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Is capsule enteroscopy useful for the therapeutic management of Crohn 's disease?

To analyze therapeutic changes in Crohn's disease (CD) patients following video capsule endoscopy (VCE) and to assess the usefulness of Lewis score and the Patency Capsule. Patency Capsule was performed in every patient that had indication for VCE, and those with negative patency did not undergo VCE. Patients with established CD that underwent VCE between January 2011 and February 2014 were selected for this study; those with suspected CD were excluded, independent of VCE results, since our purpose was to address differences in therapeutic regimen in CD patients before and after VCE. Patients with inconclusive VCE were also excluded. Patients had to be free of non-steroidal anti-inflammatories for at least 1 mo. Those patients who met these criteria were allocated into one of three groups: Staging group (asymptomatic CD patients that underwent VCE for staging of CD), Flare group (patients with active CD), or Post-op group (CD patients evaluated for post-operative recurrence). Lewis score was calculated for every VCE procedure. Statistical analysis was performed to address the impact of VCE findings on the therapeutic management of CD patients and to evaluate the utility of the Lewis score. From a total of 542 VCEs, 135 were performed in patients with CD. Patency capsule excluded nearly 25% of the patients who were supposed to undergo VCE. No videocapsule retention during VCE was reported. From these 135 patients, 29 were excluded because CD diagnosis was not established at the time of VCE. Therefore, a total of 106 patients were included in the final analysis. From these, the majority were in the Staging group (n = 73, 69%), and the remaining were in the Flare (n = 23, 22%) or Post-op (n = 10, 9%) group. Median time between diagnosis and VCE was 5.5 years. Overall, VCE determined changes in the treatment of 40% of patients: only 21% remained free of immunosuppressors after VCE compared to 44% before VCE (P < 0.001). The differences in therapy before and after VCE achieved statistical significance in the Staging and Flare groups. In addition, patients were significantly different when stratified regarding time since diagnosis to the date of VCE. A higher Lewis score was associated with therapeutic modifications (P < 0.0001); where a score higher than 1354 was related to 90% probability of changing therapy [area under the receiver operative characteristic (AUROC) 0.80 (95%CI: 0.69-0.88)].

VCE significantly changed the therapeutic management of CD patients, even in those with long-term disease. Systematic use of Patency capsule allowed for no videocapsule retention.

Does expression of epidermal growth factor receptor correlate with disease relapse and progression to androgen-independence in human prostate cancer?

The transforming growth factor alpha-epidermal growth factor receptor (EGFR) autocrine pathway has been implicated in prostate cancer cell growth. Amplification and/or overexpression of c-erbB-2, a receptor closely related to the EGFR, has been recently involved in prostate cancer progression. We investigated EGFR and c-erbB-2 expression in primary androgen-dependent and in advanced androgen-independent prostate cancer and their potential role as markers of disease progression. EGFR and c-erbB-2 expression were evaluated by immunohistochemistry in a consecutive series of 74 prostate cancer patients with the following characteristics: 29 patients (group 1) treated with radical prostatectomy; 29 patients (group 2) treated with luteinizing hormone-releasing hormone analogues and antiandrogen therapy followed by radical prostatectomy; and 16 patients with hormone-refractory metastatic disease. In all patients we evaluated: association between EGFR and/or c-erbB-2 expression and clinicopathological parameters; and disease-free survival according to EGFR and c-erbB-2 expression in univariate analysis (Kaplan-Meier product-limit method) and in multivariate analysis (Cox proportional hazards regression model). EGFR expression was found in 12 of 29 (41.4%) group 1 patients, in 22 of 29 (75.9%) group 2 patients (P < 0.0005), and in 16 of 16 (100%) metastatic patients (P < 0.005), whereas c-erbB-2 expression was found in 11 of 29 (37.9%) group 1, in 10 of 29 (34.5%) group 2 patients, and in 9 of 16 (56.3%) metastatic patients. A significant association was found between EGFR expression and a high Gleason score (P < 0.01) and between EGFR expression and higher serum prostate-specific antigen values (P < 0.02) in all groups of patients. Among the 58 patients treated with radical prostatectomy, 23 of 34 EGFR-positive patients (67.6%) relapsed, whereas only 2 of 24 EGFR-negative patients (8.3%) relapsed (P < 0.00004). c-erbB-2 expression did not significantly correlate with disease relapse (P = 0.07). In a Cox multivariate analysis, the only parameter with an independent prognostic effect on disease-free survival was EGFR expression (relative hazard, 11.23; P = 0.0014).

EGFR expression increases during the natural history of prostate cancer. Correlation with disease progression and hormone-refractory disease suggests that EGFR-targeted drugs could be of therapeutic relevance in prostate cancer.

Does surfactant improve graft function after gastric acid-induced lung damage in lung transplantation?

The number of available donor lungs is still the limiting factor in lung transplantation. We have recently shown that diluted surfactant lavage during ex vivo lung evaluation improved the graft function after gastric acid aspiration. In the present study, we hypothesized that diluted surfactant administration would recondition and improve the graft function after acid aspiration-induced lung injury in a porcine model of pulmonary transplantation. Left lung injury was induced by intrabronchial administration of 1 mL/kg betaine HCl and pepsin mixture. The animals were subsequently ventilated for 24 hours. After organ retrieval, the donor lungs were stored at 4°C for 4 hours. In the control group, left lung transplantation was performed without any surfactant treatment. In the surfactant group, the recipients received intratracheal diluted surfactant lavage just before reperfusion and ventilation. During 7 hours of reperfusion, the hemodynamic and respiratory variables were recorded on an hourly basis. Surfactant lavage resulted in lower mean pulmonary artery pressure, higher mixed venous oxygen saturation, and better oxygenation compared with the control group (p = 0.001). Bronchoalveolar lavage interleukin-6 level, protein, and neutrophil percentage at the end of the experiment were significantly higher in the control group compared with the surfactant group (p = 0.03). Minimal surface tension was significantly lower in the surfactant group compared with controls (p = 0.03).

These results demonstrate that application of diluted surfactant before reperfusion can be used effectively to improve the graft function from donor lungs injured by gastric acid aspiration.

Do transgenic mice overexpressing alpha2A-adrenoceptors in pancreatic beta-cells show altered regulation of glucose homeostasis?

To study the role of the human alpha2A-adrenoceptor in the regulation of insulin secretion and the maintenance of glucose homeostasis in transgenic mice overexpressing this receptor in pancreatic beta cells. A human insulin promoter/human alpha2C10-adrenoceptor chimeric gene was microinjected into mouse embryos and transgenic mice were obtained. Analysis by RT-PCR showed that the expression of the transgene was restricted to pancreatic islets. Study of the binding of the alpha2-antagonist [3H]RX821002 to membrane preparations showed that islets from transgenic mice had ninefold higher alpha2-adrenoceptor density than those from controls. Immunohistological analysis showed, however, no change in the number or size of islets between control and transgenic mice. Transgenic animals had normal glycaemia and insulinaemia in basal conditions but greater hyperglycaemic and hypoinsulinaemic responses after injection of the alpha2-agonist, UK14304. The lower blood insulin concentration detected in transgenic mice was a reflection of a stronger inhibitory effect of the alpha2-agonist on glucose-stimulated insulin secretion in transgenic islets than in controls. Furthermore, transgenic mice did not have lower glycaemia to basal values after an intraperitoneal glucose tolerance test. This defect was abolished by treatment with the alpha2-adrenoceptor antagonist, RX821002.

These results provide evidence in vivo that overexpression of alpha2-adrenoceptors in beta cells can lead to impaired insulin secretion and glucose intolerance.

Do use of Six-Minute Walk Test to Measure Functional Capacity After Liver Transplantation?

Functional impairment is common in people with chronic liver disease (CLD), and improvement is expected following liver transplantation (LT). The Six-Minute Walk Test (6MWT) is an objective measure of functional performance. The aims of this study were: (1) to evaluate the feasibility of 6MWT performance after LT, (2) to compare post-LT 6MWT performance over time between patients with and without CLD, (3) to determine when post-LT 6MWT performance approaches expected values, and (4) to investigate predictors of poor 6MWT performance. The 6MWT was performed by 162 consecutive ambulatory participants (50 healthy controls, 62 with CLD, 50 with LT). Sex, age, and body mass index were used to predict expected 6MWT performance. Chi-square testing, analysis of variance, and Pearson coefficients compared percentage of predicted 6-minute walk distance (%6MWD) across groups. Multivariable mixed models assessed predictors of improvement. The participants' mean age was 53.5 years (SD=13.0), 39.5% were female, and 39.1% were nonwhite. At 1-month post-LT, only 52% of all LT recipients met the inclusion criteria for 6MWT performance. Mean %6MWD values for female participants improved from 49.8 (SD=22.2) at 1 month post-LT to 90.6 (SD=12.8) at 1 year post-LT (P<.0001), which did not differ statistically from the CLD group (X̅=95.9, SD=15.6) or the control group (X̅=95.6, SD=18.0) (P=.58). However, at 1-year post-LT, mean %6MWD values for male participants (X̅=80.4, SD=19.5) remained worse than for both the CLD group (X̅=93.3, SD=13.7) and the control group (X̅=91.9, SD=14.3) (P=.03). Six-Minute Walk Test performance was directly correlated with the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) physical component score (r=.51, P<.01) and was inversely correlated with nonalcoholic steatohepatitis (r=-.52, P<.01) and diabetes (r=-.48, P<.05). In multivariate analysis adjusted for age and sex, hepatitis C independently predicted 6MWT improvement (estimated β=69.8, standard error=27.6, P=.01).

A significant proportion of patients evaluated for enrollment were excluded due to level of illness early after LT (n=99, 47.4%). Thus, sampling bias occurred in this study toward patients without significant postoperative complications.

Is continent cutaneous urinary diversion still a valid alternative after cystectomy for bladder carcinoma?

We compared patient opinions concerning reservoir/bladder function as well as quality of life (QOL) after cystectomy for bladder carcinoma and continent cutaneous urinary diversion or orthotopic bladder reconstruction. Fifteen patients with Kock reservoirs (11 females, 4 males) and 11 men with orthotopic bladders answered the European Organization for Research and Treatment of Cancer quality-of-life questionnaire-C30 as well as specially constructed questions concerning reservoir/bladder function. The glomerular filtration rate (GFR) was determined using Cr-EDTA or iohexol clearance. Functioning and global health/QOL scales did not differ between the two groups of operated patients or between diverted patients and gender- and age-matched groups from the general population. The majority of the patients were satisfied/very satisfied with their diversion but more patients were troubled by leakage in the orthotopic bladder group than in the Kock reservoir group. The GFR was similar in the two groups.

Continent cutaneous urinary diversion is associated with fewer leakage problems than orthotopic bladder reconstruction after cystectomy for bladder carcinoma.

Is dual health care system use associated with higher rates of hospitalization and hospital readmission among veterans with heart failure?

Heart failure (HF) frequently causes hospital admission and readmission. Patients receiving care from multiple providers and facilities (dual users) may risk higher health care utilization and worse health outcomes. To determine rates of emergency department (ED) visits, hospitalizations, and hospital readmissions relative to dual use among HF patients, we analyzed a retrospective cohort of 13,977 veterans with HF hospitalized at the Veterans Affairs (VA) or non-VA facilities from 2007 to 2011; we analyzed rates of acute health care utilization using zero-inflated negative binomial regression. Compared to VA-only users and dual users, individuals receiving all of their ED and hospital care outside the VA tended to be older, more likely to be non-Hispanic white and married, and less likely to have high levels of service connected disability. Compared to VA-only users, dual users had significantly higher rates of ED visits for HF as a primary diagnosis (adjusted rate ratio 1.15, 95% CI 1.04-1.27), hospitalization for HF (adjusted rate ratio 1.4, 95% CI 1.26-1.56), hospital readmission after HF hospitalization (all cause) (1.46, 95% CI 1.30-1.65), and HF-specific hospital readmission after HF hospitalization (1.46, 95% CI 1.31-1.63). With the exception of hospitalization for any primary diagnosis, non-VA-only users had significantly lower rates of ED visits, hospitalization, and readmission compared to VA-only users.

Dual use is associated with higher rates of health care utilization among patients with HF. Interventions should be devised to encourage continuity of care where possible and to improve the effectiveness and safety of dual use in instances where it is necessary or desired.

Does sUMOylation of the farnesoid X receptor ( FXR ) regulate the expression of FXR target genes?

Small ubiquitin-like modifiers (SUMO) are covalently conjugated to other proteins including nuclear receptors leading to modification of various cellular processes. Ligand-dependent SUMOylation of farnesoid X receptor (FXR) negatively regulates the expression of its target genes.

SUMO modification attenuates the capacity of FXR to function as a transcriptional activator.

Does caffeine ingestion improve power output decrement during 3-min all-out exercise?

To investigate the effect of caffeine ingestion on the 3-min all-out test (3MT) performance and plasma electrolytes in athletes. Fifteen collegiate male basketball players were recruited and completed two trials separated by at least 1 week in caffeine (CAF, 6 mg kg(-1)) and placebo conditions. During the first visit, participants performed an incremental cycling test to determine their 3MT resistance. After a familiarization trial, participants performed a CAF or PL trial according to a randomized crossover design. One hour after ingesting capsules, the participants performed the 3MT to estimate the end-test power (EP) and work done above EP (WEP). Blood samples for sodium (Na(+)), potassium (K(+)), pH, and lactate concentrations were drawn pretest, 1 h after ingestion, and posttest. Significant differences in WEP (CAF vs. PL, 13.4 ± 3.0 vs. 12.1 ± 2.7 kJ, P < 0.05) but not in EP (CAF vs. PL, 242 ± 37 vs. 244 ± 42 W, P > 0.05) were determined between the conditions. Compared with the PL condition, the CAF condition yielded significantly higher power outputs (60-150 s), a lower fatigue rate during the 3MT (CAF vs. PL, 0.024 ± 0.007 vs. 0.029 ± 0.006 s(-1), P < 0.05), a significantly higher lactate concentration after the 3MT, and significantly lower K(+) concentrations at 1 h after caffeine ingestion. There were no significant interaction effects for pH and Na(+) concentrations.

Caffeine ingestion did not change EP but improved WEP and the rate of decline in power output during short-term, severe exercise.

Does insertion of self-expandable nitinol stents without previous balloon angioplasty reduce restenosis compared with PTA prior to stenting?

To compare the development of intimal hyperplasia after deployment of a self-expanding nitinol stent with and without previous percutaneous transluminal balloon angioplasty (PTA), with the results after PTA alone. In nine healthy pigs, the iliac arteries were divided into three groups: group 1 (n = 6 arteries) was treated with PTA; group 2 n = 6) with insertion of self-expanding stents after PTA; and group 3 (n = 6) with stent insertion without previous PTA. After 8 weeks the vessels were examined with intravascular ultrasonography, histologic examination and morphometric analysis. Although the injury index in group 1 (0.17 +/- 0.57) was lower (p <0.05) than in group 2 (0.26 +/- 0.06) and group 3 (0.26 +/- 0.08), PTA-treated arteries showed significantly (p <0.05) reduced mean luminal gain (0.53 +/- 2.84) compared with arteries treated with PTA prior to stenting (2.58 +/- 1.38) and compared with stenting alone (4.65 +/- 5.34). Stenting after PTA resulted in a higher (p <0.05) restenosis index (2.63 +/- 1.06) compared with stenting without PTA (1.35 +/- 0.59). Group 2 also had a significantly thicker intima p <0.05) and 83% and 74% higher intima/media ratio (p <0.05) compared with groups 1 and 3, respectively.

Insertion of a self-expandable nitinol stent without previous PTA results in less intimal hyperplasia than if PTA is performed prior to stenting, suggesting that direct stenting can be used in angioplasty sessions with a favorable outcome.

Does routine fecal occult blood testing predict necrotizing enterocolitis in very low birth weight neonates?

To determine sensitivity, specificity, predictive value of routine fecal occult blood (FOB) testing on the identification of Bell's Stage II or III necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. Retrospective medical record review of VLBW infants from 2012- 2013 evaluating FOB results and clinical and demographic risk factors. We determined predictive values of positive FOB testing within 48 hours of definite NEC diagnosis. We performed logistic regression analyses for predictors of NEC and for predictors of having positive FOB during NICU admission. The incidence of NEC in our cohort of 203 infants was 3.9% (n = 8). None had positive FOB results within 48 hours of diagnosis, and only 12.5% had any positive FOB within 7 days. Sensitivity of positive FOB for predicting definite NEC = 0%, specificity = 34.4%, and positive predictive value = 0%. A majority of VLBWs (67.0%) had > one positive FOB result during their NICU course. On logistic regression, intrauterine growth restricted (IUGR) infants had significantly higher odds of both developing NEC and of having positive FOB. Positive FOB was not a significant predictor of NEC. Those with lower birth gestational ages had higher odds of positive FOB.

Positive FOB testing occurred in a majority of VLBW infants, with higher odds in the more preterm and IUGR. However, the sensitivity, specificity, and predictive value of routine FOB testing for identifying NEC were all very poor. Our data demonstrates that this test offers no advantages in the early diagnosis of NEC.

Do human TSLP and TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under Th2-polarizing conditions?

BACKGROUND" Human thymic stromal lymphopoietin (TSLP) is expressed in the human asthmatic lung and activates dendritic cells (DCs) to strongly induce proallergic T-helper type 2 (Th2) cell responses, suggesting that TSLP plays a critical role in the pathophysiology of human asthma. Th2 cells are predominantly involved in mild asthma, whereas a mixture of Th1 and Th2 cells with neutrophilic inflammation, probably induced by Th17, affects more severe asthmatic disease. Exacerbation of asthmatic inflammation is often triggered by airway-targeting RNA viral infection; virus-derived double-stranded RNA, Toll-like receptor (TLR)3 ligand, activates bronchial epithelial cells to produce pro-inflammatory mediators, including TSLP. Because TSLPR-expressing DCs express TLR3, we examined how the relationship between TSLP and TLR3 ligand stimulation influences DC activation. CD11c(+)DCs purified from adult peripheral blood were cultured in TLR ligands containing media with or without TSLP and then co-cultured with allogeneic naïve CD4(+)T cells. CD11c(+) DCs responded to a combination of TSLP and TLR3 ligand, poly(I : C), to up-regulate expression of the functional TSLP receptor and TLR3. Although TSLP alone did not induce IL-23 production by DCs, poly(I : C) alone primed DCs for the production of IL-23, and a combination of TSLP and poly(I : C) primed DCs for further production of IL-23. The addition of poly(I : C) did not inhibit TSLP-activated DCs to prime naïve CD4(+) T cells to differentiate into inflammatory Th2 cells. Furthermore, DCs activated by a combination of TSLP and poly(I : C) primed more naïve CD4(+) T cells to differentiate into Th17-cytokine-producing cells with a central memory T cell phenotype compared with DCs activated by poly(I : C) alone.

