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Do adverse events after pars plana vitrectomy among medicare beneficiaries?

To assess the complication rates of pars plana vitrectomy (PPV) among older Americans and to determine whether rates of adverse events and additional operations have changed during the past decade. Claims data were reviewed to identify all adults aged 68 years or older in the 5% Medicare sample who underwent their first PPV during 1994-1995, 1999-2000, and 2004-2005. One-year rates of severe complications (endophthalmitis, suprachoroidal hemorrhage, or retinal detachment), less severe complications, receipt of an additional operation, and blindness were calculated and compared among the 3 groups using Cox regression. Analyses were adjusted for prior adverse events (during the previous 3 years), demographic characteristics, and comorbid conditions. The 1994-1995, 1999-2000, and 2004-2005 cohorts had 3263, 5064, and 5263 patients, respectively. The 1-year severe complication rates did not differ among the 3 groups (range, 4.8%-5.5%). The hazard of a less severe complication or an additional operation was higher in the 2004-2005 cohort than in the earlier cohorts (P < .05 for all comparisons). The hazard of endophthalmitis was higher in black individuals (P = .07) and those of other races (P = .02) than in white patients.

During the past decade, rates of severe complications after PPV remained stable, but rates of less severe complications and subsequent operations increased. Future studies should explore the potential factors that explain these changes and the alarming elevated incidence of post-PPV endophthalmitis among nonwhite individuals.

Are elevated levels of neopterin associated with carotid plaques with complex morphology in patients with stable angina pectoris?

Neopterin is an activation marker for monocytes/macrophages, and circulating levels of neopterin are elevated in patients with coronary complex lesions in unstable angina pectoris. We investigated the possible association between neopterin and complex carotid plaques which may be associated with the risk of ischemic stroke in patients with stable angina pectoris (SAP). We measured plasma levels of neopterin in 102 patients with SAP and carotid ultrasound was performed for evaluation of the presence of carotid plaques and plaque surface characteristics categorized as complex or noncomplex. In addition, endarterectomy specimens of extracranial high-grade carotid stenosis with complex plaques from five patients with SAP were immunohistochemically examined with antibodies to smooth muscle cells, endothelial cells, platelets, macrophages, and T cells. Plasma neopterin levels were significantly higher in patients with complex carotid plaques than in those with noncomplex plaques (median [interquartile range]: 24.2 [19.2-39.3]nmol/L vs. 19.4 [11.9-25.1]nmol/L; P=0.01) or without any plaques (18.8 [14.9-23.6]nmol/L; P=0.001). On multivariate logistic analyses after adjustment for traditional atherosclerotic risk factors, multi-vessel coronary disease and high sensitivity C-reactive protein, neopterin levels were independently associated with the presence of complex carotid plaques (adjusted OR 2.21 per SD increase, 95%CI 1.13-4.33, P=0.02). Immunohistochemical staining revealed abundant neopterin-positive macrophages in carotid complex lesions.

These findings demonstrate that carotid plaques with complex morphology have increased circulating neopterin levels and immunohistochemical localization of neopterin in patients with SAP. Neopterin can be considered an important biomarker of plaque destabilization in carotid artery atherosclerotic lesions in this population.

Does [ Vector-mediated shRNA inhibit HIF-1alpha expression in prostate cancer cells ]?

To construct a short hairpin RNA (shRNA) vector of the hypoxia inducible factor-1alpha (HIF-1alpha), determine its inhibitory effect on the expression of the HIF-1alpha gene in PC-3M cells, and investigate its application prospects in the treatment of prostate cancer. We designed and synthesized the shRNA template sequence specific against HIF-lalpha, inserted it into the vector psilencer 2.1-U6 to generate the plasmid psilencer-HIF, transfected the recombinant plasmid into prostate cancer cell line PC-3M cells and detected the transfection efficiency by cotransfection with the pEGFP vector as well as the expression of HIF-1alpha by RT-PCR and Western blot. The DNA sequencing analysis showed a complete consistency of the recombinant plasmid psilencer-HIF with the design. Twenty-four hours after the transfection, the rate of transfected plasmid was about (89.26 +/- 4.72)% and the vector-mediated shRNA induced RNA interference (RNAi), while 48 hours transfection reduced the HIF-1alpha mRNA and protein levels by 82.09% and 81.61% respectively (P < 0.01) in PC-3M cells.

The shRNA vector was successfully constructed, which can effectively suppress the expression of HIF-1alpha in prostate cancer cells.

Is endoscopic retrograde cholangiopancreatography safe in patients 90 years of age and older?

This case-control study evaluated the safety and efficacy of endoscopic retrograde cholangiopancreatography (ERCP) in patients 90 years of age and older. From January 2005 to August 2011, 5,070 cases of ERCP were performed at our institution. Of these, 43 cases involved patients 90 years of age and older (mean age, 91.7±1.9 years). A control group of 129 cases (mean age, 65.7±14.8 years) was matched by the patient sex, sphincterotomy, and presence of choledocholithiasis using a propensity score. The patients' medical records were retrospectively reviewed for comorbidity, periampullary diverticulum, urgent procedure, conscious sedation, technical success, procedure duration, ERCP-related complication, and death. Between the case and control groups, there was no significant difference with regard to comorbidity, periampullary diverticulum, and urgent procedure. Conscious sedation was performed significantly less in the patient group versus the control group (28 [65%] vs 119 [92%], respectively; p=0.000). There was no significant difference in the technical success, procedure duration, or ERCP-related complications. In both groups, there was no major bleeding or perforation related to ERCP. Post-ERCP pancreatitis occurred significantly less in the patient group compared to the control group (0 vs 13 [10%], respectively; p=0.004). One death occurred from respiratory arrest in the case group.

ERCP can be performed safely and successfully in patients aged 90 years and older without any significant increase in complications.

Does newborn adiposity by body mass index predict childhood overweight?

To evaluate the association between adiposity at birth and in infancy with overweight at age 5 years. This study hypothesizes that adiposity at birth as approximated by body mass index (BMI) predicts childhood fatness. Anthropomorphic data from birth to 5 years were used to calculate BMI percentiles. Multiple logistic regression assessed the association between BMI percentile > or =85% at 2 weeks and BMI percentile > or =85% at 6, 12, 36, and 60 months. Elevated BMI at age 2 weeks > or =85th percentile was associated with significant increases in risk of overweight at 6, 12, 36, and 60 months of age. Infants with a BMI at age 2 weeks > or =85th percentile had an adjusted odds ratio of 3.42 (95% confidence interval [CI] = 1.79, 6.50) and an adjusted risk ratio of 2.12 (95% CI = 1.71, 2.61) of being overweight at 60 months of age.

Adiposity at birth as approximated by BMI is a significant predictor of overweight at 5 years.

Does new York Heart Association functional class influence the impact of diabetes on cardiac autonomic function?

Diabetes (D) and heart failure (HF) are associated with abnormal heart rate variability (HRV). It is unclear whether the HRV effect of having both is cumulative. Pretreatment HRV (traditional, nonlinear, and heart rate [HR] turbulence) in 80 D versus 74 non-D (ND) systolic HF patients was compared by New York Heart Association II versus III among patients entered into an HF drug evaluation study. Age-adjusted HR was lower in class II D versus class III and most HRV including HR turbulence was better in class II ND versus all others, with few differences between class II D and class III ND and D patients.

The effect of D and HF on autonomic function may be cumulative in class II, but D may have little additional effect on most HRV in class III patients. The prognostic value of different HRV measures in D versus ND HF patients should be further investigated.

Can digital selenium-based radiography in thoracic diagnosis replace the analog x-ray imaging technic?

To find out the diagnostic value of digital selenium radiography, we compared the image quality of chest x-ray images from 50 patients who had been examined via conventional chest x-ray and digital selenium radiography of the chest. 50 patients with a malignant melanoma underwent chest x-ray within 3 months in conventional technique and with digital selenium radiography (Thoravision: Philips Medical Systems, Hamburg, Germany). In this period none of the patients showed a difference in respect of clinical status or radiological diagnosis. Simultaneous examinations on the same day were not performed to avoid unnecessary exposure to x-rays. The digital and conventional images were compared by 4 radiologists with regard to image quality by the detection of defined anatomic structures. Image quality of digital selenium radiography was considered superior to that of conventional chest x-rays in the mediastinum, the retrocardiac and retrodiaphragmatic areas, the superior and inferior lobes of the lung especially near the parietal pleura, and the chest wall.

Compared to analogous techniques there is no loss of image information when employing digital selenium radiography in chest x-rays. On the contrary, new assessment criteria may be gained. We conclude that digital selenium radiography offers diagnostic advantages in chest x-ray examination.

Are long-term outcomes of cardiac resynchronization therapy worse in patients who require atrioventricular junction ablation for atrial fibrillation than in those with sinus rhythm?

The aim of the study was to assess the impact of atrial fibrillation (AF) with and without the need for atrioventricular junction (AVJ) ablation on outcomes in patients undergoing cardiac resynchronization therapy (CRT). A single center cohort of 200 consecutive CRT patients was divided into three groups: 1) AF with CRT pacing < 95% in which AVJ ablation was performed (AF-ABL, n = 40; 20%), 2) AF without the need for AVJ ablation (AF-non ABL, n = 40; 20%), 3) sinus rhythm (SR, n = 120; 60%). All patients were assessed before CRT implantation and at 6-month follow-up. Positive clinical response to CRT was considered alive status without the need for heart transplantation and improvement ≥ 1 NYHA after 6 months. The comparative analysis among all study groups with respect to response-rate and long-term survival was performed. The 6-month response-rate in both AF-ABL and AF-nonABL was significantly lower than in SR (52.5 and 50 vs.77.5%, respectively; both p < 0.017), though there were no differences in baseline characteristics among study groups apart from higher baseline NT-proBNP levels in AF-ABL. However, after adjustment for this confounder, and despite optimal CRT pacing burden in study groups, the remote all-cause mortality during median follow-up of 36.1 months was significantly higher in AF-ABL than in SR (adjusted HR = 2.57, 95% CI 1.09-6.02, p = 0.03). What is more, no difference in long-term survival between SR and AF-nonABL was observed.

Despite the improvement of CRT pacing burden and thus response-rate up to the level of AF subjects without the need for ablation, the long-term survival of AF patients requiring AVJ ablation remains still worse than in SR.

Is eRBB2 amplification superior to protein expression status in predicting patient outcome in serous ovarian carcinoma?

The objective of this study was to evaluate the frequency and clinical significance of ERBB2 gene amplification in serous ovarian carcinoma. In addition, concordance of the findings of ERBB2 immunohistochemistry and ERBB2 amplification was assessed. Tissue microarray constructed of 401 serous ovarian carcinomas was examined by chromogenic in situ hybridization (CISH) using probe for ERBB2 gene and by immunohistochemistry using CB11 monoclonal antibody against ERBB2 protein. Amplification (>5 copies per cell) of ERBB2 was detected in 7% and low copy number increase (three-five copies) in 14% of the carcinomas. Increased copy number of ERBB2 was associated with poor prognosis, that is, poor response to therapy (P = 0.024), shorter disease-free (P < 0.0001) and overall survival (P < 0.0001). ERBB2 copy number status was identified as an independent prognostic factor for overall survival. Increased copy number of ERBB2 was also associated with high tumor grade, greater patient age, large residual tumor size, high proliferation index, aberrant p53 and negative progesterone receptor status. A significant association was found between ERBB2 amplification and ERBB2 protein overexpression. However, a substantial number of cases showed discrepant results by the two methods, especially in cases with low-level amplification or moderate protein overexpression. Overexpression of ERBB2 protein was associated with poor overall survival, but the prognostic value was weaker than that of ERBB2 gene copy number status.

