA attenuate neuropathic pain via inhibiting glial activation and immune response?

Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose-dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-α and IL-1β in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord.

Taken together, our study provides evidence that TIIA inhibited SNL-induced neuropathic pain through depressing microglial activation and immune response by the inhibition of mitogen-activated protein kinases (MAPKs) pathways. Our findings suggest that TIIA might be a promising agent in the treatment of neuropathic pain.

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Are microcirculatory perfusion and vascular reactivity altered in post cardiac arrest patients , irrespective of target temperature management to 33 °C vs 36 °C?

In previous reports both microcirculatory alterations and impaired vascular reactivity have been described in post cardiac arrest patients treated with mild therapeutic hypothermia. As of now it is unknown whether these alterations are related to the temperature management or to the cardiac arrest itself. Aim of the present study was to investigate the potential difference in microcirculatory alterations and vascular reactivity in comatose patients after out of hospital cardiac arrest treated with target temperature management of 33 °C (TTM33) in comparison to patients treated with 36 °C (TTM36). Our study was designed as a predefined substudy of the open label randomized controlled TTM trial in 2 Dutch mixed ICU's. Sublingual microvascular flow index (MFI) was assessed by Side Stream Darkfield imaging and vascular reactivity at the thenar region of the hand by near infrared spectroscopy. Variables, including systemic hemodynamics were recorded at start study (T1), after 12h (T2) and after 24h (T3). 22 patients were included, 13 in TTM33 and 9 in TTM36. At T1 MFI between groups did not differ significantly (1.08 [0.4-1.9] versus 1.67 [0.7-2.4] respectively, p = 0.59). The difference between groups remained insignificant over time. At T1 tissue oxygenation (StO2) was significantly lower in TTM36 in comparison to TTM33: (44.6 ± 15.8 versus 58.9 ± 13.5, p = 0.03). Over time this difference between groups disappeared. However, vascular reactivity, expressed as the descending and ascending slope of StO2 after a standardized ischemic occlusion test was similar between groups.

In this relatively small sample size study microcirculatory blood flow and vascular reactivity did not differ nor change between TTM33 and TTM36.

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Does gRIN2B mediate susceptibility to intelligence quotient and cognitive impairments in developmental dyslexia?

Developmental dyslexia (DD) is a complex heritable condition associated with impairments in multiple neurocognitive domains. Substantial heritability has been reported for DD and related phenotypes, and candidate genes have been identified. Recently, a candidate gene for human cognitive processes, that is, GRIN2B, has been found to be associated significantly with working memory in a German DD sample. In this study, we explored the contribution of six GRIN2B markers to DD and key DD-related phenotypes by association analyses in a sample of Italian nuclear families. Moreover, we assessed potential gene-by-environment interactions on DD-related phenotypes. We carried out a family-based association study to determine whether the GRIN2B gene influences both DD as a categorical trait and its related cognitive traits in a large cohort of 466 Italian nuclear families ascertained through a proband affected by DD. Moreover, we tested the role of the selected GRIN2B markers and a set of commonly described environmental moderators using a test for G×E interaction in sib pair-based association analysis of quantitative traits in 178 Italian nuclear families. Evidence for a significant association was found with the categorical diagnosis of DD, performance intelligence quotient, phonemic elision, and auditory short-term memory. No significant gene-by-environment effects were found.

Our results add further evidence in support of GRIN2B contributing toward DD and deficits in DD. More specifically, our data support the view that GRIN2B influences DD as a categorical trait and its related quantitative phenotypes, thus shedding further light on the etiologic basis and the phenotypic complexity of this disorder.

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Are arterial stiffness and central arterial wave reflection associated with serum uric acid , total bilirubin , and neutrophil-to-lymphocyte ratio in patients with coronary artery disease?