These results suggest that through DC activation, human TSLP and TLR3 ligands promote differentiation of Th17 cells with the central memory T cell phenotype under Th2-polarizing conditions.

Do pharmacological methyl group donors block skeletal metastasis in vitro and in vivo?

DNA hypomethylation was previously implicated in metastasis. In the present study, we examined whether methyl supplementation with the universal methyl donor S-adenosylmethionine (SAM) inhibits prostate cancer associated skeletal metastasis. Highly invasive human prostate cancer cells PC-3 and DU-145 were treated with vehicle alone, S-adenosylhomocysteine (SAH) or SAM and their effects on tumour cell proliferation, invasion, migration and colony formation were monitored. For in vivo studies, control (SAH) and SAM-treated PC-3 cells were injected into the tibia of Fox chase SCID mice and skeletal lesions were determined by X-ray and μCT. To understand possible mechanisms involved, we delineated the effect of SAM on the genome-wide methylation profile of PC-3 cells. Treatment with SAM resulted in a dose-dependent inhibition of tumour cell proliferation, invasion, cell migration, colony formation and cell cycle characteristics. Animals injected with 250 μM SAM-treated cells developed significantly smaller skeletal lesions, which were associated with increases in bone volume to tumour volume ratio and connectivity density as well as decreased trabecular spacing. Genome-wide methylation analysis showed differential methylation in several key signalling pathways implicated in prostate cancer including the signal transducer and activator of transcription 3 (STAT3) pathway. A selective STAT3 inhibitor decreased tumour cell invasion, effects which were less pronounced as compared with SAM.

These studies provide a possible mechanism for the role of DNA demethylation in the development of skeletal metastasis and a rationale for the use of hypermethylation pharmacological agents to impede the development and progression of skeletal metastasis.

Does [ Protein kinase inhibitor flavopiridol inhibit the replication of influenza virus in vitro ]?

To investigate the antiviral effect of the flavonoid compound flavopiridol on influenza A virus and explore its antiviral mechanism. The A549 or Madin-Darby canine kidney (MDCK) cells were infected with influenza A virus A/WSN/33 and treated with flavopiridol. The viral proteins were determined by immunolotting and immunofluorescence. The virus titer was measured by plaque assay. To verify whether the activity of host RNA polymerase II was affected by flavopiridol, the phosphorylation status of RNA polymerase II CTD domain was analyzed by immunoblotting with phosphor-specific antibody. The amount of viral mRNA, vRNA and cRNA was measured by reverse transcription and PCR. The amount of viral proteins was significantly decreased and the titer of virus was greatly reduced in cells treated with flavopiridol. Further analysis showed that the phosphorylation of Ser-2 in the heptad repeat of the CTD domain in RNA polymerase II was decreased in falvopiridol treated cell. This result indicated that the transcription elongation activity of RNA pol II was impaired upon treatment with flavopiridol. Then we found that the amount of viral vRNA was significantly decreased in flavopiridol treated cells while only moderate decrease of mRNA was observed and almost no reduction of cRNA was detected.

Flavopiridol can greatly suppress the replication of influenza virus. We propose that the inhibition of the transcription elongation activity of host RNA polymerase II would cause the decrease of viral mRNA transcription.

Are voltage-gated sodium channels required for heart development in zebrafish?

Voltage-gated sodium channels initiate action potentials in excitable tissues. Mice in which Scn5A (the predominant sodium channel gene in heart) has been knocked out die early in development with cardiac malformations by mechanisms which have yet to be determined. Here we addressed this question by investigating the role of cardiac sodium channels in zebrafish heart development. Transcripts of the functionally-conserved Scn5a homologs scn5Laa and scn5Lab were detected in the gastrulating zebrafish embryo and subsequently in the embryonic myocardium. Antisense knockdown of either channel resulted in marked cardiac chamber dysmorphogenesis and perturbed looping. These abnormalities were associated with decreased expression of the myocardial precursor genes nkx2.5, gata4, and hand2 in anterior lateral mesoderm and significant deficits in the production of cardiomyocyte progenitors. These early defects did not appear to result from altered membrane electrophysiology, as prolonged pharmacological blockade of sodium current failed to phenocopy channel knockdown. Moreover, embryos grown in calcium channel blocker-containing medium had hearts that did not beat but developed normally.

These findings identify a novel and possibly nonelectrogenic role for cardiac sodium channels in heart development.

Does iL-17A increase the expression of proinflammatory chemokines in human pancreatic islets?

Cytotoxic T cells and macrophages contribute to beta cell destruction in type 1 diabetes at least in part through the production of cytokines such as IL-1β, IFN-γ and TNF-α. We have recently shown the IL-17 pathway to be activated in circulating T cells and pancreatic islets of type 1 diabetes patients. Here, we studied whether IL-17A upregulates the production of chemokines by human pancreatic islets, thus contributing to the build-up of insulitis. Human islets (from 18 donors), INS-1E cells and islets from wild-type and Stat1 knockout mice were studied. Dispersed islet cells were left untreated, or were treated with IL-17A alone or together with IL-1β+IFN-γ or TNF-α+IFN-γ. RNA interference was used to knock down signal transducer and activator of transcription 1 (STAT1). Chemokine expression was assessed by quantitative RT-PCR, ELISA and histology. Cell viability was evaluated with nuclear dyes. IL-17A augmented IL-1β+IFN-γ- and TNF-α+IFN-γ-induced chemokine mRNA and protein expression, and apoptosis in human islets. Beta cells were at least in part the source of chemokine production. Knockdown of STAT1 in human islets prevented cytokine- or IL-17A+cytokine-induced apoptosis and the expression of particular chemokines, e.g. chemokine (C-X-C motif) ligands 9 and 10. Similar observations were made in islets isolated from Stat1 knockout mice.

Our findings indicate that IL-17A exacerbates proinflammatory chemokine expression and secretion by human islets exposed to cytokines. This suggests that IL-17A contributes to the pathogenesis of type 1 diabetes by two mechanisms, namely the exacerbation of beta cell apoptosis and increased local production of chemokines, thus potentially aggravating insulitis.

Is the Combination of Piperacillin-Tazobactam and Vancomycin Associated with Development of Acute Kidney Injury?

To evaluate the association of the development of acute kidney injury (AKI) when piperacillin-tazobactam is used in combination with vancomycin compared with vancomycin with or without a β-lactam. Meta-analysis of 15 observational cohort studies. A total of 3258 adult inpatients who received vancomycin + piperacillin-tazobactam versus vancomycin alone (10 studies); vancomycin + piperacillin-tazobactam versus vancomycin + β-lactam (four studies); or vancomycin + piperacillin-tazobactam versus vancomycin alone or vancomycin + other antibiotics (one study). The PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and Cochrane databases, as well as meeting proceedings, were searched (1966-June 1, 2016). Quality of studies was assessed by using the Newcastle-Ottawa Quality Assessment Scale (NOQAS). The primary outcome of this meta-analysis was to evaluate the association of development of AKI with the combined use of piperacillin-tazobactam and vancomycin. A subgroup analysis was also performed that examined the outcome by comparison groups (vancomycin alone or vancomycin + β-lactam). Sensitivity analysis was performed to explore if the results differed based on removal of abstracts and removal of low-quality studies (NOQAS scores of 6 or lower). All analyses were performed using the random effects model. NOQAS scores for the 15 studies ranged from 3-7 points (of a total of 9). Overall, there was an association with the development of AKI with vancomycin + piperacillin-tazobactam compared with vancomycin ± β-lactam (odds ratio [OR] 3.649, 95% confidence interval [CI]2.157-6.174; I2= 83.5%, p<0.001). The association remained significant when abstracts were removed (OR 3.498, 95% CI 1.747-7.003, I2= 82.3%, p<0.001) and when low-quality studies were removed (OR 4.596, 95% CI 2.929-7.212, I2= 0%, p<0.001). The association for the development of AKI with vancomycin + piperacillin-tazobactam compared with vancomycin alone was significant (OR 3.980, 95% CI 2.749-5.763, I2= 31.4%, p<0.001), although the association did not remain significant for the vancomycin + β-lactam subgroup (OR 3.029, 95% CI 0.942-9.738, I2= 82.3%, p=0.063).

Vancomycin + piperacillin-tazobactam was associated with an increased risk of AKI compared with vancomycin ± β-lactam. Practitioners need to be vigilant about this association when prescribing this combination of antibiotics.

Is obstetric outcome of natural and assisted conception twin pregnancies similar?

The risk of obstetric intervention and adverse fetal or neonatal outcome is considerably higher in multiple gestation than in singleton pregnancy. How assisted conception influences obstetric management and outcome in twin pregnancies has not been evaluated. A survey of all twin pregnancies in Iceland and the Tayside Region, Scotland for a four year period, 1990-93, comparing twins after assisted fertilization with natural conception. The total number of twin pregnancies was 522, of which 453 were natural conceptions and 69 assisted. The twin rate was 1:75 among natural conceptions, but 1:5 in women having assisted fertilization. Mean gestational age in both groups was 36 weeks. Elective Cesarean section was used more often in the assisted conception group (odds ratio 2.57; p = 0.003). Induction rates did not differ to any significant degree and once labor commenced, no difference was seen between assisted and natural conception twins in the mode of delivery or neonatal short term morbidity. Birthweight, gestational length and perinatal mortality rates by conventional and extended classification were not different.

After allowing for more frequent elective Cesarean section in the obstetric care of the assisted conception pregnancies, there was no major difference in obstetric and neonatal management or outcome between twins resulting from natural and assisted conception.

Do cortisol-secreting adrenal adenomas express 11beta-hydroxysteroid dehydrogenase type-2 gene yet possess low 11beta-HSD2 activity?

11beta-hydroxysteroid dehydrogenase Type-2 (11beta-HSD2) is an unidirectional enzyme that catalyzes the conversion of glucocorticoid hormones cortisol and corticosterone (B) into their corresponding inactive forms, cortisone, and 11-dehydrocorticosterone (DH-B). We have provided evidence that 11beta-HSD2 is expressed as messenger RNA (mRNA) and protein in human adrenocortical cells, where its activity is inhibited in vitro by the main glucocorticoid agonists, adrenocorticotropic hormone (ACTH) and angiotensin-II. It seemed worthwhile, therefore, to study the gene expression and activity of 11beta-HSD2 in cortisol-secreting adrenocortical adenomas. Three adrenal adenomas that produced Cushing syndrome were recruited. Three normal adrenal glands were obtained from patients who underwent unilateral nephrectomy with ipsilateral adrenalectomy for renal cancer. 11beta-HSD2 gene expression was studied by reverse transcriptionpolymerase chain reaction (RT-PCR) in adenoma and normal adrenocortical tissue. Cortisol, B, cortisone, and DH-B production by adenoma and adrenal slices in vitro was assayed by quantitative high-performance liquid chromatography (HPLC), and the activity of 11beta-HSD2 was evaluated by measuring the conversion of [3H]-cortisol to [3H]-cortisone. RT-PCR allowed the detection of the 11beta-HSD2 mRNA in the three adrenal adenomas and normal adrenal cortices examined. Under basal conditions, adenoma slices secreted higher amounts of cortisol and B, but markedly lower amounts of cortisone and DH-B than adrenal slices. ACTH raised cortisol and B production from both specimens, and it lowered cortisone and DH-B yield. The level basal conversion of [3H]-cortisol to [3H]-cortisone was notably less in adenomas than in adrenals, and ACTH decreased it in both tissues.

Collectively, our findings indicate that cortisol-secreting adrenal adenomas express the 11beta-HSD2 gene, but the activity of the enzyme is suppressed in adenomas when compared with the normal adrenal cortex. We advance the hypothesis that the elevated local concentration of steroid hormones that occur in adenomas down-regulates 11beta-HSD2 activity, thereby contributing to their abnormal steroidogenic function.

Do germline mutations of the CBL gene define a new genetic syndrome with predisposition to juvenile myelomonocytic leukaemia?

CBL missense mutations have recently been associated with juvenile myelomonocytic leukaemia (JMML), an aggressive myeloproliferative and myelodysplastic neoplasm of early childhood characterised by excessive macrophage/monocyte proliferation. CBL, an E3 ubiquitin ligase and a multi-adaptor protein, controls proliferative signalling networks by downregulating the growth factor receptor signalling cascades in various cell types. CBL mutations were screened in 65 patients with JMML. A homozygous mutation of CBL was found in leukaemic cells of 4/65 (6%) patients. In all cases, copy neutral loss of heterozygosity of the 11q23 chromosomal region, encompassing the CBL locus, was demonstrated. Three of these four patients displayed additional features suggestive of an underlying developmental condition. A heterozygous germline CBL p.Y371H substitution was found in each of them and was inherited from the father in one patient. The germline mutation represents the first hit, with somatic loss of heterozygosity being the second hit positively selected in JMML cells. The three patients display a variable combination of dysmorphic features, hyperpigmented skin lesions and microcephaly that enable a 'CBL syndrome' to be tentatively delineated. Learning difficulties and postnatal growth retardation may be part of the phenotype.

A report of germline mutations of CBL in three patients with JMML is presented here, confirming the existence of an unreported inheritable condition associated with a predisposition to JMML.

Do preterm infants with high polyunsaturated fatty acid and plasmalogen content in tracheal aspirates develop bronchopulmonary dysplasia less often?

Oxygen toxicity causes chronic bronchopulmonary dysplasia (BPD) in extremely preterm infants. Polyunsaturated fatty acids (PUFA) and plasmalogens are the two main substrates for lipid peroxidation in the pulmonary surfactant. In the present study, we tested whether low concentrations of both were associated with development of BPD and whether both were further reduced during mechanical ventilation with oxygen. Prospective, noninterventional, descriptive study. Level III neonatal intensive care unit in a university hospital. In 25 extremely low birth weight infants with respiratory distress syndrome, tracheal aspirates were collected immediately after birth and in the following 4 days. As control, tracheal and pharyngeal aspirates were collected from healthy infants immediately after birth. The amount of PUFA and dimethylacetals (DMA, representing plasmalogens) was determined gas-chromatographically. None. The relative percentages of PUFA and DMA on all fatty acids in non-BPD infants (PUFA% 26+/-8.9, DMA% 3.5+/-1.2) were higher compared with infants who developed BPD (PUFA% 14.5+/-3.8, DMA% 1.8+/-0.9). In term healthy infants, DMA% and PUFA% were in the same range as in the BPD group. The higher levels found for non-BPD infants decreased after day 1 to values equal to the BPD group and remained low.

The results suggest that initially higher levels of PUFA and plasmalogens in the tracheal effluent are associated with a reduced risk of developing BPD and are reduced during the first day of ventilation.

Does helicobacter pylori induce cell migration and invasion through casein kinase 2 in gastric epithelial cells?

Chronic infection with Helicobacter pylori (H. pylori) is causally linked with gastric carcinogenesis. Virulent H. pylori strains deliver bacterial CagA into gastric epithelial cells. Induction of high motility and an elongated phenotype is considered to be CagA-dependent process. Casein kinase 2 plays a critical role in carcinogenesis through signaling pathways related to the epithelial mesenchymal transition. This study was aimed to investigate the effect of H. pylori infection on the casein kinase 2-mediated migration and invasion in gastric epithelial cells. AGS or MKN28 cells as human gastric epithelial cells and H. pylori strains Hp60190 (ATCC 49503, CagA(+)) and Hp8822 (CagA(-)) were used. Cells were infected with H. pylori at multiplicity of infection of 100 : 1 for various times. We measured in vitro kinase assay to examine casein kinase 2 activity and performed immunofluorescent staining to observe E-cadherin complex. We also examined β-catenin transactivation through promoter assay and MMP7 expression by real-time PCR and ELISA. H. pylori upregulates casein kinase 2 activity and inhibition of casein kinase 2 in H. pylori-infected cells profoundly suppressed cell invasiveness and motility. We confirmed that casein kinase 2 mediates membranous α-catenin depletion through dissociation of the α-/β-catenin complex in H. pylori-infected cells. We also found that H. pylori induces β-catenin nuclear translocation and increases MMP7 expressions mediated through casein kinase 2.

We show for the first time that CagA(+) H. pylori upregulates cellular invasiveness and motility through casein kinase 2. The demonstration of a mechanistic interplay between H. pylori and casein kinase 2 provides important insights into the role of CagA(+) H. pylori in the gastric cancer invasion and metastasis.

Is vasodilation to bradykinin mediated by an ouabain-sensitive pathway as a compensatory mechanism for impaired nitric oxide availability in essential hypertensive patients?

In essential hypertension, endothelium-dependent vasodilation is impaired because of reduced nitric oxide (NO) availability, which is mainly caused by oxidative stress. The present study was designed to identify the mechanism(s) responsible for NO-independent vasodilation to bradykinin in patients with essential hypertension. In 16 healthy subjects (49.5+/-5.8 years; 118.6+/-3.5/78.9+/-2.9 mm Hg) and 16 patients with essential hypertension (47.9+/-4.8 years; 154.6+/-4.5/102.9+/-3.2 mm Hg), we measured modifications in forearm blood flow (strain-gauge plethysmography) during intrabrachial infusion of bradykinin (5, 15, or 50 ng/100 mL of forearm tissue per minute) in the presence of saline, N(omega)-monomethyl-L-arginine (L-NMMA; used to inhibit NO synthase; 100 microg/100 mL of forearm tissue per minute), and ouabain (to block Na(+)K(+)/ATPase and prevent hyperpolarization; 0.7 microg/100 mL of forearm tissue per minute). In healthy subjects, vasodilatation to bradykinin was significantly blunted by L-NMMA and unaffected by ouabain. In hypertensive patients, vasodilatation to bradykinin was not modified by L-NMMA, but it was significantly reduced by ouabain. In an adjunctive group of 8 hypertensive patients (49.9+/-3.8 years; 155.9+/-5.5/103.7+/-3.9 mm Hg), the response to bradykinin was repeated during the administration of intrabrachial vitamin C (a scavenger for oxygen free radicals; 8 mg/100 mL of forearm tissue per minute). In these patients, L-NMMA-induced inhibition of vasodilation to bradykinin was restored, and ouabain was no longer effective. In a final group of 6 normotensive controls (45.9+/-4.1 years; 115.1+/-2.9/79.3+/-2.1 mm Hg), vasodilation to bradykinin residual to L-NMMA blockade was further inhibited by simultaneous ouabain infusion.

Vasodilation to bradykinin is impaired in essential hypertensive patients because of an NO-system alteration caused by oxidative stress, and it is mediated by an alternative pathway, possibly involving endothelium-dependent hyperpolarization.

Does neuroticism influence brain activity during the experience of visceral pain?