ERBB2 amplification positive tumors identified by CISH constitute a subgroup of serous ovarian carcinomas associated with aberrant p53, negative progesterone receptor status and aggressive behavior, a suitable group for testing the effect of trastuzumab in clinical trials.

Symptoms of depression in late luteal phase dysphoric disorder: a variant of mood disorder?

In premenstrual syndrome, depressed mood in the luteal phase of the menstrual cycle is acknowledged, whereas the presence of symptoms of depression during the follicular phase remains in debate. On the basis of prospective daily recording of the presence and severity of symptoms for at least two menstrual cycles, 43 women were diagnosed with Late Luteal Phase Dysphoric Disorder (LLPD) according to the criteria of the third edition revision of the Diagnostic and Statistical Manual of Mental Disorders. They were compared to a group of 85 women who showed no evidence of LLPD for two menstrual cycles. Structured psychiatric interviews were administered during the follicular phase. Only those subjects without Axis I disorders were subsequently included in the study. Those women with minor/moderate symptoms of depression had an odds of suffering from LLPD of 1.9 (95% CI=1.5-2.4, p<0.001) in relation to increasing severity of symptoms of depression at the total MADRS scale (1-point increase). The ORs of LLPD in relation to each dimension (1-point increase) of the emotional/affective, cognitive, and neurovegetative symptoms were 1.6 (95% CI=1.2-2.3, p=0.003), 2.8 (95% CI=0.9-8.5, p=0.077) and 3.3 (95% CI=1.9-5.9, p<0.001), respectively. No hormonal changes that may be associated with symptoms of LLPD were determined in this study.

LLPD is likely to represent a variant of a depressive disorder, where premenstrual psychobiological changes seem to exacerbate mild depressive symptoms and signs to which LLPD women are otherwise predisposed. This hypothesis opens new perspectives for prevention and of even treatment for LLPD. Further longitudinal studies with larger populations and evaluation of hormonal changes are needed to confirm these data.

Does non-mitogenic human acidic fibroblast growth factor reduce retinal degeneration induced by sodium iodate?

To investigate the protective effects of non-mitogenic human acidic fibroblast growth factor on retinal degeneration induced by NaIO(3) in rats. Retinal degeneration was induced in adult male Wistar rats via caudal-vein injection of 1% NaIO(3) at 50 mg/kg. One h after NaIO(3) treatment, the right eyes received intravitreal injection of 2.5 microg nm-haFGF in 10 microL saline and the left eyes received saline alone as vehicle-treated eyes. Retinal function in rats was evaluated by electroretinogram (ERG) before injection and 1, 7, and 21 days postinjection. Additional rat eyes were enucleated 7 and 21 days postinjection, fixed, and processed for histological examination. A model of retinal degeneration in rat was established successfully using NaIO(3) injection. Significant decreases in both ERG a- and b-wave amplitudes were detected in NaIO(3)-injected rats when compared with the normal animals (P < 0.05) on day 7 postinjection. Importantly, at the seventh day after intravitreal nm-haFGF treatment on NaIO(3)-injected rats, the nm-haFGF-treated eyes showed a significant improvement in the ERG amplitudes of both a- and b-waves when compared with vehicle-treated eyes (P < 0.05). In addition, the disruptions of photoreceptor outer segments and the retinal pigment epithelium monolayer were much less frequently observed in the nm-haFGF-treated eyes than the vehicle-treated eyes, and the outer nuclear layer thickness in the nm-haFGF-treated eyes was similar to that of the normal eyes.

Intravitreal delivery of nm-haFGF appears to have neuroprotective effect on retinal degeneration induced by NaIO(3).

Is perioperative change in creatinine following cardiac surgery with cardiopulmonary bypass useful in predicting acute kidney injury : a single-centre retrospective cohort study?

Acute kidney injury is common following cardiac surgery. Experimental models of acute kidney injury suggest that successful therapy should be implemented within 24-48 h of renal injury. However, it is difficult to detect acute kidney injury shortly after cardiac surgery, because creatinine concentration is diluted by cardiopulmonary bypass. We hypothesized that, following cardiopulmonary bypass, creatinine reduction ratios would correlate with haematocrit reduction ratios and would be associated with the incidence of acute kidney injury. We collected demographic and blood test data from consecutive patients (n = 1137) who had undergone cardiac surgery with cardiopulmonary bypass. The creatinine reduction ratio was calculated as follows: (preoperative creatinine-postoperative creatinine)/preoperative creatinine. Patients were assigned to either of two groups. The first group (Group 1) was used to determine the threshold for acute kidney injury, and the second group (Group 2) was used to assess diagnostic performance. Acute kidney injury was defined as an increase in serum creatinine level >0.3 mg/dl or >150% from baseline. The incidence of acute kidney injury was 14.5% (79/545) in Group 1 and 15.5% (92/592) in Group 2. Postoperatively, creatinine concentration correlated strongly with haematocrit concentration (Pearson's r(2): 0.91). In Group 1, the area under the receiver operating characteristic curve, sensitivity and specificity were 0.71, 64.1 and 66.4%, respectively, for creatinine reduction ratios of <20%. In Group 2, the odds ratio, positive predictive value, negative predictive value and relative risk for creatinine reduction ratio performance were 4.3 (95% confidence interval 2.6-7.0), 0.27 (0.21-0.32), 0.92 (0.89-0.95) and 3.42 (2.22-5.27), respectively.

The creatinine reduction ratio may be associated with perioperative renal injury. Therefore, it is a good diagnostic indicator with high performance, and may be useful in detecting acute kidney injury at an earlier stage relative to conventional means. In addition, using creatinine reduction ratios in this manner is financially feasible.

Does matrix metalloproteinase activity predict severity of acute pancreatitis?

Matrix metalloproteinases (MMP) modulate end-organ complications of acute pancreatitis, but the correlation between increased MMP production and histological severity of disease remains unclear. We examined the role of MMP and pancreas histology on experimental acute pancreatitis. Forty male Wistar albino rats were subjected to cerulein-induced pancreatitis (8, 16, 24 and 32 h groups) or sham treatment. The animals were killed at different time points and pancreatic tissues were harvested to assess MMP (1, 2 and 9) activity and inflammatory changes. Compared with other groups, 8 h group had decreased tissue MMP-1 concentrations. MMP-9 concentrations were lower in 24-h and 32-h groups, as were histological severity scores. MMP-2 activity did not differ among groups. Pancreatitis was prominent in 8-h, 16-h and 24-h groups by means of histology.

Induction of pancreatitis by cerulein altered pancreatic MMP levels in the early phase of inflammation. Inhibition of MMP-2 and MMP-9 paralleled histological scores. Therefore, MMP may have a predictive value to assess histological severity.

Does microRNA-125b regulate the expression of aggrecanase-1 ( ADAMTS-4 ) in human osteoarthritic chondrocytes?

Increased expression of aggrecanase-1 (ADAMTS-4) has emerged as an important factor in osteoarthritis (OA) and other joint diseases. This study aimed to determine whether the expression of ADAMTS-4 in human chondrocytes is regulated by miRNA. MiRNA targets were identified using bioinformatics. Chondrocytes were isolated from knee cartilage and treated with interleukin-1 beta (IL-1β). Gene expression was quantified using TaqMan assays and protein production was determined by immunoblotting. Luciferase reporter assay was used to verify interaction between miRNA and target messenger RNA (mRNA). In silico analysis predicted putative target sequence of miR-125b on ADAMTS-4. MiR-125b was expressed in both normal and OA chondrocytes, with significantly lower expression in OA chondrocytes than in normal chondrocytes. Furthermore, IL-1β-induced upregulation of ADAMTS-4 was suppressed by overexpression of miR-125b in human OA chondrocytes. In the luciferase reporter assay, mutation of the putative miR-125b binding site in the ADAMTS-4 3'UTR abrogated the suppressive effect of miR125.

Our results indicate that miR-125b plays an important role in regulating the expression of ADAMTS-4 in human chondrocytes and this identifies miR-125b as a novel therapeutic target in OA.

Does [ Urinary iodine excretion in German adults in 2005 meet WHO target ]?

Recent regional and Germany-wide investigations have shown that the abolition of the requirement to declare iodine in foodstuffs and the greater emphasis on information about goitre prevention led to an increase in urinary iodine excretion in German schoolchildren. There was also a decrease in thyroid size and goitre prevalence in children. No up-to-date results in adults for the whole of Germany are available. In 2005, the authors examined the urinary iodine excretion in the spontaneous morning urine of 1,538 healthy adults in 357 places from all over Germany. The iodine was measured by the cer-arsenite method. The median iodine excretion amounted to 132 microg/l. There were no significant differences between age groups, sexes or regions. 64% had no iodine deficiency (> or = 100 microg/l). In 23% the deficiency was slight (50-99 microg/l), in 10% moderate (20-49 microg/l), and in 3% there was severe iodine deficiency (< 20 microg/l). 29% excreted > 200 microg iodide/l urine.

According to the WHO (World Health Organization) guidelines, there is no longer an iodine deficiency in German adults.

Are levels of asymmetrical dimethylarginine predictive of brachial artery flow-mediated dilation 6 years later . The Cardiovascular Risk in Young Finns Study?

Plasma asymmetric dimethylarginine (ADMA) is a novel risk factor for atherosclerosis and has been observed to associate with endothelial function in cross-section studies. In the present study our aim was to investigate whether plasma ADMA levels are predictive of brachial artery endothelial function in a prospective setting. Using ultrasound we measured brachial artery flow-mediated dilation (FMD) both in 2001 and 2007 in 1808 healthy subjects aged 24-39 years at baseline. Plasma methylarginines were determined by isocratic high-pressure liquid chromatography in 2001. In a multivariable model adjusted with brachial diameter and conventional cardiovascular risk factors, baseline ADMA levels had a significant inverse association with FMD measured 6 years later (β±SE: -1.89±0.69%, P=0.006).

We conclude that plasma ADMA can predict brachial artery FMD in subjects without prevalent atherosclerotic disease. These data suggest that plasma ADMA may have a determinative role in predicting endothelial function.

Do antibiotic supplements affect electrophysiological properties and excitability of rat hippocampal pyramidal neurons in primary culture?

Antibiotic supplements are regularly used in neuronal culture media to control contamination; however, they can interfere with the neuronal excitability and affect electrophysiological properties. Therefore, in this study, the effect of penicillin/streptomycin supplements on the spontaneous electrophysiological activity of hippocampal pyramidal neurons was examined. Electrophysiological whole-cell patch-clamp recordings from rat hippocampal pyramidal cells in primary culture were performed to investigate the effects of antibiotic supplements on the intrinsic excitability of cultured cells. The present findings indicated that presence of antibiotic supplements (penicillin/streptomycin) in the culture medium altered the intrinsic electrical activity of hippocampal pyramidal neurons in primary culture. These alterations included: 1) depolarized resting membrane potential; 2) a significant enhancement in the after-hyperpolarization amplitude; 3) a significant increase in the area under the action potential and in the decay and rise time of the action potential; 4) a significant broadening of action potential and 5) a significant reduction in the firing frequency.