Total bilirubin (TB) was recently recognized as an endogenous anti-inflammatory and anti-oxidant molecule. Uric acid (UA) takes part in cardiovascular diseases by inducing oxidative stress, inflammation, and endothelial dysfunction. We assessed the relationship between serum TB levels, serum UA levels, and inflammatory status assessed by neutrophil-to-lymphocyte ratio (N/L) and arterial stiffness and arterial wave reflection in patients with a clinical diagnosis of coronary artery disease (CAD). We included 145 consecutive patients admitted with stable angina pectoris (SAP) or acute coronary syndrome (ACS). Blood samples were drawn at admission for complete blood count and biochemistry. Non-invasive pulse waveform analysis for the determination of augmentation index (AIx) and carotid-femoral pulse wave velocity (PWV) measurements were performed with the commercially available SphygmoCor system. When patients were divided into tertiles of PWV and AIx, median N/L and median serum UA levels were the highest and mean TB levels were the lowest in the third tertile (p<0.001 for all). AIx and PWV were positively associated with serum UA and N/L and negatively associated with serum TB levels (p<0.001 for all). After adjustments for age, gender, heart rate, systolic blood pressure, and presence of diabetes, significant correlations persisted for N/L, UA, and TB in ACS patients (p<0.05). In the SAP group, TB was significantly negatively correlated with AIx and PWV, and UA was significantly positively correlated with PWV (p<0.05).

N/L ratio and serum UA and TB levels might be used to risk-stratify patients with respect to arterial stiffness in CAD patients, especially in the presence of ACS.

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Is minimally invasive coronary artery bypass grafting associated with improved clinical outcomes?

Minimally invasive coronary artery bypass grafting (MICS CABG) via left minithoracotomy is an alternative to off-pump coronary artery bypass (OPCAB) via sternotomy. Our objective was to evaluate the clinical outcomes after MICS CABG versus OPCAB. The medical records of patients who underwent MICS CABG from December 2009 to December 2011 and OPCAB from January 2005 to April 2011 were reviewed. Patients who underwent OPCAB were matched 2:1 to patients who underwent MICS CABG by age, sex, preoperative ejection fraction, creatinine concentration, as well as history of diabetes and myocardial infarction. A total of 130 MICS CABG patients were matched with 260 OPCAB patients. Mean bypasses in the MICS CABG and OPCAB groups were 2.1 and 3.2, respectively (P = 0.001). Extubation in the operating room (OR) occurred in 70.0% and 12.7% of patients in the MICS CABG and OPCAB groups, respectively (P = 0.001). Mean postoperative length of stay was 4 days for the MICS CABG patients versus 5 days for the OPCAB patients (P = 0.002) and 3.8 days versus 4.6 days for the MICS CABG patients extubated in the OR compared with those who remained intubated (P = 0.007). There were no 30-day mortalities in the MICS CABG group and 1 in the OPCAB group (P = 0.999). Thirty-day readmissions were similar, with 5.4% and 7.4% in the MICS CABG and OPCAB groups, respectively (P = 0.527).

Minimally invasive coronary artery bypass grafting is safe, and early clinical outcomes are comparable, if not superior in some respects, to OPCAB. Extubation in the OR is feasible, well tolerated, and associated with earlier discharge. Shorter hospital stays may decrease resource use and promote earlier return to activities; however, further research is needed.

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Is antiproliferative effect induced by novel imidazoline S43126 in PC12 cells mediated by ROS , stress activated MAPKs and caspases?

Some imidazoline compounds have pleiotropic effects including cell death in vitro. We examined the antiproliferative action of a novel imidazoline compound S43126, and the role of the I1-imidazoline receptor, ROS, MAPKs and caspases in S43126-induced cell death. PC 12 cells were treated with various concentrations of S43126 in the presence or absence of several ligands, and the effects on cell proliferation, ROS levels, and apoptosis were evaluated using Trypan Blue, Alamar Blue, Western blot and microscopy. We showed that S43126 reduced PC12 cell proliferation by greater than 50%, increased cell death by greater than 40% and increased apoptotic body formation. These effects were reversed by I1R-antagonist, efaroxan. S43126 also increased intracellular ROS levels by greater than 2.5-fold relative to vehicle-treated control. These effects were significantly inhibited by N-acetyl-cysteine. In addition, pharmacologic inhibitors of ERK, JNK and p38 MAPK, significantly reduced S43126-induced antiproliferative activity. Caspases 3, 8 and 9 were all activated in a time-dependent manner by S43126. Pan caspase inhibitor z-VAD-fmk, ameliorated the effects of S43126 on cell death and cell proliferation.