One particularly important individual dynamic known to influence the experience of pain is neuroticism, of which little is known about in visceral pain research. Our aim was to study the relationship between neuroticism, psychophysiologic response, and brain processing of visceral pain. Thirty-one healthy volunteers (15 male; age range, 22-38 years) participated in the study. The Eysenck Personality Questionnaire was used to assess neuroticism. Skin conductance level, pain ratings, and functional magnetic resonance imaging data were acquired during anticipation of pain and painful esophageal distention. The effect of neuroticism was assessed using correlation analysis. There was a wide spread of neuroticism scores (range, 0-22) but no influence of neuroticism on skin conductance level and pain tolerance or pain ratings. However, a positive correlation between brain activity and neuroticism during anticipation was found in regions associated with emotional and cognitive pain processing, including the parahippocampus, insula, thalamus, and anterior cingulate cortex. These regions showed a negative correlation with neuroticism during pain (P < .001).

This study provides novel data suggesting higher neuroticism is associated with engagement of brain regions responsible for emotional and cognitive appraisal during anticipation of pain but reduced activity in these regions during pain. This may reflect a maladaptive mechanism in those with higher neuroticism that promotes overarousal during anticipation and avoidance coping during pain.

Does valproic Acid increase expression of neuronal stem/progenitor cell in spinal cord injury?

This study investigates the effect of valproic acid (VPA) on expression of neural stem/progenitor cells (NSPCs) in a rat spinal cord injury (SCI) model. Adult male rats (n=24) were randomly and blindly allocated into three groups. Laminectomy at T9 was performed in all three groups. In group 1 (sham), only laminectomy was performed. In group 2 (SCI-VPA), the animals received a dose of 200 mg/kg of VPA. In group 3 (SCI-saline), animals received 1.0 mL of the saline vehicle solution. A modified aneurysm clip with a closing force of 30 grams was applied extradurally around the spinal cord at T9, and then rapidly released with cord compression persisting for 2 minutes. The rats were sacrificed and the spinal cord were collected one week after SCI. Immunohistochemistry (IHC) and western blotting sample were obtained from 5 mm rostral region to the lesion and prepared. We analyzed the nestin immunoreactivity from the white matter of ventral cord and the ependyma of central canal. Nestin and SOX2 were used for markers for NSPCs and analyzed by IHC and western blotting, respectively. Nestin and SOX2 were expressed significantly in the SCI groups but not in the sham group. Comparing SCI groups, nestin and SOX2 expression were much stronger in SCI-VPA group than in SCI-saline group.

Nestin and SOX2 as markers for NSPCs showed increased expression in SCI-VPA group in comparison with SCI-saline group. This result suggests VPA increases expression of spinal NSPCs in SCI.

Does expression of haem oxygenase-1 correlate with tumour aggressiveness and BRAF V600E expression in thyroid cancer?

Haem oxygenase-1 (HO-1) is an inducible enzyme that participates in haem degradation. Recent studies have indicated that HO-1 activation may play a role in tumour development and progression. The aim of this study was to evaluate the expression of HO-1 in thyroid cancer and its clinicopathological significance. We observed up-regulation of HO-1 in papillary thyroid tumours in comparison with normal thyroid tissue. Immunohistochemical analysis revealed that 48% of papillary cancers and 36% of follicular cancers, but none of normal thyroid tissues, were positive for HO-1 expression. Among 129 differentiated thyroid cancers, HO-1 expression was associated with patient age (P = 0.001), TNM stage (P = 0.001), and Mayo Clinic metastasis, patient age, completeness of resection, local invasion and tumour size score (P = 0.001). BRAF V600E expression was evaluated immunohistochemically and validated by Sanger sequencing. There was a strong association between HO-1 and BRAF V600E expression in papillary cancers (P = 0.002).

Overexpression of HO-1 in a subset of thyroid cancers is associated with tumour aggressiveness and BRAF V600E expression. HO-1 might have a potential role in prognosis and targeted treatment in patients with thyroid cancer.

Does continuous tissue glucose monitoring correlate with measurement of intermittent capillary glucose in patients with distributive shock?

Intermittent glycemic measurements in patients admitted to the intensive care unit (ICU) can result in episodes of severe hypoglycemia or in a poor control of glycemia range. We designed a study to assess accuracy and reliability of continuous monitoring of tissue glucose for patients with distributive shock. Consecutive patients admitted to the ICU with a diagnosis of distributive shock and the need of insulin infusion for glycemic control were included in the study. These patients were implanted a Continuous Glucose Control Monitoring System (CGMS) with the sensor inserted subcutaneously into the abdominal wall. CGMS values were recorded every 5min. Capillary glucose (CG) was monitored for adjusting insulin perfusion according to the ICU protocol. Correlation between both methods was assessed. A total of 11,673 CGMS and 348 CG values were recorded. In five patients, CGMS failed to detect tissue glucose. A glucose value <3.33mmol/l (<60mg/dl) was observed in 3.6% of CGMS and in 0.29% CG values. 295 pairs of measurements were included in the statistical analysis for correlation assessment. The intraclass correlation coefficient was 0.706. The Pearson correlation coefficient was 0.71 (p<0.0001, 95% CI 0.65-0.76). The mean of differences between both measurement methods was 0.22mmol/l (3.98mg/dl) (95% CI 0.66-7.31).

When the Continuous Glucose Control Monitoring System (CGMS) is able to obtain data (75% of the patients), there is correlation between the values obtained by this method and capillary blood glucose in patients with distributive shock. CGMS can detect more episodes of glycemic excursions outside the normal range than intermittent capillary glucose monitoring. Variables that may impair glucose metabolism and peripheral soft tissues perfusion could impair CGMS measurements.

Does contact sensing provide a highly accurate means to titrate radiofrequency ablation lesion depth?

Transmural lesions are essential for efficacious ablation. There are, however, no accurate means to estimate lesion depth. Explore use of the electrical coupling index (ECI) from the EnSite Contact™ System as a potential variable for lesion depth estimation. Radiofrequency (RF) ablation lesions were created in atria and the thighs of swine using an irrigated RF catheter. Power was 30 W for 20 or 30 seconds intracardiac and 30-50 W for 10-60 seconds for the thigh. Intracardiac, the percentage change in ECI during ablation was compared with transmurality and collateral damage occurrence. For the thigh model, an algorithm estimating lesion depth was derived. Factors included: power, duration, and change in the ECI subcomponents (ΔECI+) during ablation. The ΔECI+ algorithm was compared to one using power and duration (PD) alone. Intracardiac, lesions with ≥12% reduction in ECI were more likely to be transmural (92.3% vs. 59.4%, P < 0.001). Twenty-second lesions were less likely to cause collateral damage compared to 30 seconds (33% vs. 70%, P = 0.003), while transmurality was similar. With the thigh model, ΔECI+ had a better correlation than the PD algorithm (P < 0.01). Accuracy of the ΔECI+ algorithm was unimproved with inclusion of tip orientation, while PD improved (R(2) = 0.64).

Change in ECI provides evidence of transmural versus nontransmural swine intracardiac atrial lesions. A lesion depth estimation algorithm using ECI subcomponents is unaffected by tip orientation and is more accurate than using PD alone.

Does endogenous carbon monoxide production correlate weakly with severity of acute illness?

The enzyme haeme oxygenase-1 is highly inducible by oxidative agents. Its product carbon monoxide is thought to exert anti-inflammatory properties. We recently showed, that critically ill patients produce higher amounts of carbon monoxide compared to healthy controls. In the present study we compare endogenous carbon monoxide production with the severity of illness of intensive care unit patients. Exhaled carbon monoxide concentration was measured in 95 mechanically ventilated, critically ill patients (mean age +/- SD, 59.5 +/- 15.7) on a carbon monoxide monitor. Measurements were taken every hour for 24 h in each patient. Data were analysed using Mann-Whitney rank sum test. Correlation analysis was performed with the Spearman's rank order correlation. Carbon monoxide production correlated weakly with the multiple organ dysfunction score (R = 0.27; P = 0.009). Patients suffering from cardiac disease (median 22.5, interquartile range 16.2-27.4 microL kg(-1) h(-1) vs. median 18.2, interquartile range 14.2-21.8 microL kg(-1) h(-1), P = 0.008) and critically ill patients undergoing dialysis (median 25.0, interquartile range 21.4-30.2 microL kg(-1) h(-1), vs. median 19.4, interquartile range 14.7-23.3 microL kg(-1) h(-1), P = 0.004) produced significantly higher amounts of carbon monoxide compared to critically ill controls.

The findings suggest that endogenous carbon monoxide production might reflect the severity of acute organ dysfunction.

Is methylphenidate side effect profile influenced by genetic variation in the attention-deficit/hyperactivity disorder-associated CES1 gene?

A naturalistic, prospective study of the influence of genetic variation on dose prescribed, clinical response, and side effects related to stimulant medication in 77 children with attention-deficit/hyperactivity disorder (ADHD) was undertaken. The influence of genetic variation of the CES1 gene coding for carboxylesterase 1A1 (CES1A1), the major enzyme responsible for the first-pass, stereoselective metabolism of methylphenidate, was investigated. Parent- and teacher-rated behavioral questionnaires were collected at baseline when the children were medication naïve, and again at 6 weeks while they were on medication. Medication dose, prescribed at the discretion of the treating clinician, and side effects, were recorded at week 6. Blood and saliva samples were collected for genotyping. Single nucleotide polymorphisms (SNPs) were selected in the coding, non-coding and the 3' flanking region of the CES1 gene. Genetic association between CES1 variants and ADHD was investigated in an expanded sample of 265 Irish ADHD families. Analyses were conducted using analysis of covariance (ANCOVA) and logistic regression models. None of the CES1 gene variants were associated with the dose of methylphenidate provided or the clinical response recorded at the 6 week time point. An association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate was found. The two associated CES1 markers were in linkage disequilibrium and were significantly associated with ADHD in a larger sample of ADHD trios. The associated CES1 markers were also in linkage disequilibrium with two SNP markers of the noradrenaline transporter gene (SLC6A2).

This study found an association between two CES1 SNP markers and the occurrence of sadness as a side effect of short-acting methylphenidate. These markers were in linkage disequilibrium together and with two SNP markers of the noradrenaline transporter gene.

Does neuron-specific prolyl-4-hydroxylase domain 2 knockout reduce brain injury after transient cerebral ischemia?

Numerous factors involved in the adaptive response to hypoxia, including erythropoietin and vascular endothelial growth factor are transcriptionally regulated by hypoxia-inducible factors (HIFs). During normoxia, prolyl-4-hydroxylase domain (PHD) proteins hydroxylate HIF-α subunits, resulting in their degradation. We investigated the effect of neuronal deletion of PHD2, the most abundant isoform in brain, for stroke outcome. We generated neuron-specific Phd2 knockout mice and subjected animals to systemic hypoxia or transient middle cerebral artery occlusion. Infarct volume and cell death were determined by histology. HIF-1α, HIF-2α, and HIF target genes were analyzed by immunoblotting and real-time polymerase chain reaction, respectively. Neuron-specific ablation of Phd2 significantly increased protein stability of HIF-1α and HIF-2α in the forebrain and enhanced expression of the neuroprotective HIF target genes erythropoietin and vascular endothelial growth factor as well as glucose transporter and glycolysis-related enzymes under hypoxic and ischemic conditions. Mice with Phd2-deficient neurons subjected to transient cerebral ischemia exhibited a strong reduction in infarct size, and cell death of hippocampal CA1 neurons located in the peri-infarct region was dramatically reduced in these mice. Vessel density in forebrain subregions, except for caudate-putamen, was not altered in Phd2-deficient animals.

Our findings denote that the endogenous adaptive response on hypoxic-ischemic insults in the brain is at least partly dependent on the activity of HIFs and identify PHD2 as the key regulator for the protective hypoxia response. The results suggest that specific inhibition of PHD2 may provide a useful therapeutic strategy to protect brain tissue from ischemic injury.

Domestic violence: what are the difficulties for practitioners?

Using a qualitative approach of medical practice, the aim of this study was to specify the difficulties and pitfalls that practitioners are confronted with regarding persons suffering from domestic violence. Nineteen practitioners agreed to participate in an assessment of their attitude towards the recognition and management of domestic violence. These practitioners were aware of the medico-social dimension of their practice. A questionnaire was proposed during an interview conducted in all participants by the same investigator. The interviews were reviewed and analysed by two assessors. In the case of discordance, a second reading was made so that a consensus could be reached. The interview lasted a mean of 40 minutes. The practitioners interviewed (11 men and 8 women) were 29 to 60 years old and had practiced for 6 months to 36 years. They all knew of such violence, notably through its physical impact, but this did not permit them to recognise all the forms of violence. The medico-legal tools at their disposal are not clearly understood and are often not adapted to the demands of their female patients.

The notion of global management required in such cases must be developed and specified in medical training, because the recognition and management of "battered women" is a question of personal dignity.

Do interleukin 10 polymorphisms differentially influence the risk of gastric cancer in East Asians and Caucasians?

Although a number of association studies of gastric cancer (GC) risk have been conducted worldwide, their results have been inconsistent among different populations. The association between GC incidence and Helicobacter pylori (H. pylori) infection is somewhat of an enigma that has yet to be clearly explained. Geographically-restricted positive selection due to unique environmental pressures often result in large allele frequency differences between populations. Thus, population differences need to be investigated when attempting to identify genes that contribute to phenotypes that differ greatly between populations. We analyzed population differences in 18 polymorphisms of 12 GC-associated or immune response-related genes from 3 ethnic groups comprising 50 Koreans, 46 Indians, and 60 Caucasians; these groups differed in H. pylori seropositivity and susceptibility to GC. An interleukin 10 (IL10) polymorphism demonstrated a significantly different genotype distribution (F(ST)=0.306, P=0.014), indicating a large difference between the Korean and Caucasian populations. The odds ratio of IL10 polymorphism allele between the populations was 38.32 (95% confidence interval, 11.49-127.83).

This finding, taken together with previous evidence, provides a possible explanation for previous discrepant association results and supports the idea that IL10 gene polymorphisms can differentially affect GC development among populations.

Do establishment and assessment of new formulas for energy consumption estimation in adult burn patients?

An accurate knowledge of energy consumption in burn patients is a prerequisite for rational nutrition therapy. This study sought to create a formula that accounts for the metabolic characteristics of adult burn patients to accurately estimate energy consumption of patients with different areas and extents of burn and at different times after injury. Resting energy expenditure (REE) data on 66 burn patients, with total body surface area (TBSA) of burns ranging from 4% to 96%, were evaluated at different times after injury. REE values were determined in patients using indirect calorimetry at days 1, 2, 3, 7, 14, 21, and 28 after injury. We then constructed a mathematical model of REE changes post-burn. Next, established two new formulas (one non-linear and the other linear) for energy consumption estimation using model-based analytical solution and regression analysis. The new formulas were compared with measured REE and commonly used formulas including those of Carlson, Xie, Curreri, and Milner to determine accuracy and reliability. Comparative analysis showed that the new formulas offered significantly higher accuracy and reliability than the Milner formula, which is considered the most accurate of commonly used burn energy consumption estimate formulas. The accuracy of the new nonlinear formula (94.29%) and that of the linear formula (91.43%) were significantly higher than that of Milner formula (72.86%) when compared to measured REE (χ2  =  11.706, P  =  0.001; χ2  =  8.230, P  =  0.004, respectively). The reliabilities of the new estimation formulas were both 100% and that of Milner formula was 74.24% (χ2  =  19.513, P  =  0.000).

The new formulas constructed in this study provide reliable simulation of the impact of the degree of burn and post-burn days on energy consumption and offer notably higher accuracy and reliability than other formulas. These formulas will help determine nutritional needs of burn patients.

Does strategy training reduce age-related deficits in working memory?

Older adults typically perform worse on measures of working memory (WM) than do young adults; however, age-related differences in WM performance might be reduced if older adults use effective encoding strategies. The purpose of the current experiment was to evaluate WM performance after training individuals to use effective encoding strategies. Participants in the training group (older adults: n = 39; young adults: n = 41) were taught about various verbal encoding strategies and their differential effectiveness and were trained to use interactive imagery and sentence generation on a list-learning task. Participants in the control group (older: n = 37; young: n = 38) completed an equally engaging filler task. All participants completed a pre- and post-training reading span task, which included self-reported strategy use, as well as two transfer tasks that differed in the affordance to use the trained strategies - a paired-associate recall task and the self-ordered pointing task. Both young and older adults were able to use the target strategies on the WM task and showed gains in WM performance after training. The age-related WM deficit was not greatly affected, however, and the training gains did not transfer to the other cognitive tasks. In fact, participants attempted to adapt the trained strategies for a paired-associate recall task, but the increased strategy use did not benefit their performance.

Strategy training can boost WM performance, and its benefits appear to arise from strategy-specific effects and not from domain-general gains in cognitive ability.

Does a novel zinc compound ( zinc monocysteine ) enhance the antioxidant capacity of human retinal pigment epithelial cells?

The aim of this study was to document the effect of a novel zinc amino acid combination on the concentrations of important antioxidants in cultured human retinal pigment epithelial (hRPE) cells. Primary confluent hRPE cells were treated with 30 microM of zinc acetate, zinc chloride, zinc cysteine, and zinc sulfate. The antioxidants catalase, glutathione, glutathione peroxidase, and metallothionein were measured. MTT assays were performed to determine the relative protection of the zinc compounds from the cytotoxic effects of H202 and t-butyl hydroperoxide. Catalase and glutathione peroxidase activities were increased by the zinc formulations compared with the untreated control. Glutathione and metallothionein content were also increased. The greatest increases occurred with zinc conjugated to the amino acid cysteine. The MTT assays showed that zinc monocysteine protected cultured RPE cells from the toxicity of H2O2 and t-butyl hydroperoxide.

Our results demonstrate that zinc treatment of RPE cells increases antioxidants and protects cultured RPE cells from the cytotoxic effects of H2O2 and t-butyl hydroperoxide. The results show that zinc conjugated to cysteine offers greater benefits than either zinc salts or cysteine alone.

Does etodolac block the allyl isothiocyanate-induced response in mouse sensory neurons by selective TRPA1 activation?

The excitability of nociceptors is modulated by the transient receptor potential cation channel, ankyrin subfamily, member 1 (TRPA1). We have previously reported that etodolac, a nonsteroidal anti-inflammatory drug, attenuates mechanical allodynia in a mouse model of neuropathic pain by a mechanism that is independent of cyclooxygenase inhibition. Here, we investigate the role of TRPA1 in the mechanism of the antinociceptive action of etodolac in vitro and in vivo. Ca(2+) influx was measured in HEK-293 cells expressing mouse TRPA1 and in mouse dorsal root ganglion (DRG) neurons. The effect of etodolac on the nociceptive behavior induced in mice by the TRPA1 agonist allyl isothiocyanate (AITC) was also measured. Etodolac induced Ca(2+) influx in HEK-293 cells expressing mouse TRPA1 and in mouse DRG neurons. The Ca(2+) influx induced by etodolac was inhibited by pretreatment with the TRPA1-specific antagonist HC-030031. In contrast, etodolac did not induce Ca(2+) influx in cells expressing TRPV1, TRPV2 or TRPM8. In addition, pretreatment with etodolac inhibited the Ca(2+) influx induced by AITC.