These findings suggest that addition of antibiotic supplements to culture media influences the neuronal excitability and alters the electrophysiological properties of cultured neurons, possibly through changing the ionic conductance underlying neuronal excitability.

Does volume reduction rate by surgical ventricular restoration determine late outcome in ischaemic cardiomyopathy?

Surgical ventricular restoration (SVR) effectively reduces left ventricular (LV) volume in ischaemic cardiomyopathy (ICM), but the recent Surgical Treatment of Ischemic Heart Failure (STICH) Trial questions its importance. We report 8-year SVR experience in patients with ICM. Between 2000 and 2008, 135 patients underwent SVR for ICM. This report analyses data from 90 patients who underwent accurate pre- and post-operative assessment of LV volumes by left ventriculogram or scintigram. All patients also had echocardiograms. Pre-operative LV end-systolic volume index (ESVI) was 123.5 ± 53.2 mL/m(2) (range 92-310). Overall, 63 patients were in NHYA class III and 27 were in class IV. The SVR procedure was endoventricular circular patch plasty in 33 patients, septal-anterior ventricular exclusion in 43, and 14 patients had posterior exclusion. Coronary artery bypass grafting was performed in 78 patients (87%) and 50 underwent mitral procedures. Eighteen follow-up late deaths occurred owing to chronic heart failure (n = 12) and sudden death (n = 6). Post-operative ESVI was < 90 mL/m(2) (Group-S) in 54 patients, 90-120 mL/m(2) (Group-M) in 16, and >120 mL/m(2) (Group-L) in 20 patients. The 8-year survival rate was 82.4% in group-S following a > 33% LV volume reduction. In contrast, in Group-M and Group-L, the volume reduction was ∼ 15%, and 100% of patients died within 7 years following the SVR procedure (or 0% 8-year survival).

SVR is most effective when a >33% volume reduction rate achieves an ESVI of < 90 mL/m(2). No long-term benefits occur when SVR induces an LV volume reduction of < 15% leaving a residual ESVI >90 mL/m(2). This database contradicts the STICH trial findings.

Does pelvic floor muscle training abolish symptoms of urinary incontinence?

To determine whether symptoms of urinary incontinence is reduced by pelvic floor muscle training, to determine whether urinary incontinence can be totally eliminated by strengthening the pelvic floor muscle to grade 5 on the Oxford scale. Prospective randomized controlled clinical trial. Outpatient urogynecology department. One hundred thirty cases with stress and mixed urinary incontinence. All participants were randomly allocated to the pelvic floor muscle training group or control group. A 12-week home based exercise program, prescribed individually, was performed by the pelvic floor muscle training group. Urinary incontinence symptoms (Incontinence Impact Questionnaire-7, Urogenital Distress Inventory-6, bladder diary, stop test and pad test) were assessed, and the pelvic floor muscle strength was measured for (PERFECT testing, perineometric and ultrasound) all participants before and after 12 weeks of treatment. The pelvic floor muscle training group had significant improvement in their symptoms of urinary incontinence (P=0.001) and an increase in pelvic floor muscle strength (P=0.001, by the dependent t test) compared with the control group. All the symptoms of urinary incontinence were significantly decreased in the patients that had reached pelvic floor muscle strength of grade 5 and continued the pelvic floor muscle training (P<0.05).

The study demonstrated that pelvic floor muscle training is effective in reducing the symptoms of stress and mixed urinary incontinence and in increasing pelvic floor muscle strength.

Do a technology-based programme to help a post-coma man with profound multiple disabilities manage stimulation access and posture improvement?

To evaluate a technology-based programme to help a post-coma man with multiple disabilities access stimulation and control head posture (i.e. reduce head forward tilting). The response targeted within the programme was closing the sweater's zipper. This response (which could be repeated since the zipper tended to reopen automatically) was selected, as it led the man to raise his head spontaneously. The programme relied on microswitch sensors to monitor the response and turn on preferred stimuli following response occurrences. The programme was assessed via an ABAB design. Data showed that the man had significant increases in response frequencies during the intervention phases of the study with multiple occasions of stimulation access and head raising.

Technology-assisted programmes may represent a useful strategy for providing post-coma persons with multiple disabilities an active (self-control) role.

Does vascular Smooth Muscle Cell Senescence promote Atherosclerosis and Features of Plaque Vulnerability?

Although vascular smooth muscle cell (VSMC) proliferation is implicated in atherogenesis, VSMCs in advanced plaques and cultured from plaques show evidence of VSMC senescence and DNA damage. In particular, plaque VSMCs show shortening of telomeres, which can directly induce senescence. Senescence can have multiple effects on plaque development and morphology; however, the consequences of VSMC senescence or the mechanisms underlying VSMC senescence in atherosclerosis are mostly unknown. We examined the expression of proteins that protect telomeres in VSMCs derived from human plaques and normal vessels. Plaque VSMCs showed reduced expression and telomere binding of telomeric repeat-binding factor-2 (TRF2), associated with increased DNA damage. TRF2 expression was regulated by p53-dependent degradation of the TRF2 protein. To examine the functional consequences of loss of TRF2, we expressed TRF2 or a TRF2 functional mutant (T188A) as either gain- or loss-of-function studies in vitro and in apolipoprotein E(-/-) mice. TRF2 overexpression bypassed senescence, reduced DNA damage, and accelerated DNA repair, whereas TRF2(188A) showed opposite effects. Transgenic mice expressing VSMC-specific TRF2(T188A) showed increased atherosclerosis and necrotic core formation in vivo, whereas VSMC-specific TRF2 increased the relative fibrous cap and decreased necrotic core areas. TRF2 protected against atherosclerosis independent of secretion of senescence-associated cytokines.

We conclude that plaque VSMC senescence in atherosclerosis is associated with loss of TRF2. VSMC senes cence promotes both atherosclerosis and features of plaque vulnerability, identifying prevention of senescence as a potential target for intervention.

Does an acute injection of Porphyromonas gingivalis lipopolysaccharide modulate the OPG/RANKL system and interleukin-6 in an ovariectomized mouse model?

In the present study, we attempted to develop a simulated model to explore the causal effects of periodontal pathogens on skeletal homeostasis in postmenopausal osteoporosis. Fifty-three female adult ICR mice were randomly assigned to an experimental group (ovariectomized) or a control group. A single injection of Porphyromonas gingivalis lipopolysaccharide (P. gingivalis-LPS, ATCC 33277) or Escherichia coli lipopolysaccharide (E. coli-LPS) was administered intraperitoneally 4 weeks after an ovariectomy. Concentrations of interleukin-6 (IL-6), osteoprotegerin (OPG), and the receptor activator of nuclear factor-kappaB ligand (RANKL) in serum were subsequently analyzed using an enzyme-linked immunosorbent assay (ELISA). Under stimulation with P. gingivalis-LPS or E. coli-LPS, the concentration of OPG rose in both groups. The serum level of RANKL showed a decreasing trend 24 h after the injection in both groups. After injection of P. gingivalis-LPS in both the experimental and control animals, the OPG : RANKL ratio increased 24 h after the booster (22.26-620.99, P < 0.05). The serum level of IL-6 in the experimental group significantly increased 1-6 h after administration of E. coli-LPS and 1-3 h after administration of P. gingivalis-LPS (P < 0.05).

A single booster injection of P. gingivalis-LPS induced short-term changes in OPG, RANKL, and IL-6 serum levels in this ovariectomized mouse model.

Does electrical stimulation of deep peroneal nerve mimicking acupuncture inhibit the pressor response via capsaicin-insensitive afferents in anesthetized rats?

To assess the inhibitory modulation of blood pressure by stimulation of the deep peroneal nerve (DPN) and to determine the involvement of nociceptive fibers in the modulation. All the animals were divided into six groups (A-F). The rats in groups A and B received no pretreatment. The rats in groups C and D received subcutaneous injection of capsaicin or control vehicle, respectively, near the DPN for 2 days. Those in groups E and F had the DPN exposed to capsaicin or control vehicle, respectively, for 20 min. Subsequently, pressor responses were induced by stimulation of paraventricular nucleus (PVN) either electrically (groups A and C C-F) or chemically via injection of glutamate (group B). After two stable pressor responses (baseline), all groups were subject to 5-min DPN stimulation followed by PVN stimulation for 10 s. Arterial blood pressure, heart rate, and electrocardiogram were recorded. The pressor response was calculated as the difference in the mean arterial pressure (MAP) before and after PVN stimulation, and changes from baseline in pressor response after DPN stimulation were compared between the groups. Increases of MAP of 22.88±2.18 mm Hg and 20.32±5.25 mm Hg were induced by electrical (group A) or chemical (group B) stimulation of the PVN, respectively. These pressor responses were inhibited by stimulation of the DPN, and the MAP was reduced to 12.00±2.10 mm Hg in group A (n=6, P<0.01) and 7.00±2.85 mm Hg in group B (n=6, P<0.01). Subcutaneous injection of capsaicin (125 mg/kg) near the DPN in group C (n=7) had no effect on the inhibitory effect of DPN stimulation compared with the group D (n=9), and neither did blockade of nociceptive fibers with capsaicin in group E (n=6) compared with group F (n=8).

Stimulation of the DPN mimicking acupuncture has an inhibitory effect on the pressor response, and the effect is mediated by capsaicin-insensitive afferent fibers in the DPN.

Does cEVL e-learning teach GUMS method to `` score '' hypospadias preoperatively and predict postoperative outcomes?

Pediatric urological surgeons recognize the importance of formalizing the assessment of outcomes after hypospadias repair. To this end, surgical outcomes may be predicted by correlation with a summative score of objective assessments (Likert 1-4) of each: glans size, urethra plate appearance, meatus position, and extent of shaft chordee (GUMS). The best surgical outcome will be found in cases with the lowest score (GUMS = 4) and the worst surgical outcome in cases with the highest score (GUMS = 16). We aimed to determine if e-learning is suitable for training of the GUMS method. We did this by re-formatting the GUMS method of assessment of the hypospadias penis into an e-learning platform. Re-formatting was done using the CEVL (Computer Enhanced Visual Learning) context. A total of 49 cases provided content for the following content groups: learn basics (4 cases), scoring samples (16 cases), learn by examples (4 cases), practice scoring (15 cases), and self-test (10 cases). The content was formatted, edited (Adobe), and imported for interactive use (Articulate Storyline). Various frequently asked questions on how to score are also presented. The survey respondents were pediatric urology attendings or fellows (60%) or urology residents (40%). E-learning GUMS scoring was done under 40 min before completion of the survey. Over 80% of respondents agreed/strongly agreed with the utility of the CEVL platform for learning the method. Respondents assigned GUMS scores to the survey cases and, on average, agreed on exactly the same scores for each component 63% of the time. The respondents chose the consensus score, or the next most common consensus score, 90% of the time.