Our data showed that the effects of S43126 on PC12 cell death were partly mediated by ROS production, MAPK and caspase activation. These results further indicate an emerging role for I1R in apoptotic processes.

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Does chronic administration of phenytoin induce efflux transporter overexpression in rats?

Efflux transporters overexpression has been proposed as one of the responsible mechanism for refractory epilepsy by preventing access of the antiepileptic drug to the brain. In this work we investigated whether phenytoin (PHT), could induce efflux transporters overexpression, at different biological barriers and to evaluate the implication it could have on its pharmacokinetics and therapeutic/toxic response. Forty-two adult females Sprague Dawley divided in five groups were treated with oral doses of 25, 50 and 75mg/kg/6h of PHT for 3 days and two additionally groups were treated with intraperitoneal (ip) doses of 25mg/kg/6h or 100mg/kg/24h. At day 4 PHT plasma concentrations were measured and, obtained several organs, brain, parotid gland, liver and duodenum in which were analyzed for the Pgp expression. At day 4 PHT plasma concentrations were measured and several tissues: brain, parotid gland, liver and duodenum were obtained in order to analyze Pgp expression. In order to evaluate the oral bioavailability of PHT, two groups were administered with oral or intraperitoneal doses of 100mg/kg and plasma level were measured. An induction of the expression of efflux transporter mediated by phenytoin in a concentration-and-time dependent manner was found when increasing oral and ip doses of phenytoin, One week after the interruption of ip treatment a basal expression of transporters was recovered.

Overexpression of efflux transporters can be mediated by inducer agents like PHT in a local-concentration dependent manner, and it is reversible once the substance is removed from the body. The recovery of basal Pgp expression could allow the design of dosing schedules that optimize anticonvulsant therapy.

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Is negative feedback loop of cholesterol regulation impaired in the livers of patients with Alagille syndrome?

To characterize cholesterol regulation in the liver of patients with Alagille syndrome (AGS). Serum total cholesterol (TC) and total bile acid (TBA) levels were measured in 23 AGS patients. The expressions of genes involved in cholesterol regulation, including low-density lipoprotein receptor (LDLR), scavenger receptor class B type I (SR-BI), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), cholesterol 7α-hydroxylase (CYP7A1), ATP-binding cassette transporter (ABC) A1, and ABCG1/5/8, were measured in liver tissues from five of these patients. Expression of regulators for these genes, including farnesoid X receptor/small heterodimer partner (SHP), liver X receptor α (LXRα) and mature Sterol regulatory element-binding protein 2 (SREBP2) was measured. The expression of mature SREBP2 protein was also examined. Serum TC and TBA levels were correlated in the AGS patients. Liver cholesterol was also increased compared with controls, and correlated with bile acid contents. LDLR, SR-BI, HMGCR, and ABCGs mRNA expression were upregulated, while CYP7A1 mRNA expression was downregulated in AGS livers. SHP and LXRα mRNA expression was also increased, but maturation of SREBP2 was not suppressed in the patients.

The major upregulators of liver cholesterol might be increased in AGS patients, indicating an impaired negative feedback mechanism and accelerated liver cholesterol accumulation.

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Is sULF2 , a heparan sulfate endosulfatase , present in the blood of healthy individuals and increases in cirrhosis?

SULF2 is an extracellular sulfatase that acts on heparan sulfate proteoglycans and modulates multiple signaling pathways. It is normally bound to the cell surface but can be released into the medium of cultured cells. SULF2 is known to be increased in cirrhotic liver compared to healthy liver. We asked whether SULF2 protein was present in the blood of healthy controls and increased in patients with liver cirrhosis. We devised a sandwich ELISA for SULF2 using 2 novel monoclonal antibodies (mAbs) and measured its levels in sera of normal individuals and cirrhosis patients. SULF2 was higher in cirrhosis patients (1460 ± 1160 pg/ml, N=34) than in healthy individuals (728 ± 400 pg/ml, N=37). SULF2 levels increased with age in both healthy and patient groups.

SULF2 may be a useful serologic biomarker for liver cirrhosis.

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