Etodolac showed a selective TRPA1 agonist action, providing evidence that etodolac desensitizes nociceptors by the selective activation of TRPA1. Etodolac may be clinically useful in the treatment of neuropathic pain.

Does crocin improve lipid dysregulation in subacute diazinon exposure through ERK1/2 pathway in rat liver?

Diazinon Yis one of the most broadly used organophosphorus insecticides in agriculture. It has been shown that exposure to diazinon may interfere with lipid metabolism. Moreover, the hypolipidemic effect of crocin has been established. Earlier studies revealed the major role of Extracellular signal-regulated kinase (ERK) pathways in low-density lipoprotein receptor (LDLr) expression. The aim of this study was to evaluate changes in the regulation of lipid metabolism, ERK and LDLr expression in the liver of rats exposed to subacute diazinon. Furthermore ameliorating effect of crocin on diazinon induced disturbed cholesterol homeostasis was studied. 24 Rats were divided into 4 groups and received following treatments for 4 weeks; Corn oil (control), diazinon (15mg/kg per day, orally) and crocin (12.5 and 25mg/kg per day, intraperitoneally) in combination with diazinon (15 mg/kg). The levels of cholesterol, triglyceride and LDL in blood of rats were analyzed. Moreover mRNA levels of LDLr and ERK1/2 as well as protein levels of total and activated forms of ERK1/2 in rat liver were evaluated by Western blotting and quantitative real time polymerase chain reaction analysis. Our data showed that subacute exposure to diazinon significantly increased concentrations of cholesterol, triglyceride and LDL. Moreover diazinon decreased ERK1/2 protein phosphorylation and LDLr transcript. Crocin reduced inhibition of ERK activation and diazinon-induced hyperlipemia and increased levels of LDLr transcript.

Crocin may be considered as a novel protective agent in diazinon-induced hyperlipemia through modulating of ERK pathway and increase of LDLr expression.

Etrurians vs Greeks: May ACE I/D polymorphism still be considered as a marker of susceptibility to SSc?

SSc is characterized by immune dysfunction and microvascular involvement. A different genetic background may determine a different polymorphic allele frequency between different populations, and data from literature reported conflicting results about the role of genetic components in predisposing to the disease. We carried out this study in order to compare the ACE I/D polymorphism genotype distribution and alleles frequency in two different populations from the Mediterranean area. Forty-eight Italian and 41 Greek SSc patients compared with 112 Italian and 93 Greek controls, have been studied. The ACE I/D polymorphism has been analysed. The genotype distribution and allele frequency were in Hardy-Weinberg equilibrium for Italian and Greek SSc patients and controls. Among the Italian patients a significantly higher ACE D allele frequency than in the controls was found, whereas among the Greeks a higher prevalence was observed in the healthy subjects. A significant difference in ACE D allele frequency between Italian and Greek controls was observed (p = 0.04). ACE D allele was associated to the predisposition to SSc in Italians, but not in Greeks.

We confirm that Italian SSc patients have a higher ACE D allele frequency that is not present in the Greek patients. Thus, the two populations living in different Mediterranean areas and resulting from the Mediterranean civilization, do not show the same ACE-gene related allele frequencies. Other populations of the Mediterranean area must be investigated by using unlinked genetic markers to verify the homogeneity of the genetic background, and to test for a "true" difference in their ethnic origin.

Pareto optimal communication of the medical qualities of practicing ophthalmologists: a new option for patient information?

This investigation analyzed the possibility to provide information about the medical qualities of ophthalmologists to make it easier for patients to find the right physician in a Pareto optimal way, i.e. to supply information so that nobody is harmed and at least one derives benefits. Extensive interviews with key deciders in the system for ophthalmological care were carried out and analyzed. Pareto optimization is possible. However, implementation is not yet feasible mainly because of legal and economic restrictions and because of difficulties of the measuring system. In order to come to a result, a major medical, economic and legal effort would be required which is unlikely to come into place in the short-term.

At least in the near future there will be no new Pareto optimal information systems available for patients in order to find the appropriate ophthalmologist. In the mid-term the situation could change if the open questions can be resolved.

Consumers and Carers Versus Pharmacy Staff: Do Their Priorities for Australian Pharmacy Services Align?

Health professionals, including pharmacists, are encouraged to meet the needs of their consumers in an efficient and patient-centred manner. Yet, there is limited information as to what consumers with chronic conditions need from pharmacy as a healthcare destination or how well pharmacy staff understand these needs. The aim of this study was to identify service user priorities for ideal community pharmacy services for consumers with chronic conditions and their carers, and compare these priorities with what pharmacy staff think these groups want. The nominal group technique was undertaken with pharmacist, pharmacy support staff, consumer and carer groups in four Australian regions between December 2012 and April 2013. Participant ideas and priorities for ideal services or care were identified, and contextual insight was obtained by thematic analysis. Twenty-one nominal group sessions are accepted, including 15 consumer and carer, four pharmacist and two pharmacy support staff groups. Pharmacy staff views generally aligned with consumer priorities, such as access, affordability, patient-centred care and continuity and coordinated care, yet diverged with respect to consumer information or education on medication and services. Fundamentally, consumers and carers sought streamlined access to information and medication, in a coordinated, patient-centred approach. Alleviating financial burden was a key consumer priority, with a call for the continuation and extension of medication subsidies.

Overall, pharmacy staff had a reasonable understanding of what consumers would prioritise, but further emphasis on the importance, delivery, or both, of consumer information is needed. Greater consideration is needed from policy makers regarding the financial barriers to accessing medication for consumers with chronic conditions.

Do prediction of morbidity and mortality on admission to a burn unit?

Improvements in burn care during the last two decades call for new prediction models of morbidity and mortality. The aim of the study was to identify parameters that are predictive of major morbidity factors and risk of mortality in patients with burn injury. The charts of 249 patients (236 survivors) aged 1 to 94 years who were treated for second- and third-degree burns from 1995 to 2002 were reviewed. A multivariate linear stepwise regression model was fitted to the data to predict length of hospitalization, length of operations, and mortality rate. Survivors' mean burn size was 14 +/- 15 percent of the total body surface area (range, 5 to 90 percent), with a mean hospitalization time of 22.9 +/- 17.1 days and a mean operative time of 127.5 +/- 166.8 minutes. The prognostic factors in each of the regression models predicted 40 percent and 55 percent of the variance in length of hospital stay and operative time, respectively. Total body surface area alone explained most of the variance (29 percent and 44 percent, respectively). As a result, the authors created shorter formulas: Length of hospitalization (days) = 18 + [total body surface area]/3; Operative time (minutes) = 55 + 4[total body surface area]. Total body surface area and smoke inhalation were the only statistically significant predictors of death. Every 1 percent increase in total body surface area was associated with a 6 percent increase in mortality risk. The presence of smoke inhalation increased mortality risk by nine-fold.

Using objective measurements in burn treatment is of great importance. The formulas presented by the authors explain a considerable percentage of the probability of morbidity in burn victims. The authors suggest that other burn units develop their own statistically supported prediction models.

Do regulatory T cells inhibit CD8 ( + ) T-cell tissue invasion in human skin graft-versus-host reactions?

Regulatory T cells (Tregs) effectively ameliorate graft-versus-host disease (GVHD). The mechanisms underlying Treg therapeutic effect on GVHD are not fully elucidated. This study investigates whether Treg prevention of GVH tissue damage is associated with blocking CD8 effector T-cell tissue invasion, a question not yet addressed in humans. Tissue-infiltrating T cells and histopathology scores were detected using an in vitro human GVHD skin explant model, together with immunohistochemistry, cytometric bead array, functional adhesion and migration assays, flow cytometry, and quantitative real-time polymerase chain reaction. Treg intervention during priming significantly decreased effector T-cell infiltration into target tissue (P<0.01) resulting in a striking reduction in the histopathology score of tissue injury (P<0.0001). These results were coupled with reduced CXCR3 and cutaneous lymphocyte antigen expression by effector T cells, together with decreased CXCL10 and CXCL11 expression in target tissue. Treg intervention also impaired the functional interaction of CXCR3 and cutaneous lymphocyte antigen with their specific ligands (P<0.01) and suppressed the secretion of CXCL9, CXCL10, and interferon-γ (P<0.01, P<0.05, and P<0.001, respectively). Late addition of Tregs into the effector phase abolished their ability to suppress effector T-cell tissue invasion, resulting in a total loss of their ability to ameliorate GVH tissue damage.

Preventing effector T-cell tissue invasion is a critical mechanistic event leading to Treg attenuation of GVH tissue damage. This therapeutic effect is associated with a failure of CD8 T cells to increase tissue homing receptors after allo-stimulation, together with a breakdown of interferon-γ-induced chemoattractant expression in the target tissue.

Is customized vestibular rehabilitation effective in patients with multiple sclerosis?

Balance disorders are among the most common problems encountered by patients diagnosed with multiple sclerosis (MS).AIM: The purpose of this randomized, controlled trial was to investigate the effects of customized vestibular rehabilitation (VR) on balance, functional capacity, quality of life, and depression in patients with MS. This study was designed as a prospective, randomized, controlled trial. The study was carried out in a single tertiary referral center. Forty consecutive patients referred with a diagnosis of MS were randomized into two groups: an exercise group (N.=20) and a control group (N.=20). The experimental group underwent customized VR and the wait-listed control group received the usual medical care. All of the patients were assessed with objective balance tests (Romberg Test, Tandem Romberg Test, Foam Romberg Test, Static Posturography, Six-Meter Walk Test, Five Times Sit-to-Stand Test, Berg Balance Scale, Timed Up and Go Test, Functional Gait Assessment, and Dynamic Gait Index), subjective balance parameters (Activities-Specific Balance Confidence Scale and Dizziness Handicap Inventory), and functional capacity (Six-Minute Walking Test), quality of life (Multiple Sclerosis Quality of Life-54), and depression (Beck Depression Inventory) scales. At the end of the trial, the exercise group exhibited significant changes in most of the evaluated parameters compared to the control group [except the Tandem Romberg with eyes closed and the Foam Romberg, standing with eyes open (P<0.05). No significant differences were observed in any of the parameters in the control group (P>0.05). The intergroup comparisons of differences indicated significant recoveries in favor of the exercise group in all of the evaluated parameters (P<0.05).

This study confirms the effects of customized VR programs on balance, quality of life, and functional capacity in patients with MS.

Is the scope for nuclear selection within Termitomyces fungi associated with fungus-growing termites limited?

We investigate the scope for selection at the level of nuclei within fungal individuals (mycelia) of the mutualistic Termitomyces cultivated by fungus-growing termites. Whereas in most basidiomycete fungi the number and kind of nuclei is strictly regulated to be two per cell, in Termitomyces mycelia the number of nuclei per cell is highly variable. We hypothesised that natural selection on these fungi not only occurs between mycelia, but also at the level of nuclei within the mycelium. We test this hypothesis using in vitro tests with five nuclear haplotypes of a Termitomyces species. First, we studied the transition from a mixture of five homokaryons (mycelia with identical nuclei) each with a different nuclear haplotype to heterokaryons (mycelia with genetically different nuclei). In vitro cultivation of this mixture for multiple asexual transfers led to the formation of multiple heterokaryotic mycelia, and a reduction of mycelial diversity over time. All heterokaryotic mycelia contained exactly two types of nucleus. The success of a heterokaryon during in vitro cultivation was mainly determined by spore production and to a lesser extent by mycelial growth rate. Second, heterokaryons invariably produced more spores than homokaryons implying that homokaryons will be outcompeted. Third, no homokaryotic 'escapes' from a heterokaryon via the formation of homokaryotic spores were found, despite extensive spore genotyping. Fourth, in contrast to most studied basidiomycete fungi, in Termitomyces sp. no nuclear migration occurs during mating, limiting the scope for nuclear competition within the mycelium.

Our experiments demonstrate that in this species of Termitomyces the scope for selection at the level of the nucleus within an established mycelium is limited. Although 'mate choice' of a particular nuclear haplotype is possible during mating, we infer that selection primarily occurs between mycelia with two types of nucleus (heterokaryons).

Is interleukin-11 receptor signaling required for normal bone remodeling?

IL-6 and -11 regulate bone turnover and have been implicated in estrogen deficiency-related bone loss. In this study, deletion of IL-11 signaling, but not that of IL-6, suppressed osteoclast differentiation, resulting in high trabecular bone volume and reduced bone formation. Furthermore, IL-11 signaling was not required for the effects of estradiol or estrogen deficiency on the mouse skeleton. Interleukin (IL)-6 and -11 stimulate osteoclastogenesis and bone formation in vitro and have been implicated in bone loss in estrogen deficiency. Because of their common use of the gp130 co-receptor signaling subunit, the roles of these two cytokines are linked, and each may compensate for the absence of the other to maintain trabecular bone volume and bone cell differentiation. To determine the interactions in bone between IL-11 and IL-6 in vivo and whether IL-11 is required for normal bone turnover, we examined the bone phenotype of mature male and female IL-11 receptor knockout mice (IL-11Ralpha1-/-) and compared with the bone phenotype of IL-6-/- mice and mice lacking both IL-6 and IL-11Ralpha. To determine whether IL-11 is required for the effects of estrogen on trabecular bone, mature IL-11Ralpha1-/- mice were ovariectomized and treated with estradiol. In both male and female IL-11Ralpha1-/- mice, trabecular bone volume was significantly higher than that of wildtype controls. This was associated with low bone resorption and low bone formation, and the low osteoclast number generated by IL-11Ralpha1-/- precursors was reproduced in ex vivo cultures, whereas elevated osteoblast generation was not. Neither trabecular bone volume nor bone turnover was altered in IL-6-/- mice, and compound IL-6-/- :IL-11Ralpha1-/- mice showed an identical bone phenotype to IL-11Ralpha1-/- mice. The responses of IL-11Ralpha1-/- mice to ovariectomy and estradiol treatment were the same as those observed in wildtype mice.

IL-11 signaling is clearly required for normal bone turnover and normal trabecular bone mass, yet not for the effects of estradiol or estrogen deficiency on the skeleton. In the absence of IL-11Ralpha, increased trabecular bone mass seems to result from a cell lineage-autonomous reduction in osteoclast differentiation, suggesting a direct effect of IL-11 on osteoclast precursors. The effects of IL-11Ralpha deletion on the skeleton are not mediated or compensated for by changes in IL-6 signaling.

Do glutamate and histidine improve both solvent yields and the acid tolerance response of Clostridium beijerinckii NCP 260?

This study aims to examine the effect of amino acid supplementation on solvent production by Clostridium beijerinckii during the acetone-butanol fermentation and to determine whether amino acids are involved in the acid tolerance response (ATR), which results in increased solvents. Fermentation studies with Cl. beijerinckii NCP 260 in limited-nitrogen media supplemented with glutamate, glutamine, lysine, proline, histidine or asparagine revealed that only glutamate, glutamine or histidine increased butanol titres comparable to control media. Acid survival tests at pH 5 showed that glutamate and histidine were effective in protecting Cl. beijerinckii cells against acid shock, and may be involved in the ATR. Using quantitative PCR, the transcription of the glutamine synthetase, nitrogen regulator and glutamate synthase operon (glnA-nitR-gltAB) was monitored during acid shock conditions, and expression of both the nitR and gltA genes was shown to be increased twofold.

Glutamate and histidine specifically enhance the ATR in Cl. beijerinckii NCP 260, and the genes encoding glutamate synthase and the NitR regulator are both upregulated, predicted to lead to increased endogenous glutamate pools during acidogenesis. This may enhance the ATR and allow more viable cells to enter solventogenesis, thereby increasing butanol titres. Glutamine, glutamate and histidine may also afford protection from butanol stress directly.

Is chronic pain treatment in children and adolescents : less good , more is sometimes better?

In children with chronic pain, interdisciplinary outpatient and intensive inpatient treatment has been shown to improve pain intensity and disability. However, there are few systematic comparisons of outcomes of the two treatments. The present naturalistic study aimed to compare the clinical presentation and achieved changes at return in three outcome domains (pain intensity, disability, school absence) between a) outpatients vs. inpatients and b) patients who declined intensive inpatient treatment and completed outpatient treatment instead (decliners) vs. those who completed inpatient treatment (completers). The study compared treatment outcomes between n = 992 outpatients vs. n = 320 inpatients (Analysis A) who were treated at a tertiary treatment centre and returned for a return visit within a one-year interval. In Analysis B, treatment outcomes were compared between n = 67 decliners vs. n = 309 completers of inpatient treatment. The three outcome domains were compared by calculating standardized change scores and clinically significant changes. In analysis A, outpatients and inpatients reported comparably low levels of pain intensity (NRS 0-10; mean = 4, SD = 2.7) and disability (Paediatric Pain Disability Index (PPDI: 12-60; mean = 24; SD = 10) at the return visit. Compared to outpatients, more inpatients achieved clinically significant changes in pain intensity (52% vs. 45%) and disability (46% vs. 31%). There were also significantly greater changes in disability in the inpatient group (change score outpatients = 1.0; change score inpatients = 1.4; F(1,1138) = 12.6, p = .011). School absence was substantially reduced, with approximately 80% in each group attending school regularly. Analysis B showed that even though inpatient decliners achieved improvements in the outcome domains, they reported greater disability at the return visit (PPDI mean decliners = 27, SD = 9.9; PPDI mean completers = 24, SD = 10) because they had achieved fewer changes in disability (change score decliners = 0.9; change score completers = 1.4; F(1.334) = 5.7, p = .017). In addition, less decliners than completers achieved clinically significant changes in disability (25% vs. 47%).

Inpatient and outpatient treatments are able to elicit substantial changes in pain intensity, disability and school absence. The results highlight the necessity of intensive inpatient pain treatment for highly affected children, as children who declined inpatient treatment and were treated as outpatients did less well.

Are course of hepatitis C virus ( HCV ) RNA and HCV core antigen testing predictors for reaching sustained virologic response in liver transplant recipients undergoing sofosbuvir treatment in a real-life setting?