We show that CEVL e-learning is an effective tool, which requires a minimal time investment, for teaching GUMS scoring. We believe that e-learning is a good platform to promote uniform clinical practices in outcomes research and for resident training.

Does acetylbritannilactone induce G1 arrest and apoptosis in vascular smooth muscle cells?

The present study was designed to determine the effects of Acetylbritannilactone (ABL), a naturally occurring Inula britannica L., on vascular smooth muscle cell (VSMC) proliferation and apoptosis. In vitro experiments were performed to evaluate the effects of ABL on the VSMC cycle and apoptosis stimulated by chemoattractant. In addition, to examine the effects of ABL in vivo, balloon injury to rat carotid arteries was performed. ABL treatment inhibited platelet-derived growth factor (PDGF) induced DNA synthesis and proliferation in cultured VSMC. Such growth-inhibitory effects of ABL were associated with G1 phase arrest, which were correlated with reduction of cyclins D1, A, and E expression and cyclin-dependent kinase (CDK) 2, CDK4, and CDK6 proteins, increased the CDK inhibitory protein p21cip1 expression, and enhanced the binding of p21cip1 to CDKs. In addition, ABL also induced apoptosis in proliferative VSMCs, as evidenced by the induction of a higher ratio of Bax/Bcl-2, activation of caspase-9, caspase-3, and the cleavage of endogenous substrate Poly (ADP-ribose) polymerase. However, pretreatment with pan-caspases inhibitor (z-VAD-fmk) only partially reversed ABL-induced apoptosis, suggesting the involvement of both caspase-dependent and caspase-independent pathways in these processes. Furthermore, the effects of ABL on VSMCs were associated with the downregulation of extracellular signal-regulated kinase (ERK) 1/2 signaling pathways. In vivo, ABL (26 mg/kg/day) significantly suppressed injury-induced ERK1/2 phosphorylation, and increased VSMC apoptosis 14 days after balloon injury.

Our findings demonstrated that ABL was capable of suppressing the abnormal VSMC proliferation, accompanied by the induction of apoptosis in vivo and in vitro. It suggested that ABL could be considered a pharmacological candidate for the prevention of restenosis after balloon angioplasty.

Does mortality risk after head injury increase at 30 years?

Age has long been recognized as a critical factor in predicting outcomes after head injury, with individuals older than 60 years predicted to have a worse outcome than those younger than 60. The object of this study was to determine the effect of age by decade of life beginning at birth in patients with head injuries of all levels of severity. The New York State Trauma Registry was searched for head injuries from January 1, 1994 to December 31, 1995; the 13,908 cases found were placed into age groups by decade. Data were sought for each patient on demographics, Glasgow Coma Score, ICD-9 injury code, New Injury Severity Score (NISS), and mechanism of injury. These data were analyzed with chi-square and one-way ANOVA tests, with significance set at p < 0.05. The risk of dying was significantly increased in patients beginning at 30 years of age compared with those in the younger age groups, with the greatest increases occurring after age 60 (p < 0.001). For the population with available Glasgow Coma Score data (n = 12,844), the mortality rate for patients ages 0 to 30 was 10.9%, and for patients ages 31 to 50 was 12.4%. The mean Glasgow Coma Score for nonsurvivors ages 0 to 20 (3.9) and for nonsurvivors ages 31 to 50 (5.1) were significantly different, with a risk ratio of 1.3 (p < 0.001).

The risk of dying for patients suffering head injuries increases as early as 30 years of age, making it necessary for health-care providers to consider increased monitoring and treatment for patients in this younger age group.

Does tracheal occlusion in fetal rats alter expression of mesenchymal nuclear transcription factors without affecting surfactant protein expression?

Mesenchymal nuclear transcription factors (MNTF) are involved in lung development and maturation and regulate surfactant protein (SP) expression. Prolonged (>2 weeks) fetal tracheal occlusion (TO) has been shown to accelerate lung growth and inhibit pulmonary surfactant synthesis. The effects of TO on SP expression and MNTF, however, have not been formally assessed. The objectives of this study were to evaluate the effects of short-term (3 days) TO on normal lung growth and protein expression of pulmonary MNTF involved in SP synthesis. At E19 (term, 22 days), 2 fetuses per time-dated Sprague-Dawley rats underwent either TO (n = 23) or a sham (n = 22) operation. Lungs were harvested 72 hours post surgery. Pulmonary SP-A; SP-B; SP-C messenger RNA (mRNA) expression; and SP-A and SP-B, Hoxb5, thyroid transcription factor 1, and retinoic X receptor-alpha protein expression were analyzed. Lung weight was significantly increased by TO (TO 0.32 +/- 0.02g vs SHAM 0.14 +/- 0.01 g; P < .001), resulting in 123% increase of the lung-to-body-weight ratio. No difference of SP-A-mRNA (177 +/- 4.3 TO vs 169 +/- 4.4 SHAM; P = .25), SP-B-mRNA (87.7 +/- 0.2 TO vs 87.4 +/- 0.02 SHAM; P = .33), and SP-C-mRNA (186.5 +/- 3.2 TO vs 183.2 +/- 2.7 SHAM; P = .45) expression was found. Surfactant protein A (175.6 +/- 25.3 TO vs 192.5 +/- 19.8 SHAM; P = .59) and SP-B (163.4 +/- 5.2 TO vs 166.8 +/- 9.3 SHAM; P = .75) protein expression were similar in both groups; however, Hoxb5 (70.3 +/- 18.9 TO vs 130.6 +/- 5.1 SHAM; P = .02) and thyroid transcription factor 1 (102.6 +/- 19 TO vs 181.1 +/- 6.3 SHAM; P = .007) expression were significantly decreased. Retinoic X receptor-alpha expression tended to be increased by TO (171.9 +/- 6.0 TO vs 155.4 +/- 6.7 SHAM; P = .06).

Short-term TO late in gestation induces rapid lung growth. Surfactant protein-mRNA and protein expression are not significantly altered. Thyroid transcription factor 1 and Hoxb5 are down-regulated by TO, suggesting that duration and timing of occlusion are important in balancing the effects of TO on lung growth vs lung maturation.

Does carotid artery stenting have increased risk of external carotid artery occlusion compared with carotid endarterectomy?

The external carotid artery (ECA) can be an important source of cerebral blood flow in cases of high-grade internal carotid artery stenosis or occlusion. However, the treatment of the ECA is fundamentally different between carotid endarterectomy (CEA) and carotid artery stenting (CAS). CEA is routinely associated with endarterectomy of the ECA, whereas CAS excludes the ECA from direct flow. We hypothesize that these differences make ECA occlusion more common after CAS. Further, the impact of CAS on blood flow into the ECA is interesting because the flow from the stent into the ECA is altered in a way that may promote local inflammation and may influence in-stent restenosis (ISR). Thus, our objective was to use our institutional database to identify whether CAS increased the rate of ECA occlusion and, if it did, whether ECA occlusion was associated with ISR. Patients undergoing CAS or CEA from February 2007 to February 2012 were identified from our institutional carotid therapy database. Preoperative and postoperative images of patients who followed up in our institution were included in the analysis of ECA occlusion and rates of ISR. There were 210 (67%) CAS patients and 207 (60%) CEA patients included in this analysis. Despite CAS patients being younger (68 vs 70 years), having shorter follow-up (12.5 vs 56.2 months), and being more likely to take clopidogrel (97% vs 35%), they had an increased rate of ECA occlusion (3.8%) compared with CEA patients (0.4%). CAS patients who went on to ECA occlusion had an increased incidence of prior neck irradiation (50% vs 15%; P = .03), but we did not identify an association of ECA occlusion with ISR >50%.

Whereas prior publications have identified increased rates of external carotid stenosis, this is the first demonstration of increased ECA occlusion after CAS. However, ECA occlusion is uncommon (∼4%) and did not have an association with ISR >50%. Future work modeling ECA flow patterns before and after CAS will be used to further test this interaction.

Does spontaneous respiratory modulation improve cardiovascular control in essential hypertension?

Recent studies show that controlled breathing improves baroreflex and heart rate variability and lowers blood pressure in hypertensive patients. To evaluate the effects of slow breathing training on cardiorespiratory system modulation of patients (n=10, men and women, ages ranging from 45 to 60) with essential hypertension seen in an outpatient setting. According to the study design, each patient was used as his/her own control, and data were collected before and after the intervention. The following parameters were assessed: heart rate variability (HRV), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), respirometry, chest expansion measurement, and statistical data analysis. Respiratory training was performed in 30-minute sessions held twice a week over one month using slow breathing exercises. Our results were as follows: a reduction in SBP, DPB, and MAP (p < 0.05 vs control); an increase in heart rate variability, as evidenced by greater RR interval variation and SDNN index; a decline in respiratory rate (p < 0.01 vs control); and an increase in tidal volume (p < 0.01 vs control) and thoracic expansibility (p < 0.01 vs control).

Respiratory retraining using the slow breathing technique appears to be a useful adjunctive for cardiorespiratory control in hypertensive patients.

Is a fecal occult blood test a useful tool for judging whether to perform capsule endoscopy in low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy?

Aspirin use is reportedly not to be associated with fecal immunochemical occult blood test (FIT) false-positive results for the detection of colorectal cancer. The need for additional small bowel exploration in FIT-positive, low-dose aspirin users with a negative colonoscopy is controversial. The aim of this study was to assess the ability of FIT to judge whether capsule endoscopy (CE) should be performed in low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy findings by comparing FIT results with CE findings. A total of 264 consecutive low-dose aspirin users with negative colonoscopy and esophagogastroduodenoscopy who were scheduled to undergo CE at five hospitals in Japan were enrolled. Patients had been offered FIT prior to the CE. The association between the FIT results and the CE findings was then assessed. One hundred and fifty-seven patients were included in the final analysis. Eighty-four patients (53.5 %) had positive FIT results. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of positive FIT results for small bowel ulcers were 0.56, 0.47, 0.30, and 0.73, respectively. Furthermore, the NPV of positive FIT results for severe small bowel injury (Lewis score ≥790) was markedly high (0.90). When the analysis was performed only in low-dose aspirin users with anemia, the sensitivity of the positive FIT results was notably improved (0.72).

Small bowel evaluation using CE is not recommended for FIT-negative, low-dose aspirin users. However, small bowel evaluation using CE should be considered in both FIT-positive and anemic low-dose aspirin users.

Do natriuretic peptides enhance the production of adiponectin in human adipocytes and in patients with chronic heart failure?

We investigated the functional relationship between natriuretic peptides and adiponectin by performing both experimental and clinical studies. Natriuretic peptides are promising candidates for the treatment of congestive heart failure (CHF) because of their wide range of beneficial effects on the cardiovascular system. Adiponectin is a cytokine derived from adipose tissue with various cardiovascular-protective effects that has been reported to show a positive association with plasma brain natriuretic peptide (BNP) levels in patients with heart failure. The expression of adiponectin messenger ribonucleic acid (mRNA) and its secretion were examined after atrial natriuretic peptide (ANP) or BNP was added to primary cultures of human adipocytes in the presence or absence of HS142-1 (a functional type A guanylyl cyclase receptor antagonist). Changes of the plasma adiponectin level were determined in 30 patients with CHF who were randomized to receive intravenous ANP (0.025 microg/kg/min human ANP for 3 days, n = 15) or saline (n = 15). Both ANP and BNP dose-dependently enhanced the expression of adiponectin mRNA and its secretion, whereas such enhancement was inhibited by pre-treatment with HS142-1. The plasma adiponectin level was increased at 4 days after administration of human ANP compared with the baseline value (from 6.56 +/- 0.40 microg/ml to 7.34 +/- 0.47 microg/ml, p < 0.05), whereas there was no change of adiponectin in the saline group (from 6.53 +/- 0.57 microg/ml to 6.55 +/- 0.56 microg/ml).