Hepatitis C virus (HCV) infection is associated with reduced graft survival in orthotopic liver transplant recipients. Treatment with the new direct-acting antivirals (DAAs) is safe and efficient, but no reliable predictive factors for sustained virologic response (SVR) have been identified so far. The HCV core antigen assay (HCV-core-Ag) is a new, inexpensive, and efficient method to detect viral antigens, but the value of this technique to predict treatment response in orthotopic liver transplantation (OLT) patients is still unclear. All OLT patients who were treated with a sofosbuvir-based antiviral regimen at our center between March 2014 and August 2014 were included in the analysis (n = 20). HCV-core-Ag and HCV RNA (polymerase chain reaction [PCR]) were determined at each visit. Primary endpoints of this study were SVR at 4 or 12 weeks after end of treatment (SVR 4 and SVR 12). HCV-core-Ag tested negative after a median of 2 weeks (range 1-16 weeks) while PCR tests became negative after a median of 4 weeks (range 2-12 weeks). Time until PCR negativity and until HCV-core-Ag negativity showed a good correlation (R = 0.711, P < 0.001, Fig. ). Seventeen of 20 patients (85%) achieved SVR 12. SVR 12 was associated with a short time interval between treatment start and HCV PCR negativity (P = 0.005) or HCV-core-Ag negativity (P = 0.003, Mann-Whitney test). No severe side effects were observed.

DAA treatment is safe and well tolerated in OLT. The time points of HCV-core-Ag loss and PCR negativity were predictors of SVR 12.

Transcranial Doppler: Does Addition of Blood to Agitated Saline Affect Sensitivity for Detecting Cardiac Right-to-Left Shunt?

Transcranial Doppler (TCD) with agitated saline has been shown to be an alternative for the detection of right-to-left shunts (RLS) with similar diagnostic accuracies as transesophageal echocardiography (TEE). It is hypothesized that the addition of blood to agitated saline increases the sensitivity of TCD for the detection of RLS. The aim of this meta-analysis was to determine whether agitated saline with blood increases the sensitivity of TCD for the detection of RLS compared to agitated saline alone and other contrast agents. A systematic review of Medline, Cochrane, and Embase was performed to look for all prospective studies assessing intracardiac RLS using TCD compared with TEE as the reference; both tests were performed with a contrast agent and a maneuver to provoke RLS in all studies. A total of 27 studies (29 comparisons) with 1,968 patients met the inclusion criteria. Of 29 comparisons, 10 (35%) used echovist contrast during TCD, 4 (14%) used a gelatin-based solution, 12 (41%) used agitated saline, and 3 (10%) utilized 2 different contrast agents. The addition of blood to agitated saline improved the sensitivity of TCD to 100% compared to agitated saline alone (96% sensitivity, P = 0.161), echovist (94% sensitivity, P = 0.044), and gelatin-based solutions (93% sensitivity, P = 0.041).

The addition of blood to agitated saline improves the sensitivity of TCD for the detection of RLS to 100% when compared to other conventional contrast agents; these findings support the addition of blood to agitated saline during TCD bubble studies.

Does the recent increase in HIV diagnoses among men who have sex with men in the UK reflect a rise in HIV incidence or increased uptake of HIV testing?

To determine whether the increase in HIV diagnoses since 1997 among men who have sex with men (MSM) in the UK reflects a rise in HIV incidence or an increase in HIV testing. Estimates of HIV incidence were derived using data from UK HIV surveillance systems (HIV diagnoses; CD4 surveillance; unlinked anonymous surveys) for 1997-2004. Data on HIV testing were provided by KC60 statutory returns, voluntary testing and unlinked anonymous surveys in sentinel genitourinary medicine (GUM) clinics. HIV diagnoses among MSM in the UK rose by 54% between 1997 and 2004 (from 1382 to 2124), with variation by age and geographical location. The number of HIV diagnoses among MSM<35 years of age in London showed no increase, but in all other groups it increased. Throughout the UK, uptake of HIV testing increased significantly among MSM attending GUM clinics between 1997 and 2004, including "at-risk" MSM (p<0.001). Direct incidence estimates (serological testing algorithm for recent HIV seroconversion assay) provided no evidence of a statistically significant increase or decrease in HIV incidence. Indirect estimates suggested that there may have been a rise in HIV incidence, but these estimates were influenced by the increased uptake of HIV testing.

The number of HIV diagnoses increased among MSM in the UK between 1997 and 2004, except among younger MSM in London, in whom there was no change. The increase in HIV diagnoses among MSM in the UK since 1997 seems to reflect an increase in HIV testing rather than a rise in HIV incidence.

Is high Ki67 expression an independent good prognostic marker in colorectal cancer?

To correlate Ki67 expression with outcome in colorectal cancer (CRC). Ki67 labelling index (Ki67LI) was analysed by immunohistochemistry on a tissue microarray containing 1800 CRCs. The results were compared with clinicopathological and molecular parameters. Ki67LI was considered low in 26.3%, moderate in 56.7% and high in 17.0% of 1653 interpretable CRCs. High Ki67 expression was associated with low tumour stage (p<0.0001) and nodal status (p=0.0315), but not with tumour grade (p=0.8639), histological tumour type (p=0.1542) or tumour localisation, and was an independent prognosticator of favourable survival (p=0.0121). High Ki67 expression was also significantly associated with high-level nuclear β-catenin and p53 expression (p<0.0001 and p=0.0095, respectively).

In summary, our data show that high Ki67 expression in CRCs is associated with good clinical outcome. Ki67, p53 and β-catenin overexpression seem to be linked to CRC, and indicate a cellular state of high proliferative activity. Finally, our findings strongly argue for a clinical utility of Ki67 immunostaining as an independent prognostic biomarker in CRC.

Does reference range for blood concentrations of nucleated red blood cells in neonates?

Previous studies reported a relationship between high nucleated red blood cells (NRBC) in neonates and the development of intraventricular hemorrhage (IVH) and/or retinopathy of prematurity (ROP). We sought to (1) establish reference ranges for NRBC in neonates based on a large data set, (2) compare NRBC from automated versus manual counts, (3) determine the effect of an elevated NRBC, on the day of birth, on the odds of developing grade ≥3 IVH or ROP. We analyzed all NRBC obtained during 8.5 years in a multihospital system, displaying the 5th and 95th percentile limits according to gestational age and postnatal age. NRBC counts were retrieved from 61,932 neonates, 26,536 of which were excluded from the data set. Comparing 9,000 samples run simultaneously on manual versus automated methods, the manual counts yielded slightly higher counts, but the difference is likely insignificant clinically. Altitude of the birth hospital did not correlate with NRBC, and no correlations were observed with cord pH or 1- or 5-min Apgar. An NRBC count >95th percentile limit was associated with higher odds of developing a grade ≥3 IVH (OR 4.28; 95% CI 3.17-5.77) and grade ≥3 ROP (OR 4.18; 95% CI 2.74-6.38).

The figures of this report display reference ranges for NRBC according to gestational age and postnatal age. An NRBC count above the 95% limit at birth is associated with a higher risk of subsequently developing severe IVH and severe ROP. We speculate that this association is because an elevated NRBC count is a marker for prenatal hypoxia.

Natural health product labels: is more information always better?

To explore how the information provided on labels as mandated by the new Canadian natural health product (NHP) regulations impacts consumers' perceptions of risks associated with using NHPs. Six focus groups were conducted in three locations across Ontario. Consumers were asked to react to two labels for a fictitious product called Saturnflower that represented the "old" standards (label 1) and the new standards (label 2). Groups were audio-taped and transcribed verbatim. Qualitative content analysis was used to identify key themes. The 38 participants criticized label 1 for lacking information about the uses of the product and discussed their frustration at trying to obtain good quality information about NHPs. The lack of risk information on label 1 reinforced their perceptions of NHPs as natural, mild and safe. The majority of participants found label 2 much more informative, but a few were unsettled by the extent of the risk information, questioning if it was necessary.

The label requirements of the new NHP regulations were generally viewed positively by the consumers who participated in this study.

Crystal methamphetamine-associated cardiomyopathy: tip of the iceberg?

Crystal methamphetamine has become a drug of widespread use. Previous reports describe myocardial infarction, pulmonary edema, and aortic dissection related to methamphetamine use. Cardiomyopathy due to methamphetamine exposure has been rarely described. We identified 1640 patients admitted in a 4-yr period with a primary or secondary diagnosis of cardiomyopathy. We excluded patients with known cause of cardiomyopathy other than substance abuse. We found 120 patients had a diagnosis of substance abuse, including 21 patients with methamphetamine use. We retrospectively reviewed the medical records of these 21 crystal methamphetamine users. Nineteen (84%) underwent echocardiography with consistent findings of dilated cardiomyopathy and global ventricular dysfunction. Of five who had a nuclear myocardial perfusion study, none had evidence of ischemia or infarct. Of six who underwent cardiac catheterization, only one had evidence of coronary stenosis.

Methamphetamine use appears to produce cardiomyopathy in some users. The pathogenesis is probably similar to that of cocaine and catecholamine-induced cardiomyopathy. Cellular, animal, and clinical data support the link between methamphetamine exposure and myocardial pathology.

Is intrahepatic triglyceride content independently associated with chronic kidney disease in obese adults : A cross-sectional study?

Non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are associated with some common critical cardio-metabolic risk factors. The aim of this study was to explore the association between intrahepatic triglyceride (IHTG) content and CKD in obese subjects. A total of 1068 obese participants received anthropometric, biochemical measurements and hepatic ultrasonography. Of those, 485 participants received magnetic resonance spectroscopy ((1)H-MRS) for the determination of IHTG content. CKD was defined as a urinary albumin:creatinine ratio (UACR)≥30 mg/g and/or estimated glomerular filtration rate (eGFR)<60 mL/min per 1.73 m(2). The prevalence of CKD was significantly higher in NAFLD subjects compared to subjects without NAFLD, while the prevalence of CKD was gradually increased as the IHTG content increased by quartiles (P for trend<0.001). After adjustment for multivariate metabolic factors, the risk of abnormal albuminuria and CKD was increased by 68% [OR (95% CI): 1.68 (1.21-2.33), P<0.01] and 54% [OR (95% CI): 1.54 (1.14-2.07), P<0.01] respectively per one standard deviation (SD) increase in IHTG content. The association between IHTG content and CKD was not changed by conventional risk factors, including age, BMI and hypertension (all P<0.05).

IHTG content is independently associated with CKD in obese adults.

'Trails B or not Trails B?

Difficulties with attention contribute to behavioural and cognitive problems during childhood and may reflect subtle deficits in executive functioning (EF). Attention problems in early childhood have also been found to predict higher levels of anxiety and depression symptoms at 10 years old. It has also been reported that attention problems during childhood may be differentially related to later-emerging distinct EF difficulties. Many of these findings, however, rely on teacher-ratings of attention difficulties. This study administered neuropsychological tests of attention-switching and EF to 67 healthy children aged 9-15 years of age. It additionally measured socio-emotional behavioural functioning. A critical phase of improvement was found at 10 years of age. Correlations were found between attention-switching skills and EF. Attention-switching skills were also correlated with socio-emotional functioning.

Attention-switching skills have some interdependence with EF, but in paediatric assessment such skills are easier to routinely assess than many of the currently available tests of EF. It is suggested that attention-switching ability may prove to be a useful predictor of EF performance in understanding long-term outcome after a neurological event such as traumatic brain injury.

Does uVR protection influence fructosamine level after sun exposure of healthy adults?

Seasonal variation in glycated hemoglobin levels has been observed, and sun exposure has been considered as one of the factors associated with this relationship. Fructosamine is a short-time marker of blood protein glycation. We investigated the effect of seven days of sunbathing on blood fructosamine concentration in healthy volunteers using different ultraviolet radiation (UVR) protections. Participants were assigned to one of three groups: group A - used a UVA and UVB absorbing sunscreen (N = 15), group B - used a UVB absorbing sunscreen (N = 18), and group C - followed uncontrolled sun protection habits (N = 22). Overall, the fructosamine concentration did not change after sun exposure (baseline 248.8 μmol/l, 25-75%: 238.5 to 258.8 μmol/l vs. after 247.3 μmol/l, 25-75%: 234.9 to 261.8 μmol/l, P = 0.6637). Median change of fructosamine differed significantly between groups (A: -1.90 μmol/l, 25-75%: -17.10 to 1.80 μmol/l vs. B: -3.80 μmol/l, 25-75%: -18.50 to 2.40 μmol/l vs. C: +4.05 μmol/l, 25-75%: -3.20 to 22.0 μmol/l; one-way ANOVAP = 0.0277). After age adjustment and combining groups A and B, the difference in change of fructosamine concentration was statistically significant between groups A + B (decrease) vs. group C (increase, P = 0.0193).

Appropriate sunscreen use during sunbathing resulted in decreased fructosamine concentrations, while inadequate UVR protection resulted in its increase.

Does cluster analysis in the COPDGene study identify subtypes of smokers with distinct patterns of airway disease and emphysema?

There is notable heterogeneity in the clinical presentation of patients with COPD. To characterise this heterogeneity, we sought to identify subgroups of smokers by applying cluster analysis to data from the COPDGene study. We applied a clustering method, k-means, to data from 10 192 smokers in the COPDGene study. After splitting the sample into a training and validation set, we evaluated three sets of input features across a range of k (user-specified number of clusters). Stable solutions were tested for association with four COPD-related measures and five genetic variants previously associated with COPD at genome-wide significance. The results were confirmed in the validation set. We identified four clusters that can be characterised as (1) relatively resistant smokers (ie, no/mild obstruction and minimal emphysema despite heavy smoking), (2) mild upper zone emphysema-predominant, (3) airway disease-predominant and (4) severe emphysema. All clusters are strongly associated with COPD-related clinical characteristics, including exacerbations and dyspnoea (p<0.001). We found strong genetic associations between the mild upper zone emphysema group and rs1980057 near HHIP, and between the severe emphysema group and rs8034191 in the chromosome 15q region (p<0.001). All significant associations were replicated at p<0.05 in the validation sample (12/12 associations with clinical measures and 2/2 genetic associations).

Cluster analysis identifies four subgroups of smokers that show robust associations with clinical characteristics of COPD and known COPD-associated genetic variants.

Should an assessment of Axis I comorbidity be included in the initial diagnostic assessment of mood disorders?

Axis I comorbidity in mood disorders was common in epidemiological studies. This study was designed to investigate the prevalence, pattern, and number of Axis I comorbidities and the role of the Quick Inventory of Depression Symptomatology - 16 items-Self-Report (QIDS-16-SR) in predicting the number of comorbidities in major depressive disorder (MDD) or bipolar disorder (BPD). Baseline data from the first 300 routine clinical outpatients diagnosed with the Mini International Neuropsychiatric Interview Systematic-Treatment-Enhancement - Program for BPD version 5.0.0 were used. Baseline severity was measured with QIDS-16-SR and Clinical Global Impression-Severity (CGI-S). Of 113 patients with MDD and 166 with BPD, the prevalence of any current anxiety disorder (AD), substance use disorder (SUD), and attention deficit hyperactivity disorder (ADHD) was 76% versus 74%, 14% versus 29%, and 8% versus 21%, respectively. The most common patterns of current comorbidity were MDD+AD (58.4%) for MDD, and BPD+AD (39.8%) and BPD+AD+SUD (11.4%) for BPD. More than 80% patients with MDD or BPD had ≥ 1 current comorbid disorder. About 20% patients with BPD and 10% with MDD had ≥ 4 other disorders. The number of comorbidities was positively associated with baseline severity and suicidal ideation in both MDD and BPD. A QIDS-16-SR of 10 had a positive predictive value of ≥ 90% in predicting ≥ 1 comorbidity in MDD and BPD. The sample was modest and from a tertiary medical center.

A thorough diagnostic assessment for Axis I comorbidity should be included in all patients with mood disorders, especially when a QIDS-16-SR of ≥ 10 points.

Does restorative proctocolectomy impair fertility and pregnancy outcomes in women with ulcerative colitis?

The effect of restorative proctocolectomy (RPC) on fertility and pregnancy in women with ulcerative colitis (UC) was evaluated. Post-RPC female patients with UC who were attempting to become pregnant filled out questionnaires on fertility and pregnancy. Demographic and pouch data of pregnancies ending with delivery were collected from a prospective database. Forty-one women, 44 ± 10 years of age, completed the questionnaires. The median follow-up period post-RPC was 167 (range, 20-352) months. Before RPC, 26 women had 70 pregnancies and 62 deliveries. After RPC, 17 women had 32 pregnancies and 26 deliveries (P = 0.0035). Post-RPC, 10 (37%) of 27 patients failed to conceive compared with 26/26 successful attempts before RPC (P = 0.0006). The number of offspring per patient was 2.38 ± 1.27 before, and 0.68 ± 0.93 after, RPC (P < 0.0001). A higher number of spontaneous pregnancies occurred before (56/62; 90%) than after (15/25; 60%) RPC (P = 0.0004). The time to conception was longer (5.0 ± 11.6 vs 16.3 ± 25.1 months; P = 0.039) and there were more in-vitro fertilization procedures (three vs six) post-RPC. The gestation period was similar, but after RPC more deliveries were by Caesarean section (12.9% vs 46.2%; P = 0.0007). Babies born before RPC weighed more than those born after RPC (3.16 ± 0.61 kg vs 2.79 ± 0.68 kg, respectively; P = 0.0327).

RPC is associated with an increased risk of infertility, similar duration of gestation and lower birthweight. Female candidates for RPC who have not finished family planning should be counselled accordingly.

Is high-fat but not sucrose intake essential for induction of dyslipidemia and non-alcoholic steatohepatitis in guinea pigs?

Non-alcoholic fatty liver disease (NAFLD) and dyslipidemia are closely related. Diet plays an important role in the progression of these diseases, but the role of specific dietary components is not completely understood. Therefore, we investigated the role of dietary sucrose and fat/cholesterol on the development of dyslipidemia and NAFLD. Seventy female guinea pigs were block-randomized (based on weight) into five groups and fed a normal chow diet (control: 4 % fat), a very high-sucrose diet (vHS: 4 % fat, 25 % sucrose), a high-fat diet (HF: 20 % fat, 0.35 % cholesterol), a high-fat/high-sucrose diet (HFHS: 20 % fat, 15 % sucrose, 0.35 % cholesterol) or a high-fat/very high-sucrose diet (HFvHS: 20 % fat, 25 % sucrose, 0.35 % cholesterol) for 16 and 25 weeks. All three high-fat diets induced dyslipidemia with increased concentrations of plasma cholesterol (p < 0.0001), LDL-C (p < 0.0001) and VLDL-C (p < 0.05) compared to control and vHS. Contrary to this, plasma triglycerides were increased in control and vHS compared to high-fat fed animals (p < 0.01), while circulating levels of free fatty acids were even between groups. Histological evaluation of liver sections revealed non-alcoholic steatohepatitis (NASH) with progressive inflammation and bridging fibrosis in high-fat fed animals. Accordingly, hepatic triglycerides (p < 0.05) and cholesterol (p < 0.0001) was increased alongside elevated levels of alanine and aspartate aminotransferase (p < 0.01) compared to control and vHS.

Collectively, our results suggest that intake of fat and cholesterol, but not sucrose, are the main factors driving the development and progression of dyslipidemia and NAFLD/NASH.