Natriuretic peptides enhance adiponectin production by human adipocytes in vitro and even in patients with CHF, which might have a beneficial effect on cardiomyocytes in patients receiving recombinant natriuretic peptide therapy for heart failure.

Do ageing and irradiance enhance vitamin E content in green edible tissues from crop plants?

Tocopherol (vitamin E) is an antioxidant essential in human nutrition. Several approaches have aimed to enhance tocopherol content in crops by the genetic modification of plants, a practice that generates some social concern. As tocopherol accumulates with leaf age in some wild plants and the antioxidant mechanisms respond with flexibility to stress conditions, it is hypothesised that tocopherol content can be increased in edible plants by the manipulation of harvesting time and growth conditions, in particular irradiance. Ontogenic changes in tocopherol concentration have been studied in photosynthetic tissues of edible leaves (lettuce, spinach, corn salad and dandelion) and green fruits (cucumber and pepper). In all species, tocopherol content increased with tissue age. Spinach showed the fastest rate of tocopherol accumulation, and growth at higher irradiance had a synergistic effect on the rate of accumulation. The same irradiance dependence of this accumulation was observed in fruits, but a final decrease with senescence occurred in cucumber.

This study demonstrates that the content of tocopherol in vegetables can be notably enhanced (or reduced) by simply selecting the appropriate harvesting time and/or by manipulating the environmental conditions during the growth period.

Does pancreatic stone protein predict postoperative infection in cardiac surgery patients irrespective of cardiopulmonary bypass or surgical technique?

We investigated the role of pancreatic stone protein (PSP) in predicting the occurrence of infection in the postoperative course of cardiac surgery patients. Several biomarkers indicating the presence of inflammation and infection are available in the clinical routine; yet, their utility in the postoperative course of patients following cardiac surgery remains uncertain. Moreover, cardiopulmonary bypass, also referred to as "on-pump surgery", increases the susceptibility to an exaggerated inflammatory state. However, the impact of such extracorporeal circulation on circulating PSP levels remains poorly understood. In a prospective cohort of unselected patients undergoing cardiac surgery, we set out to elucidate the diagnostic accuracy of serum PSP levels as opposed to canonical biomarkers (CRP, WBC) of inflammation to discriminate between the presence of infection and surgical trauma,. In addition, we investigated whether the biomarkers were influenced by the surgical technique employed, i.e. on-pump vs. off-pump and minimally invasive surgery vs. sternotomy. Levels of circulating PSP and routine inflammatory biomarkers (CRP, WBC) were measured in samples taken from 120 patients at baseline as well as at postoperative day 1-3. Univariate analysis showed that among the biomarkers investigated, only PSP levels had discriminatory power to differentiate infection from surgical trauma in the postoperative course of the entire cohort of patients following cardiac surgery. With regard to cardiac surgical interventions, there was no significant association between the absence or presence of extracorporeal circulation and PSP levels. However, there was a significant difference in the slope of the rise of postoperative PSP between minimally invasive surgery as opposed to patients subjected to sternotomy.

In an unselected population of cardiac surgery patients, post-operative serum PSP levels were significantly associated with the presence of infection in both the on-pump and off-pump setting. Of note, the surgical technique employed (sternotomy vs. minimally invasive approach) had a significant impact on postoperative PSP levels.

Do menthol cigarettes contribute to the appeal and addiction potential of smoking for youth?

Menthol cigarettes are a common choice of cigarettes among young smokers that contribute to the addictive potential of cigarette smoking. We reviewed prior research and analyzed the 2006 National Youth Tobacco Survey (NYTS), using logistic regression to assess the relationship between menthol cigarette use and needing a cigarette within 1 hr after smoking. In the 2006 NYTS, 51.7% (95% CI: 45.8-57.5) of middle school smokers and 43.1% (95% C.I.: 37.0, 49.1) of high school smokers reported that they usually smoked a menthol brand of cigarettes, using a menthol smoking status definition based on consistency between smokers' report of the brand and the menthol status of the cigarettes they usually smoked. A logistic regression model of dependence, controlling for background (i.e., school level, gender, and race/ethnicity) and smoking level (i.e., years, frequency, and level of smoking) found that smoking menthol cigarettes was significantly associated with reduced time to needing a cigarette among smokers with a regular brand (odds ratio [OR]: 1.86, p = .003) and among established smokers (OR: 2.06, p = .001). This is consistent with other studies that found that youth who smoked menthol cigarettes were significantly more likely than those who smoked nonmenthol cigarettes to report signs of nicotine dependency.

Menthol cigarettes contribute to the appeal of youth smoking and to the addictive potential of smoking cigarettes among youth. It is important to control the use of menthol cigarettes and to implement cessation strategies that are effective with youth smokers.

Is postoperative hyperbilirubinemia an independent predictor of longterm outcomes after cardiopulmonary bypass?

Two decade-old studies of cardiopulmonary bypass (CPB) patients documented a 25% to 35% incidence of postoperative hyperbilirubinemia, associated with increased in-hospital morbidity and mortality. Longterm consequences of this complication are unknown. Medical records of CPB patients were reviewed. Mortality was ascertained through the National Death Index. Proportional hazards determined important factors in post-CPB survival. Logistic regression delineated predictors of hyperbilirubinemia. Kaplan-Meier and Mantel-Cox log-rank survival analyses compared hyperbilirubinemia groups. Bilirubin levels were followed in 826 (59.7%) patients. Bilirubin was normal in 570 (69.0%) patients (group 1), it was 1.4 to 2.8 mg/dL in 184 (22.3%) patients (group 2), and it exceeded 2.8 mg/dL in 72 (8.7%) patients (group 3). Elevated bilirubin was associated with decreased body mass index, congestive heart failure, heparin before operation, postoperative transfusion requirement, bleeding, and renal failure. In-hospital mortality was 4.3% in group 2 and 25.0% in group 3, compared with 0.9% in group 1 (p<0.001). Two-year crude survival was 95.8% in group 1, 84.8% in group 2, and 62.5% in group 3 (p<0.001). Multivariable predictors of longterm mortality were older age, history of stroke, emergency operation, increased duration of cardiopulmonary bypass, respiratory failure, and elevated bilirubin. Compared with survival in group 1, there was a 1.7-fold decrease in group 2 2-year survival (95% CI 0.9 to 3.0; p=0.09) and a 3.8-fold decrease in group 3 survival (95% CI 2.0 to 7.2; p<0.001).

Postoperative bilirubin elevation in CPB patients is common and deadly. The predictive power of hyperbilirubinemia is similar to that of respiratory failure. The cause of postbypass hyperbilirubinemia is unknown and is probably multifactorial. Additional prospective studies are warranted.

Association between diabetes and coronary heart disease in Aboriginal people: are women disadvantaged?

To determine the incidence rate of coronary heart disease (CHD) in Australian Aboriginal people with type 2 diabetes, and to compare the impact of diabetes on CHD risk in Aboriginal women and men. Cohort study. A remote Aboriginal community in the Northern Territory. 889 Aboriginal people aged 20-74 years followed up to 31 May 2003 after baseline examination in 1992-1995. Incidence rates of CHD (estimated for 123 participants with diabetes at baseline and 701 "non-diabetes" participants); rate ratios for diabetes risk (95% CI), with "non-diabetes" participants as the reference group. Participants with diabetes at baseline had a higher rate of CHD (37.5 per 1000 person-years) than those without diabetes (7.3 per 1000 person-years). Adjustment for multiple CHD risk factors, such as age, smoking, alcohol consumption, systolic blood pressure, body mass index, high-density lipoprotein cholesterol and total cholesterol levels, resulted in a CHD rate ratio for women of 3.7 (95% CI, 1.6-8.9) (comparing women with diabetes with those without) and a CHD rate ratio for men of 1.4 (95% CI, 0.4-4.1) (comparing men with diabetes with those without).

Aboriginal women with diabetes experienced a significantly higher risk of CHD than women without diabetes. Although the difference was not statistically significant, women with diabetes had a higher CHD risk than men with diabetes.

Does sleep deprivation increase cognitive workload during simulated surgical tasks?

There have been conflicting reports of the effects of modest sleep deprivation on surgical skills. The aim of this study was to assess the effects of a 24-hour call shift on technical and cognitive function, as well as the ability to learning a new skill. Thirty-one students trained to expert proficiency on a virtual reality part-task trainer. They then were randomized to either a control or sleep-deprived group. On the second testing day they were given a novel task. Fatigue was assessed using the Epworth Sleepiness Scale. The National Aeronautics and Space Administration-Task Load Index was used to assess cognitive capabilities. There was no difference between the control and sleep-deprived groups for performance or learning of surgical tasks. Subjectively, the Epworth Sleepiness Scale showed an increase in sleepiness. The National Aeronautics and Space Administration-Task Load Index showed an increase in total subjective mental workload for the sleep-deprived group.

Sleep-deprived subjects were able to complete the tasks despite the increased workload, and were able to learn a new task proficiently, despite an increase in sleepiness.

Is the ADP receptor P2Y1 necessary for normal thermal sensitivity in cutaneous polymodal nociceptors?

P2Y1 is a member of the P2Y family of G protein-coupled nucleotide receptors expressed in peripheral sensory neurons. Using ratiometric calcium imaging of isolated dorsal root ganglion neurons, we found that the majority of neurons responding to adenosine diphosphate, the preferred endogenous ligand, bound the lectin IB4 and expressed the ATP-gated ion channel P2X3. These neurons represent the majority of epidermal afferents in hairy skin, and are predominantly C-fiber polymodal nociceptors (CPMs), responding to mechanical stimulation, heat and in some cases cold. To characterize the function of P2Y1 in cutaneous afferents, intracellular recordings from sensory neuron somata were made using an ex vivo preparation in which the hindlimb skin, saphenous nerve, DRG and spinal cord were dissected in continuum, and cutaneous receptive fields characterized using digitally-controlled mechanical and thermal stimuli in male wild type mice. In P2Y1-/- mice, CPMs showed a striking increase in mean heat threshold and a decrease in mean peak firing rate during a thermal ramp from 31-52°C. A similar change in mean cold threshold was also observed. Interestingly, mechanical testing of CPMs revealed no significant differences between P2Y1-/- and WT mice.

These results strongly suggest that P2Y1 is required for normal thermal signaling in cutaneous sensory afferents. Furthermore, they suggest that nucleotides released from peripheral tissues play a critical role in the transduction of thermal stimuli in some fiber types.

Are high basic fibroblast growth factor levels in nipple aspirate fluid correlated with breast cancer?

The angiogenic basic fibroblast growth factor (bFGF) and vascular endothelial growth factor are important in malignant breast epithelial growth. Nipple aspirate fluid (NAF) is a physiologic fluid collected noninvasively that contains proteins secreted by the breast ductal epithelium and may contain markers of breast cancer. The purpose of this study was to determine whether high concentrations of bFGF and vascular endothelial growth factor in NAF would be associated with in situ and invasive breast cancer, and whether prostate-specific antigen, a marker in NAF associated with breast cancer, would improve our ability to determine which subjects had the disease. Both bivariate and multivariate analyses were performed to determine the effects of race, menopausal status, bFGF concentration, and prostate-specific antigen on cancer risk. Bivariate analysis was also performed to determine the relationship between vascular endothelial growth factor concentration and cancer risk. Mean NAF bFGF levels were higher in women with breast cancer than in those without (19.2 vs 1.74 ng/g). Vascular endothelial growth factor was not associated with breast cancer. Race and menopausal status did not significantly affect the relationship between bFGF and cancer risk. bFGF, race, and menopausal status were each independent predictors of breast cancer, with bFGF being the most important. With knowledge of all three variables, the model was 89.9% sensitive and 69.0% specific in predicting which women had breast cancer. Adding prostate-specific antigen increased the sensitivity to 90.9% and the specificity to 83.3%. In subjects with NAF bFGF > 150 ng/g and prostate-specific antigen < 100 ng/g, 94.1% (32/34) of subjects had cancer. For women with NAF prostate-specific antigen > 100 ng/ g and bFGF < 150 ng/g, 90.5% were cancer free.

bFGF concentration in NAF is directly associated with breast cancer, regardless of race and menopausal status. NAF bFGF may prove helpful in the early detection of breast cancer.

Is a banana aquaporin gene , MaPIP1 ; 1 , involved in tolerance to drought and salt stresses?

Aquaporin (AQP) proteins function in transporting water and other small molecules through the biological membranes, which is crucial for plants to survive in drought or salt stress conditions. However, the precise role of AQPs in drought and salt stresses is not completely understood in plants. In this study, we have identified a PIP1 subfamily AQP (MaPIP1;1) gene from banana and characterized it by overexpression in transgenic Arabidopsis plants. Transient expression of MaPIP1;1-GFP fusion protein indicated its localization at plasma membrane. The expression of MaPIP1;1 was induced by NaCl and water deficient treatment. Overexpression of MaPIP1;1 in Arabidopsis resulted in an increased primary root elongation, root hair numbers and survival rates compared to WT under salt or drought conditions. Physiological indices demonstrated that the increased salt tolerance conferred by MaPIP1;1 is related to reduced membrane injury and high cytosolic K+/Na+ ratio. Additionally, the improved drought tolerance conferred by MaPIP1;1 is associated with decreased membrane injury and improved osmotic adjustment. Finally, reduced expression of ABA-responsive genes in MaPIP1;1-overexpressing plants reflects their improved physiological status.

Our results demonstrated that heterologous expression of banana MaPIP1;1 in Arabidopsis confers salt and drought stress tolerances by reducing membrane injury, improving ion distribution and maintaining osmotic balance.

Is liver cytochrome P450 CYP1A2 markedly inhibited by systemic but not by bath PUVA in dermatological patients?

Methoxsalen (8-MOP) may cause important pharmacokinetic drug interactions as it has been shown to inhibit and/or induce several drug-metabolizing enzymes in vitro, in animal models and in humans. In order to assess the clinical importance of acute and chronic 8-MOP effects on the liver cytochrome P-450 enzyme CYP1A2 in vivo, we measured caffeine clearance in dermatological patients before the onset of systemic or bath psoralen + ultraviolet A radiation (PUVA) (8-MOP + UVA) therapy, on the first day and after 1 week of treatment. Data from four patients with systemic PUVA and seven patients with bath PUVA were available (age range 23-71 years, five women and six men). For all of the patients, individual pre-PUVA caffeine clearance values were above the lower limit of previously assessed reference ranges. Systemic PUVA markedly decreased caffeine clearance by factors of 0.17 [90% confidence interval (CI) 0.07-0.42] on the first day and 0.14 (90% CI 0.05-0.36) after 1 week of treatment, respectively, and values thus dropped below the reference ranges. In contrast, bath PUVA had no obvious effect on pre-PUVA clearance values as the latter changed by factors of 1.00 (90% CI 0.81-1.23) and 1.05 (90% CI 0.75-1.49) on the first day and after 1 week of treatment, respectively.

Systemic PUVA causes pronounced inhibition of liver CYP1A2, while bath PUVA has no such effect. The extent of interaction makes a dose adjustment for most CYP1A2 substrates such as theophylline mandatory in patients undergoing systemic PUVA.

Is the efficacy of fluticasone furoate administered in the morning or evening comparable in patients with persistent asthma?

The inhaled corticosteroid fluticasone furoate (FF) is efficacious as a once-daily treatment for the management of asthma. Asthma is associated with circadian changes, with worsening lung function at night. We compared the efficacy of once-daily FF in the morning or evening for the treatment of asthma. Adults with persistent bronchial asthma were enrolled into this randomised, repeat-dose, double-blind, double-dummy, placebo-controlled, three-way crossover study. After a 14-day run-in period, patients received either: FF 100 μg in the morning (AM); FF 100 μg in the evening (PM); or placebo, via the ELLIPTA(®) dry powder inhaler. Patients received all three treatments (14 ± 2 day duration) separated by a 14- to 21-day washout period. The primary endpoint was 24-h weighted mean forced expiratory volume in 1 s (FEV1) measured at the end of each 14-day treatment. A total of 28 patients aged between 19 and 67 years were randomised and 21 (75%) completed all three study arms. Once-daily administration of FF 100 μg resulted in an increased 24-hour weighted mean FEV1; differences between the adjusted means for AM and PM FF dosing versus placebo were 0.077 L (90% confidence interval [CI]: 0.001, 0.152) and 0.105 L (90% CI: 0.029, 0.180), respectively (adjusted mean difference: -0.028 L [90% CI: -0.102, 0.045]). AM or PM doses had comparable incidences of adverse events (AEs; 18/23 versus 18/24, respectively), no serious AEs occurred.

AM and PM doses of once-daily FF 100 μg produced comparable improvements in lung function relative to placebo.

Is s680N substitution of the follicle-stimulating hormone receptor a common polymorphism not associated with spontaneous human twinning?

To determine the influence of the A307/S680 and T307/N680 isoforms of the follicle-stimulating hormone receptor (FSHR) gene on the incidence of spontaneous human twinning. Case-control study. Departments of Obstetrics and Gynecology and of Clinical Chemistry-Grosshadern, University Hospital Munich, Germany. Fifty-four mothers with dichorionic twin pregnancies and 92 singleton mothers as controls, who had conceived without assisted reproduction. Exon 10 of the FSHR gene was screened for the G2105A/S680N mutation. Amplification of genomic DNA by the polymerase chain reaction followed by restriction fragment length polymorphism analysis. Allele frequencies for the G2105A/ S680N substitution of the FSHR in twin mothers were not different from those of controls (genotype (isoform) [twins vs. controls]: G/G (S/S) [24.1% vs. 22.3%]; A/G (N/S) [57.4% vs. 55.4%]; A/A (N/N) [18.5% vs. 22.3%]). Subgroup analysis of women with three or more successful pregnancies gave a similar result (G/G (S/S) [17.7% vs. 13.7%]; A/G (N/S) [64.7% vs. 63.6%]; A/A (N/N) [17.6% vs. 22.7%]). There was no correlation between FSHR isoform and twinning.

The S680N substitution of the follicle-stimulating hormone receptor is a common polymorphism not associated with spontaneous human twinning.

Do subthalamic stimulation and levodopa modulate cortical reactivity in Parkinson 's patients?

The effects of deep brain stimulation of the subthalamic nucleus (DBS-STN) and L-dopa (LD) on cortical activity in Parkinson's disease (PD) are poorly understood. By combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) we explored the effects of STN-DBS, either alone or in combination with L-Dopa (LD), on TMS-evoked cortical activity in a sample of implanted PD patients. PD patients were tested in three clinical conditions: i) LD therapy with STN-DBS turned on (ON/ON condition); ii) without LD therapy with STN-DBS turned on (OFF/ON condition); iii) without LD therapy with STN-DBS turned off (OFF/OFF condition). TMS pulses were delivered over left M1 while simultaneously acquiring EEG. Eight age-matched healthy volunteers (HC) were tested as a control group. STN-DBS enhanced early global TMS-evoked activity (∼45-80ms) and high-alpha TMS-evoked oscillations (11-13 Hz) as compared to OFF/OFF condition, independently from concomitant LD therapy. LD intake (ON/ON condition) produced a further increase of late TMS-evoked activity (∼80-130ms) and beta TMS-evoked oscillations (13-30 Hz), as compared to OFF/OFF and OFF/ON conditions, that normalized reactivity as compared to HC range of values.

Our data reveal that bilateral STN-DBS and LD therapy induce a modulation of specific cortical components and specific ranges of frequency. These findings demonstrate that STN-DBS and LD therapy may have synergistic effects on motor cortical activity.

Do surgeons and patients discuss what they document on consent forms?

Previous studies of surgeon behavior report that surgeons rarely meet basic standards of informed consent, raising concerns that current practice requires urgent remediation. We wondered if the Veterans Affairs Healthcare System's recent implementation of standardized, procedure-specific consent forms might produce a better practice of informed consent than has been reported previously. Our goal was to determine how the discussions shared between surgeons and patients correspond to the VA's standardized consent forms. We enrolled a prospective cohort of patients presenting for possible cholecystectomy or inguinal herniorrhaphy and the surgical providers for those patients. Audio recordings captured the clinical encounter(s) culminating in a decision to have surgery. Each patient's informed consent was documented using a standardized, computer-generated form. We abstracted and compared the information documented with the information discussed. Of 75 consecutively enrolled patients, 37 eventually decided to have surgery and signed the standardized consent form. Patients and providers discussed 37% (95% confidence interval, 0.07-0.67) and 33% (95% confidence interval, 0.21-0.43) of the information found on the cholecystectomy and herniorrhaphy consent forms, respectively. However, the patient-provider discussions frequently included relevant details nowhere documented on the standardized forms, culminating in discussions that included a median 27.5 information items for cholecystectomy and 20 items for herniorrhaphy. Fully, 80% of cholecystectomy discussions and 76% of herniorrhaphy discussions mentioned at least one risk, benefit or alternative, indication for, and description of the procedure.

The patients and providers observed here collaborated in a detailed process of informed consent that challenges the initial reports suggesting the need to remediate surgeon's practice of informed consent. However, because the discrepancy between the information documented and discussed exposes legal and ethical liability, there is an opportunity to improve the iMed system so that it better reflects what surgeons discuss and more frequently includes all the information patients need.

Does [ Resolvin E1 protect against ox-LDL-induced injury on vascular endothelial cells ]?