Is chronic neutropenia always a benign disease?

76 consecutive patients were enrolled from September 2008 to April 2012. Complete blood counts and clinical evaluation were performed at enrolment, at month 3, 6, and then every 6 months. Anti-neutrophil antibodies were tested by GIFT method. Patients (49 chronic idiopathic- and 27 autoimmune neutropenia) were followed for a median of 5 years (range 24-84 months). At enrolment, neutropenia was mild in 44 patients (median neutrophils 1.27×10(3)/μL), moderate in 23 (median 0.8×10(3)/μL), and severe in 9 (median 0.4×10(3)/μL). Neutrophil counts showed a great inter-subject but no intra-subject variability, with lower values in autoimmune neutropenia, in males, and in MGUS cases. Over time, no grade>3 infections occurred; 13/49 chronic idiopathic and 6/27 autoimmune neutropenia patients experienced a grade 2 event, irrespective of mean and nadir neutrophil values. Bone marrow evaluation at enrolment showed reduced cellularity in 23% of cases, and dyserythropoietic features in 55%, with no definite hematologic diagnosis. During the follow-up, 5 cases were diagnosed with NK expansion, 4 with hairy cell leukemia, and 3 with myelodysplasia (1 myelomonocytic leukemia, 1 refractory cytopenia with unilineage dysplasia, and 1 multilineage dysplasia), with a median time to evolution of 30 months.

Chronic idiopathic and autoimmune neutropenia, although usually benign, deserve hematological follow-up with a bone marrow evaluation at diagnosis and a re-evaluation in the presence of worsening neutropenia, appearance of additional cytopenias, and lymphocytosis.

Could local anesthesia while breast-feeding be harmful to infants?

Few studies have been carried out on the levels and possible toxicity of local anesthetics in breast milk after parenteral administration. The purpose of this study is to determine the amount of lidocaine and its metabolite monoethyl-glycinexylidide (MEGX) in breast milk after local anesthesia during dental procedures. The study population consisted of seven nursing mothers (age, 23-39 years) who received 3.6 to 7.2 mL 2% lidocaine without adrenaline. Blood and milk concentrations of lidocaine and its metabolite MEGX were assayed using high-performance liquid chromatography. The milk-to-plasma ratio and the possible daily doses in infants for both lidocaine and MEGX were calculated. The lidocaine concentration in maternal plasma 2 hours after injection was 347.6 +/- 221.8 microg/L, the lidocaine concentration in maternal milk ranged from 120.5 +/- 54.1 microg/L (3 hours after injection) to 58.3 +/- 22.8 microg/L (6 hours after injection), the MEGX concentration in maternal plasma 2 hours after injection was 58.9 +/- 30.3 microg/L, and the MEGX concentration in maternal milk ranged from 97.5 +/- 39.6 microg/L (3 hours after injection) to 52.7 +/- 23.8 microg/L (6 hours after injection). According to these data and considering an intake of 90 mL breast milk every 3 hours, the daily infant dosages of lidocaine and MEGX were 73.41 +/- 38.94 microg/L/day and 66.1 +/- 28.5 microg/L/day respectively.

This study suggests that even if a nursing mother undergoes dental treatment with local anesthesia using lidocaine without adrenaline, she can safely continue breastfeeding.

Do n-glycan-defective breast cancer cells induce a phenotypic switch in polarization of bone marrow-derived macrophages?

To investigate the effect of N-glycan-defective mammary adenocarcinoma cells on the polarization of macrophages. N-glycan-defective breast cancer cells (MA782 cells) were prepared by swainsonine (SW) treatment and the cytotoxicity of SW to MA782 cells was evaluated using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The N-glycan-defective MA782 cells were co-cultured with bone marrow-derived macrophages (BMDMs) for 48 h in vitro, and then the BMDMs and the co-cultured supernatant were analyzed for macrophage phenotypic using FQRT-PCR, FCM and ELISA. SW-treated MA782 cells expressed defective N-glycan on the cell surface in a dose-dependent manner (*p < 0.05). MTT assays showed that neither the 1 μg/mL nor 5 μg/mL SW treatments showed significant inhibition of MA782 cell growth in vitro. The expression of iNOS and agr-1 in the 5 μg/mL SW-treated group were 4.75-fold higher and 3.7-fold lower than that in the untreated group, respectively (*p < 0.05). Mean fluorescence intensity of CD16/32 expressed in the cells treated with 5 μg/mL SW was significantly higher in comparison with the untreated group (65 vs. 7, *p < 0.05), though the percentage of CD16/32-positive cells were not significantly different. Furthermore, the expression of CD206 and dectin-1 in the 5 μg/mL SW-treated group was significantly decreased (3.1±0.3% and 4.1±1.1%, respectively) in comparison with the untreated group (40±3% and 8.9±1.2%, respectively, both p < 0.05). In addition, the 5 μg/mL SW-treated group secreted more TNF-alpha (350 ±25 pg/mL) and less IL-10 (89±7.2 pg/mL) than the untreated group (80 ±3 pg/mL and 150 ±10 pg/mL, respectively, both p < 0.05).

N-glycan-defective MA782 cells can induce the differentiation of BMDM into proinflammatory M1 macrophages in vitro.

Do birefringence characteristics in sperm heads allow for the selection of reacted spermatozoa for intracytoplasmic sperm injection?

To verify clinical outcome after injection of spermatozoa that have undergone the acrosome reaction (reacted spermatozoa) vs. those still having an intact acrosome (nonreacted spermatozoa). Prospective, randomized study. Reproductive Medicine Unit, Italian Society for the Study of Reproductive Medicine, Bologna, Italy. According to a prospective randomization including 71 couples with severe male factor infertility, intracytoplasmic sperm injection (ICSI) was performed under polarized light that permitted analysis of the pattern of birefringence in the sperm head. Twenty-three patients had their oocytes injected with reacted spermatozoa, 26 patient's oocytes were injected with nonreacted spermatozoa, and in 22 patients both reacted and nonreacted spermatozoa were injected. Intracytoplasmic sperm injection was performed under polarized light to selectively inject acrosome-reacted and acrosome-nonreacted spermatozoa. Rates of fertilization, cleavage, pregnancy, implantation, and ongoing implantation. There was no effect on the fertilizing capacity and embryo development of either type of sperm, whereas the implantation rate was higher in oocytes injected with reacted spermatozoa (39.0%) vs. those injected with nonreacted spermatozoa (8.6%). The implantation rate was 24.4% in the group injected with both reacted and nonreacted spermatozoa. The delivery rate per cycle followed the same trend.

Spermatozoa that have undergone the acrosome reaction seem to be more prone to supporting the development of viable ICSI embryos.

Does chronic osteomyelitis correlate with increased risk of acute pancreatitis in a case-control study in Taiwan?

The objective of this study was to examine the relationship between chronic osteomyelitis and acute pancreatitis in Taiwan. This was a population-based case-control study utilizing the database of the Taiwan National Health Insurance Program. We identified 7678 cases aged 20-84 with newly diagnosed acute pancreatitis during the period of 1998 to 2011. From the same database, 30,712 subjects without diagnosis of acute pancreatitis were selected as controls. The cases and controls were matched with sex, age and index year of diagnosing acute pancreatitis. The odds ratio with 95% confidence interval of acute pancreatitis associated with chronic osteomyelitis was examined by the multivariable unconditional logistic regression analysis. After adjustment for multiple confounders, the multivariable analysis showed that the adjusted odds ratio of acute pancreatitis was 1.93 for subjects with chronic osteomyelitis (95% confidence interval 1.01, 3.69), when compared with subjects without chronic osteomyelitis.

Chronic osteomyelitis correlates with increased risk of acute pancreatitis. Patients with chronic osteomyelitis should be carefully monitored about the risk of acute pancreatitis.

High-dose irinotecan plus LV5FU2 or simplified LV5FU (HD-FOLFIRI) for patients with untreated metastatic colorectal cancer: a new way to allow resection of liver metastases?

The antitumor efficacy of irinotecan may be dose dependent. This study aimed to determine the safety and efficacy of high-dose (HD) irinotecan combined with LV5FU2 or simplified LV5FU (LV5FUs) in first-line treatment of metastatic colorectal cancer. Patients with unresectable and measurable metastatic colorectal cancer, not pretreated for metastatic disease, were given irinotecan 260 mg/m(2) combined with LV5FU2 in the first 25 patients, then with LV5FUs (HD-FOLFIRI) in 35 patients. G-CSF was given in case of febrile neutropenia, grade 4 neutropenia>7 days or neutropenia grade>1 at day 15. The response rate was 57% (95% confidence interval 43-69%). Second surgery with curative intent was performed in 28% of patients, leading to 20% radiological complete response. Median response duration, time to progression and overall survival were 11, 9 and 22 months, respectively. The median dose intensity of irinotecan was 117 mg/m(2)/week. G-CSF was given to 45% of patients over 33% of cycles. Usual toxicity of irinotecan and 5-FU were observed without major increased frequency, except hematological toxicity. Tolerance was similar with LV5FU2 and LV5FUs, though more asymptomatic grade 3-4 neutropenia was observed with LV5FU2.

HD-irinotecan plus LV5FU2 or HD-FOLFIRI is feasible and achieved a high response rate and postsurgery complete response rate.

Are preventive HIV interventions at airports effective?

Few empirical data exist on the impact of preventive human immunodeficiency virus (HIV) interventions on intended and actual sexual behavior of international tourists. The present cross-sectional study is based on a 2 3 2 design. The sample consisted of departing and arriving passengers (n = 3100) at Zurich Airport with destinations in countries where heterosexual HIV transmission is dominant. While 41% of the tourists obtained information about safer sex, the remaining 59% without such intervention served as control group. Departing passengers completed a short questionnaire focusing on their planned sexual behavior. Arriving passengers were asked about their actual behavior during the journey. Subjects of the intervention group also evaluated the impact of the consultation. Most travelers appreciated the intervention and reported that they received important information. Members of the intervention group were better informed than those of the control group about the risk of heterosexually transmitted HIV infection (p<.01). They also indicated more often that they could imagine having casual sex abroad (23% vs 16%, p<.01). However, the two groups did not differ with regard to planned condom use or actual sexual behavior. Whereas most of departing passengers indicated that they would use condoms consistently, only half of the passengers who reported casual sex actually did so. Subjects who refused to participate in the intervention tended to consider it as irrelevant and reported less consistent condom use.

Although travel health interventions focusing on casual sex are appreciated and increase the knowledge, they failed to result in significant behavior modification. Future projects should attempt to approach possible risk groups more specifically and to have more impact.

Does toll-like receptor 2 mediate persistent chemokine release by Chlamydia pneumoniae-infected vascular smooth muscle cells?

The intracellular bacterium Chlamydia pneumoniae is present in many atherosclerotic lesions, where it could promote inflammation. This study determined whether monocyte chemoattractant protein 1 (MCP-1) release is stimulated in vascular smooth muscle cells (VSMCs) that are exposed to or infected by C pneumoniae and whether toll-like receptor 2 (TLR2) or TLR4 mediate these effects. TLR2 mRNA was expressed constitutively and was upregulated by C pneumoniae exposure in mouse aortic SMC and was inducible by C pneumoniae and TLR3 and TLR4 agonists in human coronary artery SMCs. Exposure to inactivated or viable extracellular C pneumoniae evoked a robust increase in MCP-1 release and activated nuclear factor-kappaB and extracellular signal-regulated kinase 1/2 in wild-type and TLR4 signaling-deficient mouse aortic SMCs but not in TLR2-deficient SMCs, probably because of TLR2-mediated recognition of a chlamydial antigen. Brief exposure to viable C pneumoniae led to active infection of VSMCs, shown by chlamydial protein synthesis, and caused a persistent (>48-hour) MCP-1 release that was also TLR2 dependent.

The results show that VSMCs express functional TLR2 and that TLR2 mediates both a persistent activation of chemokine release in C pneumoniae-infected VSMCs and its acute stimulation by extracellular C pneumoniae. Therefore, TLR2 expressed in VSMCs may promote inflammation within the arterial wall.

Is risk of tuberculosis higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy : The three-year prospective French Research Axed on Tolerance of Biotherapies registry?

Tuberculosis (TB) is associated with anti-tumor necrosis factor (anti-TNF) monoclonal antibody (mAb) therapy, but whether this association is drug-specific remains a concern. Our objective was to describe cases of TB associated with anti-TNF mAb therapy, identify risk factors, and estimate the incidence. We conducted an incidence study and a case-control analysis to investigate the risk of newly diagnosed TB associated with the use of anti-TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti-TNF mAb therapy for any indication; for each case, 2 patients treated with anti-TNF agents served as control subjects. We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex- and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7-15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4-25.8] and SIR 29.3 [95% CI 20.3-42.4] versus SIR 1.8 [95% CI 0.7-4.3], respectively). In the case-control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6-69.0] and OR 17.1 [95% CI 3.6-80.6], respectively). Other risk factors were age, the first year of anti-TNF mAb treatment, and being born in an endemic area.

The risk of TB is higher for patients receiving anti-TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.

Do gaseous environments modify physiology in the brewing yeast Saccharomyces cerevisiae during batch alcoholic fermentation?

To investigate the impact of different gaseous atmospheres on different physiological parameters in the brewing yeast Saccharomyces cerevisiae BRAS291 during batch fermentation. Yeasts were cultivated on a defined medium with a continuous sparging of hydrogen, helium and oxygen or without gas, permitting to obtain three values of external redox. High differences were observed concerning viable cell number, size and metabolites produced during the cultures. The ethanol yields were diminished whereas glycerol, succinate, acetoin, acetate and acetaldehyde yields were enhanced significantly. Moreover, we observed major changes in the intracellular NADH/NAD(+) and GSH/GSSG ratio.

The use of gas led to drastic changes in the cell size, primary energy metabolism and internal redox balance and E(h). These changes were different depending on the gas applied throughout the culture.

Does non-target adjacent stimuli classification improve performance of classical ERP-based brain computer interface?

The classical ERP-based speller, or P300 Speller, is one of the most commonly used paradigms in the field of Brain Computer Interfaces (BCI). Several alterations to the visual stimuli presentation system have been developed to avoid unfavorable effects elicited by adjacent stimuli. However, there has been little, if any, regard to useful information contained in responses to adjacent stimuli about spatial location of target symbols. This paper aims to demonstrate that combining the classification of non-target adjacent stimuli with standard classification (target versus non-target) significantly improves classical ERP-based speller efficiency. Four SWLDA classifiers were trained and combined with the standard classifier: the lower row, upper row, right column and left column classifiers. This new feature extraction procedure and the classification method were carried out on three open databases: the UAM P300 database (Universidad Autonoma Metropolitana, Mexico), BCI competition II (dataset IIb) and BCI competition III (dataset II). The inclusion of the classification of non-target adjacent stimuli improves target classification in the classical row/column paradigm. A gain in mean single trial classification of 9.6% and an overall improvement of 25% in simulated spelling speed was achieved.

We have provided further evidence that the ERPs produced by adjacent stimuli present discriminable features, which could provide additional information about the spatial location of intended symbols. This work promotes the searching of information on the peripheral stimulation responses to improve the performance of emerging visual ERP-based spellers.

Does paeonol attenuate advanced oxidation protein product-induced oxidative stress injury in THP-1 macrophages?

Paeonol (2'-hydroxy-4'-methoxyacetophenone) is thought to possess a broad range of clinically curative effects that are likely mediated by its anti-inflammatory and antioxidant activities. To elucidate the efficacy of paeonol's anti-inflammatory and antioxidant activities and the underlying mechanism of paeonol in advanced oxidation protein product (AOPP) stimulation of THP-1 macrophages. After incubating cells with AOPP plus paeonol, nitric oxide (NO) production and the levels of inducible NO synthase (iNOS), receptor for advanced glycation end products (RAGE), CD36, scavenger receptor (SR)-A, and SR-B1 were calculated. Moreover, THP-1 macrophages were preincubated with paeonol, the free radical scavenger N-acetylcysteine (NAC), NADPH oxidase inhibitors [apocynin, diphenylene iodonium (DPI)], and the specific inhibitor of nuclear factor-κB pyrrolidine dithiocarbamate (PDTC) prior to incubation with AOPP, and the levels of intracellular reactive oxygen species (ROS) production and tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and monocyte chemotactic protein 1 (MCP-1) were determined. Paeonol increased NO production and the mRNA level of iNOS, whereas it decreased ROS production. ROS production was also effectively attenuated by apocynin, DPI, NAC, and PDTC. Furthermore, these inhibitors and paeonol could downregulate the mRNA and protein levels of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and MCP-1). Paeonol significantly reduced the expression levels of RAGE and CD36 but increased the expression levels of SR-A and SR-B1.

These results indicate that paeonol can decrease proinflammatory cytokines in THP-1 macrophages, likely through RAGE-, CD36-, SR-A-, and SR-B1-mediated signals involving NADPH oxidase-dependent ROS generation. This suggests that paeonol can be used as a therapeutic agent for diseases contributing to oxidative stress injury.

Does biliary tract external drainage increase the expression levels of heme oxygenase-1 in rat livers?

Heme oxygenase-1 (HO-1) protects cells by anti-oxidation, maintaining normal microcirculation and anti-inflammatory under stress. This study investigated the effects of biliary tract external drainage (BTED) on the expression levels of HO-1 in rat livers. Biliary tract external drainage was performed by inserting a cannula into the bile duct. Sixty Sprague-Dawley rats were randomized to the following groups: sham 1 h group; BTED 1 h group; bile duct ligation (BDL) 1 h group; sham 6 h group and BTED 6 h group. The expression levels of HO-1 mRNA were analyzed using real-time RT-PCR. The expression levels of HO-1 were analyzed using immunohistochemistry. The expression levels of HO-1 mRNA in the liver of the BTED group increased significantly compared with the sham group 1 and 6 h after surgery (p < 0.05).The expression levels of HO-1 in the BTED group increased significantly compared with the sham group 1 and 6 h after surgery. The expression levels of HO-1 mRNA in the liver in the BDL group decreased significantly compared with the sham group 1 h after surgery (p < 0.05).The expression levels of HO-1 in the BDL group decreased significantly compared with the sham group at this time.

Biliary tract external drainages increase the expression levels of HO-1 in the liver.

Is maximum tumor diameter an independent prognostic factor in high-risk localized prostate cancer?