To investigate whether Resolvin E1 (RvE1) could protect against ox-LDL-induced injury on human vein vascular endothelial cells and reveal related molecular mechanisms. Human vein vascular endothelial cells were randomly assigned to six groups, which were treated with saline, RvE1, wortmanin, ox-LDL, ox-LDL and RvE1, ox-LDL and RvE1 and wortmanin, respectively. After 48 h, survival rates were determined by MTT, apoptosis rate of cells were determined by flow cytometry, TNF-α contents were assayed by ELISA, caspase 3 and 9 activities were measured by microplate reader, and the expression of p-AKT and LOX-1 were determined by Western blot. Compared with normal saline group, survival rate was markedly decreased and apoptosis rate, TNF-α content, caspase 3 and 9 activities, and the expression of LOX-1 were significantly increased in ox-LDL group (P < 0.01). Survival rate was significantly increased and apoptosis rate, TNF-α content, caspase 3 and 9 activities, and the expression of LOX-1 were significantly decreased in ox-LDL + RvE1 group compared to ox-LDL group (P < 0.01), these beneficial effects of RvE1 could be blocked by PI3K inhibitor wortmanin (P < 0.05).

The present data showed that RvE1 could effectively protect against ox-LDL-induced endothelial cell injury, which might be mediated by PI3K-AKT signaling pathway.

Does inhibition of CXCR7 extend survival following irradiation of brain tumours in mice and rats?

In experimental models of glioblastoma multiforme (GBM), irradiation (IR) induces local expression of the chemokine CXCL12/SDF-1, which promotes tumour recurrence. The role of CXCR7, the high-affinity receptor for CXCL12, in the tumour's response to IR has not been addressed. We tested CXCR7 inhibitors for their effects on tumour growth and/or animal survival post IR in three rodent GBM models. We used immunohistochemistry to determine where CXCR7 protein is expressed in the tumours and in human GBM samples. We used neurosphere formation assays with human GBM xenografts to determine whether CXCR7 is required for cancer stem cell (CSC) activity in vitro. CXCR7 was detected on tumour cells and/or tumour-associated vasculature in the rodent models and in human GBM. In human GBM, CXCR7 expression increased with glioma grade and was spatially associated with CXCL12 and CXCL11/I-TAC. In the rodent GBM models, pharmacological inhibition of CXCR7 post IR caused tumour regression, blocked tumour recurrence, and/or substantially prolonged survival. CXCR7 expression levels on human GBM xenograft cells correlated with neurosphere-forming activity, and a CXCR7 inhibitor blocked sphere formation by sorted CSCs.

These results indicate that CXCR7 inhibitors could block GBM tumour recurrence after IR, perhaps by interfering with CSCs.

Does pulsed electromagnetic fields dosing impact postoperative pain in breast reduction patients?

Pulsed electromagnetic fields (PEMF) reduce postoperative pain and narcotic requirements in breast augmentation, reduction, and reconstruction patients. PEMF enhances both calmodulin-dependent nitric oxide and/or cyclic guanosine monophosphate signaling and phosphodiesterase activity, which blocks cyclic guanosine monophosphate. The clinical effect of these competing responses on PEMF dosing is not known. Two prospective, nonrandomized, active cohorts of breast reduction patients, with 15 min PEMF per 2 h; "Q2 (active)", and 5 min PEMF per 20 min; "5/20 (active)", dosing regimens were added to a previously reported double-blind clinical study wherein 20 min PEMF per 4 h, "Q4 (active)", dosing significantly accelerated postoperative pain reduction compared with Q4 shams. Postoperative visual analog scale pain scores and narcotic use were compared with results from the previous study. Visual analog scale scores at 24 h were 43% and 35% of pain at 1 h in the Q4 (active) and Q2 (active) cohorts, respectively (P < 0.01). Pain at 24 h in the 5/20 (active) cohort was 87% of pain at 1 h, compared with 74% in the Q4 (sham) cohort (P = 0.451). Concomitantly, narcotic usage in the 5/20 (active) and Q4 (sham) cohorts was not different (P = 0.478), and 2-fold higher than the Q4 (active) and Q2 (active) cohorts (P < 0.02).

This prospective study shows Q4/Q2, but not 5/20 PEMF dosing, accelerated postoperative pain reduction compared with historical shams. The 5/20 (active) regimen increases NO 4-fold faster than the Q4 (active) regimen, possibly accelerating phosphodiesterase inhibition of cyclic guanosine monophosphate sufficiently to block the PEMF effect. This study helps define the dosing limits of clinically useful PEMF signals.

Does gegen Qinlian decoction alleviate experimental colitis via suppressing TLR4/NF-κB signaling and enhancing antioxidant effect?

Gegen Qinlian decoction (GQ), a Chinese medicinal herb decoction, has been widely used as efficient medicine for the treatment of acute colitis in clinics, but underlying molecular mechanisms have not been fully clarified. Inflammation and oxidative stress have been reported to constitute a crucial part in the pathogenesis of ulcerative colitis (UC). Hence, this study was designed to investigate the antiinflammatory activity and antioxidative effect of GQ. Mice induced by 5% dextran sulfate sodium (DSS) and macrophage RAW264.7 cells stimulated by lipopolysaccharide (LPS) were used in this study. Ethanol extracts of GQ were orally administered for 1 week on the dosage of 0.3, 1.5, or 7.5g/kg/day and berberine (BBR, 100mg/kg/d) was selected as a positive group in the animal experiments. In vitro, GQ (25, 50, 100µg/ml) or BBR (20µM) co-cultured with RAW264.7 for 2h prior to LPS stimulation. The results showed that GQ oral administration alleviated the severity of colitis notably. It reduced toll-like receptor 4 (TLR4) expression and NF-κB activation in mucosa, which was accompanied with down regulation of several inflammatory cytokines in the colon, including tumor necrosis factor (TNF-α), interleukin (IL)-6, IL-1β and IL-4. Furthermore, GQ oral administration attenuated the oxidative stress in the colon of UC mice, evidenced by the decrease of myeloperoxidase (MPO) activity and malondialdehyde (MDA) level, and the elevation of glutathione (GSH) content. In parallel with the vivo experiment results, cell research indicated GQ dramatically reduced the production of TNF-α, IL-6, IL-1β and nitric oxide (NO), as well as that of reactive oxygen species (ROS) upon stimulation of LPS.

Together, our present study indicates that inhibition of TLR4/NF-κB signaling and enhancement of antioxidant effect might be the potential mechanisms for the therapeutic effect of GQ against UC.

Does [ do the coexistence of cancer have an influence on the course of sepsis ]?

The guidelines for management of sepsis are constantly updated, nevertheless sepsis is still a difficult clinical problem, especially as its treatment often ends in failure. Hospitalized cancer patients diagnosed with sepsis are especially concerned, as sepsis death rate is significant in that group of patients. The aim of the study was to evaluate and compare cancer- and non-cancer patients diagnosed with sepsis. The medical records of 56 patients diagnosed with sepsis from January 1. 2007 to August 1. 2008 were reviewed retrospectively. Patients were divided into two groups: 1 group--patients with sepsis and cancer (S+N), II group--patients with sepsis without cancer (S). The etiology of sepsis, primary infectious sources, chosen clinical and laboratory parameters and mortality were analysed. 56 patients were involved in the study. The mean age for S+N patients was higher than for group S (61.3 vs. 45.5 years; p = 0.005). The mean APACHE II score value at the day of admission for the whole population was 22.1 +/- 8.8 (8-45), for S+N group--25.3 +/- 10.3 (12-41) and for group S--21.2 +/- 8.3 (8-45) (p = 0.308). The estimated risk of hospital death was retrospectively 43.4%, 53.3% and 39.0%. Patients in group S+N required larger infusion of minimal noradrenaline doses than the other patients (p = 0.015). The mortality rate was 14.3% and was higher in group S+N than in group S (16.7 vs. 13.6%). Mortality was also significantly higher among patients with larger lactate blood concentration (death: 4.6 vs. survival: 1.9 mmol/l; p = 0.020) and greater base deficit (death: -6.79 vs. survival: -2.34 mmol/l; p = 0,0006). Patients of lower mean arterial pressure (60.8 vs. 75.9 mmHg; p = 0.007) and who required larger noradrenaline infusion (0.514 vs. 0.232 microg/kg/min; p = 0.0009) at the day of admission had a significantly higher risk of death.

The analysis did not indicate evidently higher risk of more severe sepsis's course in cancer sepsis patients. However the severity of patients' general condition estimated by the APACHE II score and the mortality in this group of patients was higher (statistically insignificant results). Patients in group S+N required larger minimal doses of noradrenaline and larger infusion of colloid at the day of admission. The mortality was determined by the haemodynamic disturbance and the severity of general condition, rather than the cancer diagnosis per se.

Does s-Glutathionylation of hepatic and visceral adipose proteins decrease in obese rats?

A number of clinical and biochemical studies demonstrate that obesity and insulin resistance are associated with increases in oxidative stress and inflammation. Paradoxically, insulin sensitivity can be enhanced by oxidative inactivation of cysteine residues of phosphatases, and inflammation can be reduced by S-glutathionylation with formation of protein-glutathione mixed disulfides (PSSG). Although oxidation of protein-bound thiols (PSH) is increased in multiple diseases, it is not known whether there are changes in PSH oxidation species in obesity. In this work, the hypothesis that obesity is associated with decreased levels of proteins containing oxidized protein thiols was tested. The tissue levels of protein sulfenic acids (PSOH) and PSSG in liver, visceral adipose tissue, and skeletal muscle derived from glucose intolerant, obese-prone Sprague-Dawley rats were examined. The data in this study indicate that decreases in PSSG content occurred in liver (44%) and adipose (26%) but not skeletal muscle in obese rats that were fed a 45% fat-calorie diet versus lean rats that were fed a 10% fat-calorie diet. PSOH content did not change in the tissue between the two groups. The activity of the enzyme glutaredoxin (GLRX) responsible for reversal of PSSG formation did not change in muscle and liver between the two groups. However, levels of GLRX1 were elevated 70% in the adipose tissue of the obese, 45% fat calorie-fed rats.

These are the first data to link changes in S-glutathionylation and GLRX1 to adipose tissue in the obese and demonstrate that redox changes in thiol status occur in adipose tissue as a result of obesity.

Is quantitation of whole blood Epstein-Barr virus DNA useful for assessing treatment response in patients with non-Hodgkin 's lymphoma?

Epstein-Barr virus (EBV) is a well-known tumorigenic virus and is associated with lymphoproliferative disorders. Quantitations of EBV viral loads in plasma and peripheral blood mononuclear cells have been reported to be useful biomarkers for monitoring Hodgkin's lymphoma and EBV-associated non-Hodgkin lymphoma (NHL). In the present study, whole blood specimens were used to determine quantitatively EBV viral loads, which were then compared with clinical data. Using real-time quantitative polymerase chain reaction (RQ-PCR), EBV-DNA was monitored in whole blood samples from patients with NHL (n = 61) at the time of diagnosis, relapse, and follow-up. A statistically significant correlation was observed between positive EBV viral load and extranodal involvement in diffuse large B-cell lymphoma at the time of diagnosis or relapse (n = 29, P = 0.009). In patients who were serially checked for EBV-DNA levels (n = 16), viral load was found to fall to undetectable levels during complete remission. On the contrary, progressive disease and relapse were found to be associated with sustained or elevated EBV-DNA levels.

These results suggest that whole blood EBV-DNA quantitation might be of value as a convenient biomarker for therapeutic responsiveness of NHL.

Is volume rather than flow incentive spirometry effective in improving chest wall expansion and abdominal displacement using optoelectronic plethysmography?