Previous studies suggest that maximum tumor diameter (MTD) is a predictor of recurrence in prostate cancer (PC). This study investigates the prognostic value of MTD for biochemical recurrence (BCR) in patients with PC, after radical prostatectomy (RP), with emphasis on high-risk localized prostate cancer. RP specimens of 542 patients were evaluated with a median follow-up of 39.5 months (range 0.6-150 months). MTD was defined as the largest diameter of the largest tumor; high-risk as >or=T2c or PSA level>20 ng/ml or Gleason score>or=8 and BCR as two consecutive PSA levels>0.10 ng/ml. Proportional hazards multivariable regression models were composed to determine prognostic factors for BCR. Overall, 114 patients developed BCR after RP. The overall 5-year risk of BCR was 25% (95% CI=20.4-29.6), and median MTD was 24 mm (range 1-65). MTD in the total and high-risk group was associated with total tumor volume, volume of the largest tumor, pre-operative PSA levels, and Gleason score. In a univariable analyses, MTD was weakly associated with risk of BCR (HR=1.02 per mm increase, 95% CI=1.002-1.035, P=0.024) in the total group; in the high-risk group this association was lost (HR=1.01, 95%CI=0.99-1.03, P=0.18). Multivariable analyses indicated that positive surgical margins, higher Gleason score, advanced pathological stage, and multiple tumors were the main prognostic factors for BCR irrespective of the risk profile. MTD did not provide additional information.

MTD is not an independent prognostic factor for BCR in patients treated with RP, irrespective of the risk profile.

Does sDHA immunohistochemistry detect germline SDHA gene mutations in apparently sporadic paragangliomas and pheochromocytomas?

Pheochromocytoma-paraganglioma syndrome is caused by mutations in SDHB, SDHC, and SDHD, encoding subunits of succinate dehydrogenase (SDH), and in SDHAF2, required for flavination of SDHA. A recent report described a patient with an abdominal paraganglioma, immunohistochemically negative for SDHA, and identified a causal germline mutation in SDHA. In this study, we evaluated the significance of SDHA immunohistochemistry in the identification of new patients with SDHA mutations. This study was performed in the Erasmus Medical Center in Rotterdam (The Netherlands) and the Université Paris Descartes in Paris (France). We investigated 316 pheochromocytomas and paragangliomas for SDHA expression. Sequence analysis of SDHA was performed on all tumors that were immunohistochemically negative for SDHA and on a subset of tumors immunohistochemically positive for SDHA. Six tumors were immunohistochemically negative for SDHA. Four tumors from Dutch patients showed a germline c.91C → T SDHA gene mutation (p.Arg31X). Another tumor (from France) carried a germline SDHA missense mutation c.1753C → T (p.Arg585Trp). Loss of the wild-type SDHA allele was confirmed by loss of heterozygosity analysis. Sequence analysis of 35 SDHA immunohistochemically positive tumors did not reveal additional SDHA mutations.

Our results demonstrate that SDHA immunohistochemistry on paraffin-embedded tumors can reveal the presence of SDHA germline mutations and allowed the identification of SDHA-related tumors in at least 3% of patients affected by apparently sporadic (para)sympathetic paragangliomas and pheochromocytomas.

Does carvedilol improve functional class in patients with severe left ventricular dysfunction referred for heart transplantation?

Limited options are available to improve the functional class of patients awaiting cardiac transplantation. We assessed the effect of carvedilol on New York Heart Association (NYHA) class, heart rate (HR), blood pressure (BP), jugular venous pressure (JVP), electrolytes and renal function in patients with markedly decreased left ventricular (LV) function referred for cardiac transplantation assessment. Sixty-one patients (age = 52 +/- 12 yr, EF = 23 +/- 7%, VO2 max = 16 +/- 5 mL/kg/min) referred to the cardiac transplant clinic were reviewed before and after the addition of carvedilol (starting dose 3.125 mg twice daily to target dose of 25 mg twice daily) to usual heart-failure therapy. Over a 1-yr period, at each visit prior to initiation, at baseline initiation visit and at each follow-up visit, NYHA class, BP, HR, JVP, electrolytes, and renal function were obtained. Statistical analysis was performed using random effects regression approach. A multiple logistic regression analysis was performed on 52/61 patients to determine possible associations between NYHA improvement and the following patient characteristics: sex, etiology of cardiomyopathy, initial NYHA class, and dose of carvedilol. Three patients died (2 after stopping carvedilol) and 3 were transplanted. Median follow-up was 100 d. Sixteen patients reached the target dose after a mean of 137 d (2.75 visits). Estimated time-to-target dose is 8 months (5.6 visits). BP tended to increase (p = 0.07 for change in trend) with no change in JVP, electrolytes or renal function. HR decreased 6 +/- 3 b.p.m. (p = 0.03). Of 14 patients NYHA class I/II at baseline, none were class III/IV at last follow-up visit. Of 47 patients NYHA class III/IV at baseline, 25 were class I/II, and 22 were class III/IV at last follow-up (p < 0.001). Multiple logistic regression analysis did not demonstrate any factor predictive of subsequent NYHA class improvement.

Despite less than target doses in most patients, a favorable effect of carvedilol on functional class in patients with severe congestive heart failure (CHF) referred for transplant was observed. Those with good functional status remained stable and those with poor functional status improved or remained stable. No baseline patient characteristic predicted improvement. The shortage of donor organ requires optimal use of medical regimens which may improve functional class while awaiting transplantation and which may delay the necessity for heart transplantation. Therefore, addition of carvedilol to usual medical therapy may be beneficial even in patients with severe LV dysfunction and poor NYHA classification.

Octenidine in combination with polymethylmethacrylate: a new option for preventing infection?

Orthopedic implant infections represent a serious complication for both patient and surgeon. In order to minimize this risk, it has become standard practice in surgery and orthopedics to add antimicrobial substances to the polymethylmethacrylate (PMMA) bone cement. The aim of this study is to find new options for preventing infection by using alternative adjuvants in combination with PMMA. We hypothesized, that Octenidine, after being combined with PMMA, can be released in vitro and an antimicrobial efficacy of discharged Octenidine can be shown. The release of Octenidine from PMMA was assessed in high pressure liquid chromatography of the supernatant. In order to assess the efficacy of Octenidine on Staphylococcus aureus and Pseudomonas aeruginosa in vitro, a nutrient solution for these bacteria was incubated with a defined number of these bacteria (10(6) colony forming units) and cement pellets containing the antiseptic Octenidine for 24 h. After the incubation the number of bacteria in the solution was determined by counting the colony forming units on blood agar plates. Octenidine was shown to be released in a concentration-dependent manner from PMMA in the elution experiment. The experimental procedure using S. aureus demonstrated a bactericidal effect for bone cement containing Octenidine. For P. aeruginosa, bone cement containing 5-8% Octenidine was associated with tenfold reduction in bacterial count.

These results suggest that Octenidine is released after combining it with PMMA and reaches working concentrations in vitro. These findings suggest a new and effective alternative for prevention of infection in cemented implants. Further investigations on the biocompatibility of this combination is needed.

Is the severity of nocturnal hypoxia but not abdominal adiposity associated with insulin resistance in non-obese men with sleep apnea?

Beyond obesity, sleep apnea syndrome is frequently associated with excess abdominal adiposity that could contribute to the deteriorated cardiometabolic risk profile of apneic patients. The present study addressed the respective contribution of the severity of sleep apnea syndrome and excess abdominal adiposity to the cardiometabolic risk profile of 38 non obese men with polysomnography-diagnosed sleep apnea syndrome (apnea-hypopnea index >15 events/hour). These otherwise healthy men performed a 75g-oral glucose tolerance test (OGTT) with plasma lipid/inflammatory and redox profiles. Twenty-one apneic men with high-waist circumference (>94 cm) were compared to 17 apneic men with low-waist circumference. Apneic men with high-waist circumference had higher AUC glucose and AUC insulin than apneic men with low-waist circumference. Accordingly, apneic men with high-waist circumference had higher hepatic insulin resistance as reflected by higher HOMA-resistance index, and lower global insulin sensitivity as reflected by lower insulin sensitivity index of Matsuda (derived from OGTT). The sleep structure and the apnea-hypopnea index were not different between the two groups. However, apneic men with high-waist circumference presented with lower mean nocturnal oxyhemoglobin (SpO2). In the 38 men, waist circumference and mean nocturnal SpO2 were inversely correlated (r = -0.43, p = 0.011) and were both associated with plasma glucose/insulin homeostasis indices: the higher the waist circumference, the lower the mean nocturnal SpO2, the lower the insulin-sensitivity. Finally, in multivariable regression model, mean nocturnal SpO2 and not waist circumference was associated with insulin-resistance.

Thus, excess abdominal adiposity in non obese apneic men was associated with a deteriorated insulin-sensitivity that could be driven by a more severe nocturnal hypoxemia.

Does shorter anogenital distance correlate with the severity of hypospadias in pre-pubertal boys?

Do pre-pubertal boys with hypospadias have a shorter anogenital distance (AGD) than boys with normal genitalia?

AGD is significantly shorter in boys with hypospadias and decreases with the severity of hypospadias.

Is epithelial to mesenchymal transition increased in patients with COPD and induced by cigarette smoke?

Cigarette smoking contributes to lung remodelling in chronic obstructive pulmonary disease (COPD). As part of remodelling, peribronchiolar fibrosis is observed in the small airways of patients with COPD and contributes to airway obstruction. Epithelial to mesenchymal transition (EMT) appears to be involved in the formation of peribronchiolar fibrosis. This study examines the EMT process in human bronchial epithelial cells (HBECs) from non-smokers, smokers and patients with COPD as well as the in vitro effect of cigarette smoke extract (CSE) on EMT. HBECs from non-smokers (n=5), smokers (n=12) and patients with COPD (n=15) were collected to measure the mesenchymal markers α-smooth muscle actin, vimentin and collagen type I and the epithelial markers E-cadherin, ZO-1 and cytokeratin 5 and 18 by real time-PCR and protein array. In vitro differentiated bronchial epithelial cells were stimulated with CSE. Mesenchymal markers were upregulated in HBECs of smokers and patients with COPD compared with non-smokers. In contrast, epithelial cell markers were downregulated. In vitro differentiated HBECs underwent EMT after 72 h of CSE exposure through the activation of intracellular reactive oxygen species, the release and autocrine action of transforming growth factor β1, the phosphorylation of ERK1/2 and Smad3 and by the downregulation of cyclic monophosphate.

The EMT process is present in bronchial epithelial cells of the small bronchi of smokers and patients with COPD and is activated by cigarette smoke in vitro.

Do third year nursing students ' viewpoints about circumstances which threaten safety in the clinical setting?

Evidence emphasizes that learners, educators, clinicians, programs, and organizations share the responsibility for establishing and maintaining safety throughout undergraduate nursing education. Increased knowledge about students' perceptions of threats to safety in the clinical setting may guide educators' efforts to promote the development of safe novice practitioners while preserving patient safety. The purpose of this study was to describe third year nursing students' viewpoints of the circumstances which threaten safety in the clinical setting. Using Q methodology, 34 third year Bachelor of Science in Nursing students sorted 43 theoretical statement cards. Each card identified a statement describing a threat to safety in the clinical setting. These statements were generated through a review of nursing literature and consultation with experts in nursing education. Centroid factor analysis and varimax rotation identified viewpoints regarding circumstances that most threaten safety. Three discrete viewpoints and one consensus perspective constituted students' description of threatened safety. The discrete viewpoints were labeled lack of readiness, misdirected practices, and negation of professional boundaries. There was consensus that it is most unsafe in the clinical setting when novices fail to consolidate an integrated cognitive, behavioral, and ethical identity. This unifying perspective was labeled non-integration.

Third year nursing students and their educators are encouraged to be mindful of the need to ensure readiness prior to entry into the clinical setting. In the clinical setting, the learning of prepared students must be guided by competent educators. Finally, both students and their educators must respect professional boundaries to promote safety for students and patients.

Does adolescent exposure to nicotine results in reinforcement enhancement but affect adult responding in rats?

Adolescence is a period of development associated with a peak in an organism's responsiveness to reward. Epidemiological data indicate that the initiation of smoking is high during adolescence and that earlier age of onset is associated with increased incidence of dependence as adults. In rats, nicotine is known to have primary reinforcing and reinforcement enhancing effects. Although the primary reinforcing effects of nicotine have been demonstrated in adolescent rats (self-administration), less is known about its reinforcement enhancing effects during this period. Moreover, the impact of adolescent nicotine exposure on its reinforcement enhancing effects during adulthood has not yet been examined. The objectives of this study were to assess whether (1) nicotine enhances operant responding for an unconditioned visual reinforcer (VS) in adolescent rats, and (2) exposure to nicotine during adolescence affects responsiveness to the VS in adulthood. Rats were exposed to nicotine (0.32 mg/kg, subcutaneous injection) or saline during adolescence (postnatal day 29-42) and adulthood. Nose-poking for the VS was assessed under fixed and progressive ratio schedules. Nicotine increased responding for the VS during adolescence. Adolescent nicotine exposure failed to significantly affect adult responsiveness for the VS, regardless of adult nicotine exposure, but early exposure to the VS affected responsiveness to the VS in adulthood.

Nicotine exhibits reinforcement enhancing effects in adolescent rats. Long-term effects of adolescent nicotine on reinforcement enhancement are minimal, but the impact of early exposure to the VS and/or the primary reinforcing effects of nicotine requires further investigation.

Are tissue microstructural changes independently associated with cognitive impairment in cerebral amyloid angiopathy?

Cerebral amyloid angiopathy (CAA) is a major cause of lobar intracerebral hemorrhage and cognitive impairment and is associated with white matter hyperintensities and cerebral microbleeds. MRI diffusion tensor imaging detects microstructural tissue damage in advanced CAA even in areas that appear normal on conventional MRI. We hypothesized that higher global mean apparent diffusion coefficient (mean ADC), reflecting a higher amount of chronic tissue disruption caused by CAA, would be independently associated with CAA-related cognitive impairment. Preintracerebral hemorrhage cognitive impairment was systematically assessed using a standardized questionnaire (IQCODE) in 49 patients. Volume of white matter hyperintensities, number of microbleeds, and mean ADC were determined from MRIs obtained within 14.0+/-22.5 days of intracerebral hemorrhage cognitive impairment. White matter hyperintensities and mean ADC were measured in the hemisphere uninvolved by intracerebral hemorrhage to avoid confounding. Preintracerebral hemorrhage cognitive impairment was identified in 10 of 49 subjects. Mean ADC was the only variable associated with preintracerebral hemorrhage cognitive impairment and was elevated in those with preintracerebral hemorrhage cognitive impairment compared with those without (12.4x10(-4) versus 11.7x10(-4) mm(2)/s; P=0.03). Mean ADC positively correlated with age but not white matter hyperintensities or number of microbleeds. In logistic regression controlling for age and visible cerebral atrophy, mean ADC was independently associated with preintracerebral hemorrhage cognitive impairment (OR per 1x10(-4) mm(2)/s increase=2.45, 95% CI 1.11 to 5.40, P=0.04).

Mean ADC is independently associated with preintracerebral hemorrhage cognitive impairment in CAA. The lack of correlation with other MRI markers of CAA suggests that mean ADC may be sensitive to distinct aspects of CAA pathology and its tissue consequences. These results suggest that global MRI diffusion changes are sensitive to clinically relevant microstructural alterations and may be useful markers of CAA-related tissue damage.

Is expression of FOXP3 , CD68 , and CD20 at diagnosis in the microenvironment of classical Hodgkin lymphoma predictive of outcome?

The immune microenvironment is key to the pathophysiology of classical Hodgkin lymphoma (CHL). Twenty percent of patients experience failure of their initial treatment, and others receive excessively toxic treatment. Prognostic scores and biomarkers have yet to influence outcomes significantly. Previous biomarker studies have been limited by the extent of tissue analyzed, statistical inconsistencies, and failure to validate findings. We aimed to overcome these limitations by validating recently identified microenvironment biomarkers (CD68, FOXP3, and CD20) in a new patient cohort with a greater extent of tissue and by using rigorous statistical methodology. Diagnostic tissue from 122 patients with CHL was microarrayed and stained, and positive cells were counted across 10 to 20 high-powered fields per patient by using an automated system. Two statistical analyses were performed: a categorical analysis with test/validation set-defined cut points and Kaplan-Meier estimated outcome measures of 5-year overall survival (OS), disease-specific survival (DSS), and freedom from first-line treatment failure (FFTF) and an independent multivariate analysis of absolute uncategorized counts. Increased CD20 expression confers superior OS. Increased FOXP3 expression confers superior OS, and increased CD68 confers inferior FFTF and OS. FOXP3 varies independently of CD68 expression and retains significance when analyzed as a continuous variable in multivariate analysis. A simple score combining FOXP3 and CD68 discriminates three groups: FFTF 93%, 62%, and 47% (P < .001), DSS 93%, 82%, and 63% (P = .03), and OS 93%, 82%, and 59% (P = .002).

We have independently validated CD68, FOXP3, and CD20 as prognostic biomarkers in CHL, and we demonstrate, to the best of our knowledge for the first time, that combining FOXP3 and CD68 may further improve prognostic stratification.

Irrigation of port sites: prevention of port site metastases?

Port site metastases can occur when free viable tumor cells implant at trocar wounds. Irrigation of port sites with cytotoxic agents has been suggested to prevent port site metastases. The objective of this study is to assess whether tumor growth at port sites can be reduced by irrigation of these port sites. WAG rats were insufflated with CO(2) for 20 minutes and 5 x 10(5) CC531 tumor cells were injected intraperitoneally. Port sites were irrigated after completion of the pneumoperitoneum with povidone-iodine, a mixture of taurolidine and heparin, or sodium chloride. Controls did not undergo any irrigation of port sites. In experiment 1, all 16 rats had all 4 irrigation modalities. In experiment 2, four groups of 20 rats had one type of irrigation on two trocar wounds. Tumor growth was evaluated 4 weeks after the procedure. No difference in tumor growth at trocar wounds was found between any type of irrigation and controls in both experiments.

In this experimental model, no beneficial or adverse effects of irrigation of port sites could be shown.

Do greek pregnant women demonstrate inadequate micronutrient intake despite supplement use?

Maternal diet is important in the outcome of pregnancy and the health of the children. The present cross-sectional study aimed to assess the use of dietary supplements during pregnancy and define the maternal characteristics associated with supplement use. The diet of 100 childbearing women was recorded for three consecutive days and micronutrient supplementation was added to the dietary intake and the median values were used in the analyses. The majority of the participants (92%) consumed at least one supplement. Supplementation of folic acid (FA) was significantly lower during the third trimester compared to the second (p ≤ .007). Higher intake of Ca and Fe supplements was observed in the second trimester (p ≤ .001). The use of supplements contributed to an attenuated consumption of all reported micronutrients (Mg, Ca, FA, and Fe, p ≤ .001). The principal components analysis revealed that the most important factor contributing to supplementation was primiparity.

Overall, a high prevalence of micronutrient supplementation during pregnancy was observed without ensuring adequacy in the micronutrient intake. The increased rates of supplement users might be the result of an act for balancing diet in unplanned pregnancies.

Does netrin signaling break the equivalence between two identified zebrafish motoneurons revealing a new role of intermediate targets?

We previously showed that equivalence between two identified zebrafish motoneurons is broken by interactions with identified muscle fibers that act as an intermediate target for the axons of these motoneurons. Here we investigate the molecular basis of the signaling interaction between the intermediate target and the motoneurons. We provide evidence that Netrin 1a is an intermediate target-derived signal that causes two equivalent motoneurons to adopt distinct fates. We show that although these two motoneurons express the same Netrin receptors, their axons respond differently to Netrin 1a encountered at the intermediate target. Furthermore, we demonstrate that when Netrin 1a is knocked down, more distal intermediate targets that express other Netrins can also function to break equivalence between these motoneurons.

Our results suggest a new role for intermediate targets in breaking neuronal equivalence. The data we present reveal that signals encountered during axon pathfinding can cause equivalent neurons to adopt distinct fates. Such signals may be key in diversifying a neuronal population and leading to correct circuit formation.

Are small biparietal diameter and head circumference part of the phenotype instead of independent prognostic markers in fetuses with spinal dysraphism?

The aim of this retrospective study was to assess the fetal biparietal diameter (BPD) and head circumference (HC) in the second trimester of pregnancy in fetuses with open spinal dysraphism. BPD and HC were measured at 16-26 weeks in 74 fetuses with open spinal dysraphism and compared with reference values. BPD was smaller in fetuses with open spinal dysraphism. Of all cases with open spinal dysraphism, 62.2% had a BPD <3rd percentile and 79.7% had a BPD <10th percentile. Of all patients, 54.1% had an HC <3rd percentile and 74.3% had an HC <10th percentile.

Almost all fetuses with open neural tube defects have a smaller BPD and HC at 16-26 weeks compared with reference values, which implicates that this is part of the phenotype of children with open spinal dysraphism instead of an independent prognostic marker for a poor cognitive outcome.

Is thoracic spinal anesthesia safe for patients undergoing abdominal cancer surgery?

A double-blinded randomized controlled study to compare discharge time and patient satisfaction between two groups of patients submitted to open surgeries for abdominal malignancies using segmental thoracic spinal or general anesthesia. Open surgeries for abdominal malignancy are usually done under general anesthesia, but many patients with major medical problems sometimes can't tolerate such anesthesia. Regional anesthesia namely segmental thoracic spinal anesthesia may be beneficial in such patients. A total of 60 patients classified according to American Society of Anesthesiology (ASA) as class II or III undergoing surgeries for abdominal malignancy, like colonic or gastric carcinoma, divided into two groups, 30 patients each. Group G, received general anesthesia, Group S received a segmental (T9-T10 injection) thoracic spinal anesthesia with intrathecal injection of 2 ml of hyperbaric bupivacaine 0.5% (10 mg) and 20 ug fentanyl citrate. Intraoperative monitoring, postoperative pain, complications, recovery time, and patient satisfaction at follow-up were compared between the two groups. Spinal anesthesia was performed easily in all 30 patients, although two patients complained of paraesthesiae, which responded to slight needle withdrawal. No patient required conversion to general anesthesia, six patients required midazolam for anxiety and six patients required phenylephrine and atropine for hypotension and bradycardia, recovery was uneventful and without sequelae. The two groups were comparable with respect to gender, age, weight, height, body mass index, ASA classification, preoperative oxygen saturation and preoperative respiratory rate and operative time.

This preliminary study has shown that segmental thoracic spinal anesthesia can be used successfully and effectively for open surgeries for abdominal malignancies by experienced anesthetists. It showed shorter postanesthesia care unit stay, better postoperative pain relief and patient satisfaction than general anesthesia.

Does sphingosylphosphorylcholine potentiate vasoreactivity and voltage-gated Ca2+ entry via NOX1 and reactive oxygen species?

Sphingosylphosphorylcholine (SPC) elicits vasoconstriction at micromolar concentrations. At lower concentrations (≤1 µmol/L), however, it does not constrict intrapulmonary arteries (IPAs), but strongly potentiates vasoreactivity. Our aim was to determine whether this also occurs in a systemic artery and to delineate the signalling pathway. Rat mesenteric arteries and IPAs mounted on a myograph were challenged with ∼25 mmol/L [K+] to induce a small vasoconstriction. SPC (1 µmol/L) dramatically potentiated this constriction in all arteries by ∼400%. The potentiation was greatly suppressed or abolished by inhibition of phospholipase C (PLC; U73122), PKCε (inhibitory peptide), Src (PP2), and NADPH oxidase (VAS2870), and also by Tempol (superoxide scavenger), but not by inhibition of Rho kinase (Y27632). Potentiation was lost in mesenteric arteries from p47(phox-/-), but not NOX2(-/-), mice. The intracellular superoxide generator LY83583 mimicked the effect of SPC. SPC elevated reactive oxygen species (ROS) in vascular smooth muscle cells, and this was blocked by PP2, VAS2870, and siRNA knockdown of PKCε. SPC (1 µmol/L) significantly reduced the EC50 for U46619-induced vasoconstriction, an action ablated by Tempol. In patch-clamped mesenteric artery cells, SPC (200 nmol/L) enhanced Ba2+ current through L-type Ca2+ channels, an action abolished by Tempol but mimicked by LY83583.

Our results suggest that low concentrations of SPC activate a PLC-coupled and NOX1-mediated increase in ROS, with consequent enhancement of voltage-gated Ca2+ entry and thus vasoreactivity. We speculate that this pathway is not specific for SPC, but may also contribute to vasoconstriction elicited by other G-protein coupled receptor and PLC-coupled agonists.

Does interstitial quinacrine activate a distinctive immune response effective for tumor immunotherapy?

Interstitial immunotherapy consists of the local injection of immune cells or molecules with cytotoxic properties to destroy neoplastic cells. Intratumor injection of quinacrine induces intense recruitment of activated immune cells that leads to necrosis and elimination of experimental malignant neoplasms; this effect seems to be mediated by immune molecules. We measured the tissue content of activated immune cells and various cytokines at different times during the first 8 days after a single interstitial injection of 150 mg quinacrine in rats. A large cell infiltrate by macrophages, CD4(+), CD8(+), and natural killer cells was evident a few hours after quinacrine injection. In comparison with controls, tissue contents of 4 cytokines had a marked increase: macrophage chemoattractant protein-1 increased 115-fold; interleukin-6, 9-fold; RANTES (regulated on activation, normal T cell expressed and secreted), 13-fold; and macrophage inflammatory protein-2, 10-fold. Other cytokines, like interleukins 1beta, 2, 4, 10, interferon-gamma, tumor necrosis factor-alpha, complement 3, and C reactive protein did not increase significantly, indicating that the endogenous local response to quinacrine follows a singular pathway of immune activation.

Interstitial quinacrine is a strong activator of innate immunity and is not mediated by the usual mechanisms of immune recognition. It constitutes an original approach for regional immunotherapy of neoplasms that is not mediated solely by induction of local, cytotoxic chemical necrosis.

The irritable uterus: a risk factor for preterm birth?

Our aim was to determine the incidence and preterm delivery rate along with the indication for delivery in patients with uterine irritability. In this retrospective, descriptive study, 17,186 patients with well-defined high-risk factors were compared with 2637 women with uterine irritability. The incidence of preterm labor in patients with uterine irritability was 18.7%, significantly less than in those with other high-risk factors (odds ratio 0.35, 0.31<odds ratio<0.38). However, women with uterine irritability who experience preterm labor, compared with other high-risk factors, are much more likely to deliver before 34 weeks' gestation (odds ratio 2.50, 2.07<odds ratio<3.03) and more than twice as likely to deliver as a result of advanced preterm labor or membrane rupture (odds ratio 2.20, 1.75<odds ratio<2.78).

The incidence of preterm labor in women with uterine irritability is not as frequent as in patients with other high-risk factors. However, preterm labor does occur in patients with uterine irritability at a rate higher than that in the general obstetric population (18.7% vs 11.0%). Because it appears that women with uterine irritability have more resistance to conventional tocolytic therapy, this condition should prompt the physician to use more aggressive perinatal assessment.

Do amniotic fluid insulin levels identify the fetus at risk of neonatal hypoglycaemia?

To investigate the use of amniotic fluid insulin (AFI) as a predictor of neonatal morbidity in the macrosomic newborn of the diabetic mother, in view of the fact that raised AFI levels are a marker for fetal hyperinsulinaemia. AFI was measured by radioimmunoassay in a group of pregnant diabetic women (n = 63) with normal (n = 41) or accelerated fetal growth (n = 22). Using log transformed data, liquor insulin was found to be significantly higher in pregnant women with Type 1 and Type 2 diabetes mellitus (17.6 mU/l; 95% confidence interval (CI) 11.7-26.4) compared with women with gestational diabetes mellitus (GDM) (8.2 mU/l; 95% CI 4.8-13.8, P = 0.02) or impaired glucose tolerance (IGT) (6.2mU/l; 95% CI 4.9-8.0, P = 0.0001). In the group with macrosomic fetuses (birth weight > 90th centile for gestational age), there was a significantly higher incidence of elective Caesarean section (CS) and emergency CS (12/22) compared to those with appropriate for gestational age (AGA) fetal weights (birth weight > 10th and < 90th centiles for gestational age) (9/41, P = 0.009). There was no significant correlation between raised AFI and macrosomia except in the Type 1 diabetic women, in whom the AGA group mean was 13.2 mU/l (95% CI 7.4-23.3), and 34.6mU/l (95% CI 17.5-68.4 P = 0.022) in macrosomia. In the latter group, hypoglycaemia requiring treatment was significantly more common in the macrosomic hyperinsulinaemic neonates (8/13), compared to normoinsulinaemic neonates in the same group (0/9, P = 0.005).

Identification of the hyperinsulinaemic fetus before delivery might allow the intensification of maternal insulin therapy leading to a reduction in incidence and severity of diabetic fetopathy. Pregnancy with a normoinsulinaemic fetus could be allowed to continue to the onset of spontaneous labour, which might result in a lower CS rate.

Do interstitial cells from dogs with naturally occurring myxomatous mitral valve disease undergo phenotype transformation?

Myxomatous mitral valve disease is a common naturally occurring heart disease of dogs that is pathologically similar to myxomatous mitral valve disease in humans. It was hypothesized that interstitial cell phenotype transformation recently described in human myxomatous valves might also occur in dogs with myxomatous mitral valves, and correlate with disease severity. Normal and early-, intermediate- and late-stage myxomatous canine mitral valves were examined histologically and immunohistochemically for cytoskeletal (vimentin, desmin, smooth muscle alpha-actin, smooth muscle myosin, and non-muscle myosin), collagenolytic (MMP-1, MMP-13), cell surface (CD-31, CD-45, CD-68) and proliferation (Ki-67) proteins. Normal canine mitral valve interstitial cells were positive for vimentin, but negative for alpha-actin, desmin and non-muscle myosin (i.e., fibroblast phenotype). Interstitial cells from myxomatous valves showed progressive positive staining for alpha-actin and desmin, but were negative for smooth muscle myosin (i.e., myofibroblast phenotype). Positive-staining cells first appeared as cellular clusters in the subendocardial region of the lamina atrialis and extended into deeper layers with increasing severity. Interstitial cells from myxomatous valves showed positive staining for non-muscle myosin (i.e., activated mesenchymal cell phenotype). Positive-staining cells increased with disease severity and were dispersed throughout the valve layers. The expression of MMP-1 and MMP-13 increased in myxomatous mitral valves and correlated with disease severity. Interstitial cellularity increased dramatically in degenerative mitral valves, though Ki-67 staining was only mildly increased.

Two patterns of interstitial cell phenotype transformation were identified in dogs with myxomatous mitral valve disease, and both correlated with disease severity. Myofibroblast transformation characterized by positive staining for alpha-actin and desmin occurred in cellular clusters primarily in the lamina atrialis. Mesenchymal cell activation characterized by positive staining to non-muscle myosin occurred throughout the valve. The dog may be a natural model for studying the cell biology of progressive myxomatous valve disease.

Does fracture Classification Predict Functional Outcomes in Supracondylar Humerus Fractures : A Prospective Study?

Few studies have prospectively assessed functional outcomes after the surgical management of supracondylar humerus fractures (SCHFXs) and the relationship between fracture pattern and ultimate patient outcome has never been prospectively evaluated. The purpose of this study was to prospectively evaluate fracture classification and functional outcome in children with extension SCHFXs using validated outcome measures. An Institutional Review Board-approved prospective enrollment of consecutive patients with operative SCHFX was performed over a 3-year period. Fractures were classified by the treating surgeon using the modified Gartland classification. Functional outcome was assessed at final follow-up using the Pediatric Outcomes Data Collection Instruments (PODCI) and the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) outcome measure. Patients with flexion-type fractures, multidirectionally unstable fractures and those with <10 weeks follow-up were excluded from analysis. Statistical analysis was used to determine the relationship between fracture classification/pattern and functional outcome. Seven hundred fifty-two patients were enrolled during the study period. One hundred thirty-two patients with extension-type injuries (average age 6.7 y) completed functional outcome measures at an average follow-up of 12.4 weeks. Forty-five (34%) were type II fractures and 87 (66%) were type III fractures. Forty-five (34%) of the fractures were posteromedially displaced, 43 (33%) were posterolaterally displaced, and 44 (33%) were posteriorly displaced without coronal plane deformity. The average PODCI global functioning scale score and QuickDASH scores for the entire cohort were 93.6 and 11.4, respectively, indicating excellent function. No differences in outcome scores were noted between patients with type II and III fractures. No difference in outcome was identified based upon direction of fracture displacement.

This is the first study to prospectively analyze fracture classification and functional outcome using validated outcome measures following the operative treatment of pediatric extension-type SCHFX. Children generally have excellent functional outcomes following the operative treatment of SCHFX. Garland classification and direction of displacement do not influence functional outcomes.

Are T2-weighted images necessary in renal mass characterization?

To determine what role T2-weighted images play in characterizing renal masses. Forty-four pathologically proven renal masses (34 renal cell carcinomas, 8 oncocytomas, 1 metanephric adenoma, 1 angiomyolipoma without macroscopic fat) and 38 simple renal cysts were evaluated with T1- and T2-weighted images at 1.5T. Two independent and blinded readers initially characterized all masses using only the T1-weighed images (in- and opposed-phase chemical shift, unenhanced frequency-selective fat-suppressed, gadolinium-enhanced frequency-selective fat-suppressed and subtraction images) and placed each mass into one of three categories: nonsurgical, in need of follow-up, or surgical. The masses were then re-evaluated with the addition of the T2-weighted images. It was determined if the T2-weighted images changed the initial classification. Forty-three of the 44 (98%) pathologically proven renal masses were characterized as a surgical mass using only the T1-weighted images. The remaining renal mass (a renal cell carcinoma) was characterized as a mass in which follow-up exams would be suggested. Thirty-eight of 38 (100%) simple renal cysts were correctly characterized using only the T1-weighted images. The T2-weighted images did not change the initial interpretation of the T1-weighted images in any of the cases.

The results of this study suggest that T2-weighted images are not necessary in the evaluation of all renal masses and are specifically not necessary in the differentiation of solid and cystic renal neoplasms from simple renal cysts.

Are cARD15/NOD2 gene variants associated with familially occurring and complicated forms of Crohn 's disease?

Variants of the caspase activating recruitment domain 15/nucleotide oligomerisation domain 2 (CARD15/NOD2) gene have been associated with susceptibility to Crohn's disease (CD). Our aim was to evaluate the allele frequencies of the CARD15 variants R702W, G908R, and 1007fs in Finnish inflammatory bowel disease (IBD) patients and to search for possible associations between CARD15 variants and occurrence of familial forms of IBD or complicated forms of CD. We investigated 198 sporadic CD patients, 46 probands with familial CD, 27 CD probands from mixed IBD families, 99 unrelated patients with ulcerative colitis (UC), and 300 control individuals for the occurrence of the CARD15 gene variants R702W, G908R, and 1007fs. In CD patients, the allele frequencies for the rare variants of these polymorphisms were 3.3%, 0.6%, and 4.8% (total 8.7%), and the corresponding frequencies in healthy controls were 1.8%, 0%, and 1.7% (total 3.5%) (8.7% v 3.5%; p<0.01). In UC patients allele frequencies were comparable with those in controls. The frequency of the 1007fs polymorphism variant allele was significantly higher among all CD patients than in controls (4.8% v 1.7%; p<0.01) but there was no significant difference in allele frequencies between the CD and UC groups. The 1007fs allele frequency was higher in familial CD than in non-familial cases with CD (10.9% v 3.5%; p<0.01). There were no significant differences in the allele frequencies of the R702W and G908R polymorphisms between CD patients, UC patients, and controls. We found that 15.5% of CD patients, 9.1% of UC patients, and 6.7% of controls carried at least one of the CARD15 variants. In CD patients carrying at least one of the three NOD2 variants, the ileum was affected more often than in non-carrier CD patients (90% v 73%; p<0.05), they had stricturing or penetrating disease more often than non-carriers (88% v 56%; p<0.01), and they had an increased need for bowel surgery.

The frequency of NOD2 gene variants was lower in genetically homogenous Finns than in other populations. The 1007fs variant was associated with CD. The occurrence of CARD15 variants predicted ileal location as well as stricturing and penetrating forms of CD.

Does miR-141 contribute to fetal growth restriction by regulating PLAG1 expression?

Fetal growth restriction (FGR) is an important but poorly understood condition of pregnancy, which results in significant fetal, neonatal and long-term morbidity and mortality. Novel research has suggested that altered miRNA expression in the plasma and placenta is associated with adverse pregnancy. We hypothesized that aberrant expression of microRNA-141 (miR-141) in the placenta is associated with FGR. Additionally, expression levels of predicted target genes of miR-141 were also analyzed in placental tissues of FGR and normal controls. Using quantitative real time PCR, we analyzed the expression level of miR-141 and its target genes in placentas of FGR pregnancies (n = 21) and normal controls (n = 34). Western blot was used to detect the protein expression level of the target genes of miR-141. MiR-141 showed significant up regulation in FGR and significant down regulation of its targets, i.e. E2F transcription factor 3 (E2F3) protein, pleiomorphic adenoma gene 1 (PLAG1) mRNA and protein. Moreover, a positive correlation was found between PLAG1 and insulin-like growth factor 2 (IGF2) expression levels (Spearman r = 0.56, p<0.0001). MiR-141 yields an AUC of 0.83 with 88.5% sensitivity and 71.7% specificity for separating FGR from normal controls. This study indicates that miR-141 may be diagnostically important in FGR.

Our results indicate that aberrant high expression level of miR-141 might play important roles in the pathogenesis of FGR by suppressing E2F3 and PLAG1. We propose that miR-141 may participate in a miR-141-PLAG1-IGF2 network relating to FGR development. These findings may provide new targets via miR-141 in diagnosis and therapy of FGR in the future.