Incentive spirometers are widely used in clinical practice and classified as flow-oriented (FIS) and volume-oriented (VIS). Until recently the respiratory inductive plethysmography used to evaluate the effects of incentive spirometry on chest wall mechanics presented limitations, which may explain why the impact of VIS and FIS remains poorly known. To compare the effects of VIS and FIS on thoracoabdominal mechanics and respiratory muscle activity in healthy volunteers. This cross-sectional trial assessed 20 subjects (12 female, ages 20-40 years, body mass index 20-30 kg/m(2)). All subjects performed 8 quiet breaths and 8 deep breaths with FIS and VIS, in a randomized order. We measured thoracoabdominal chest wall, upper and lower rib-cage, and abdominal volumes with optoelectronic plethysmography, and the muscle activity of the sternocleidomastoid and superior and inferior intercostal muscles with electromyography. VIS increased chest wall volume more than did FIS (P = .007) and induced a larger increase in the upper and lower rib-cages and abdomen (156%, 91%, and 151%, respectively, P < .001). By contrast, FIS induced more activity in the accessory muscles of respiration than did VIS (P < .001).

VIS promotes a greater increase in chest wall volume, with a larger abdominal contribution and lower respiratory muscle activity, than does FIS in healthy adults.

Does second harmonic imaging improve left ventricular endocardial border identification at higher heart rates during dobutamine stress echocardiography?

The increased heart rate during dobutamine stress echocardiography (DSE) may impair endocardial border visualization. Second harmonic imaging (SHI) enhances left ventricular (LV) border visualization compared with conventional fundamental imaging (FI) at rest. However, its role during DSE is not well established yet. Our objective was to compare the additional value of SHI to FI for the LV endocardial border visualization during various stages of DSE. Eighty patients underwent DSE. Imaging was performed with both FI and SHI at rest and at low-and peak-dose dobutamine infusion. Endocardial border visualization was assessed by using a 16-segment/3-point score (0 = well visualized; 1 = poorly visualized; 2 = not visualized). Heart rate increased from rest (70 +/- 13 bpm) to low-dose dobutamine (77 +/- 17, P<.01) and showed further increase at peak dose (129 +/- 16, P<.001 versus low dose). There was a higher prevalence of segments with an invisible LV endocardial border with FI compared with SHI at rest (9.4% versus 6.2%, P<.0001), at low dose (10.8% versus 6.3%, P<.0001), and at peak dose (15.0% versus 8.2%, P<.0001). There was an increase in the number of segments with an invisible border from rest to peak stress by FI (P =.0001), whereas the difference was less significant for SHI (P =.07).

Second harmonic imaging improves visualization of the LV endocardial border compared with FI during DSE. The advantage of SHI over FI is more marked at higher heart rates than at rest.

Does the host range of gammaretroviruses and gammaretroviral vectors include post-mitotic neural cells?

Gammaretroviruses and gammaretroviral vectors, in contrast to lentiviruses and lentiviral vectors, are reported to be restricted in their ability to infect growth-arrested cells. The block to this restriction has never been clearly defined. The original assessment of the inability of gammaretroviruses and gammaretroviral vectors to infect growth-arrested cells was carried out using established cell lines that had been growth-arrested by chemical means, and has been generalized to neurons, which are post-mitotic. We re-examined the capability of gammaretroviruses and their derived vectors to efficiently infect terminally differentiated neuroendocrine cells and primary cortical neurons, a target of both experimental and therapeutic interest. Using GFP expression as a marker for infection, we determined that both growth-arrested (NGF-differentiated) rat pheochromocytoma cells (PC12 cells) and primary rat cortical neurons could be efficiently transduced, and maintained long-term protein expression, after exposure to murine leukemia virus (MLV) and MLV-based retroviral vectors. Terminally differentiated PC12 cells transduced with a gammaretroviral vector encoding the anti-apoptotic protein Bcl-xL were protected from cell death induced by withdrawal of nerve growth factor (NGF), demonstrating gammaretroviral vector-mediated delivery and expression of genes at levels sufficient for therapeutic effect in non-dividing cells. Post-mitotic rat cortical neurons were also shown to be susceptible to transduction by murine replication-competent gammaretroviruses and gammaretroviral vectors.

These findings suggest that the host range of gammaretroviruses includes post-mitotic and other growth-arrested cells in mammals, and have implications for re-direction of gammaretroviral gene therapy to neurological disease.

Oral examination: a screening tool for HIV infection?

To estimate the predictive values for HIV infection of diagnosis of oral manifestations of the infection. Prevalence of oral manifestations was compared in cross sectional blinded clinical examinations of homosexual men attending a genitourinary medicine clinic. Data were extrapolated to populations in England and Wales based on estimates of the prevalence of HIV infection. Data were analysed for 572 HIV infected and non-infected men (312 and 260 respectively). Positive predictive values for erythematous candidiasis, hairy leucoplakia and pseudomembranous candidiasis were greater than 0.96 at the genitourinary medicine clinic and are estimated to be greater than 0.72 among homosexual men in London.

Clinical diagnoses of mucosal lesions alone are poor predictors of HIV infection but are useful when used in conjunction with a social history to establish if there are risk factors for infection.

Is von Willebrand Factor elevated in HIV patients with a history of thrombosis?

Arterial and venous thrombotic events are more prevalent in HIV infected individuals compared to the general population, even in the era of combination antiretroviral therapy. Although the mechanism is not fully understood, recent evidence suggests a role for chronic immune activation. We reviewed the Dutch National HIV registry database for HIV infected patients in Rotterdam with a history of arterial or venous thrombosis and calculated the incidence. We collected samples from patients with and without thrombosis and compared plasma levels of lipopolysaccharide (LPS), LPS binding protein (LBP), soluble CD14 (sCD14), and von Willebrand Factor antigen level (vWF). During a 10-year period, a total of 60 documented events in 14,026 person years of observation (PYO) occurred, resulting in an incidence rate of 2.50, 2.21, and 4.28 for arterial, venous and combined thrombotic events per 1000 PYO, respectively. The vWF was elevated in the majority of study subjects (mean 2.36 SD ± 0.88 IU/ml); we found a significant difference when comparing venous cases to controls (mean 2.68 SD ± 0.82 IU/ml vs. 2.20 SD ± 0.77 IU/ml; p = 0.024). This difference remained significant for recurrent events (mean 2.78 SD ± 0.75; p = 0.043). sCD14 was positively correlated with LPS (r = 0.255; p = 0.003).

The incidence of venous thrombosis was two-fold higher in HIV infected patients compared to age-adjusted data from general population cohort studies. We couldn't find a clear association between immune activation markers to either arterial or venous thrombotic events. We observed a marked increase in vWF levels as well as a correlation of vWF to first and recurrent venous thrombo-embolic events. These findings suggest that HIV infection is an independent risk factor for coagulation abnormalities and could contribute to the observed high incidence in venous thrombosis. This could be a reason to prolong anti-thrombotic treatment in HIV patients with a history of thrombosis.

Can minimally invasive coronary artery bypass grafting be initiated and practiced safely?

We examined the effects of learning curve on clinical outcomes and operative time in minimally invasive coronary artery bypass grafting (MICS CABG). We studied 210 consecutive MICS CABG cases performed by the same surgeon, composed of 3 cardiopulmonary bypass (CPB)-assisted single-vessel small thoracotomy (SVST), 87 off-pump SVST, 51 CPB-assisted multivessel small thoracotomy (MVST), and 69 off-pump MVST. For each MICS CABG technique, the frequency of early clinical events (mortality, reopening, stroke, myocardial infarction, and revascularization) was compared between the first 25 cases and the remainder. Logarithmic curve regression analysis and a cumulative summation technique were performed to assess the correlation between operative time and the performed number of each technique. There was no mortality, and there were 10 conversions to standard sternotomy, all of which were intended as off-pump MVST (P<0.001, vs other procedures). Experience was otherwise not associated with perioperative outcome. However, experience numbers correlated with operative time in off-pump SVST and off-pump MVST (122 ± 30 minutes, R = 0.18, P<0.001, and 241 ± 80 minutes, R = 0.38, P<0.001, respectively) but not in CPB-assisted MVST (258 ± 44 minutes, R = 0.004, P = 0.7). No complications occurred as a result of CPB assistance.

Minimally invasive coronary artery bypass grafting can be safely initiated, with a very low perioperative risk. Pump assistance is a good strategy to alleviate some of the learning curve and avoid conversions to sternotomy when initiating a multivessel MICS CABG program.

Does mammary carcinoma cell derived cyclooxygenase 2 suppress tumor immune surveillance by enhancing intratumoral immune checkpoint activity?

Systemic inhibition of the inflammatory enzyme cyclooxygenase (COX) 2 decreases the risk of breast cancer and its recurrence. However, the biology of COX-2 in the multicellular tumor microenvironment is poorly defined. Mammary tumor onset and multiplicity were examined in ErbB2 transgenic mice that were deficient in mammary epithelial cell COX-2 (COX-2(MEC)KO) compared to wild type (WT) mice. Tumors were analyzed, by real time PCR, immune-staining and flow cytometry, for proliferation, apoptosis, angiogenesis and immune microenvironment. Lentiviral shRNA delivery was used to knock down (KD) COX-2 in ErbB2-transformed mouse breast cancer cells (COX-2KD), and growth as orthotopic tumors was examined in syngenic recipient mice, with or without depletion of CD8+ immune cells. Mammary tumor onset was delayed, and multiplicity halved, in COX-2(MEC)KO mice compared to WT. COX-2(MEC)KO tumors showed decreased expression of Ki67, a proliferation marker, as well as reduced VEGFA, its receptor VEGFR2, endothelial NOS and the vascular endothelial marker CD31, indicating reduced tumor vascularization. COX-2(MEC)KO tumors contained more CD4+ T helper (Th) cells and CD8+ cytotoxic immune cells (CTL) consistent with increased immune surveillance. The ratio of Th markers Tbet (Th1) to GATA3 (Th2) was higher, and levels of Retnla, a M2 macrophage marker, lower, in COX-2(MEC)KO tumor infiltrating leukocytes compared to WT, suggesting a prevalence of pro-immune Th1 over immune suppressive Th2 lymphocytes, and reduced macrophage polarization to the immune suppressive M2 phenotype. Enhanced immune surveillance in COX-2(MEC)KO tumors was coincident with increased intratumoral CXCL9, a T cell chemoattractant, and decreased expression of T lymphocyte co-inhibitory receptors CTLA4 and PD-1, as well as PD-L1, the ligand for PD-1. PD-L1 was also decreased in IFNγ-treated COX-2KD mouse mammary cancer cells in vitro and, compared to control cells, growth of COX-2KD cells as orthotopic tumors in immune competent mice was markedly suppressed. However, robust growth of COX-2KD tumor cells was evident when recipients were depleted of CD8+ cells.

The data strongly support that, in addition to its angiogenic function, tumor cell COX-2 suppresses intratumoral cytotoxic CD8+ immune cell function, possibly through upregulation of immune checkpoints, thereby contributing to tumor immune escape. COX-2 inhibition may be clinically useful to augment breast cancer immunotherapy.

Are lenticulostriate arterial lumina normal in cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy : a high-field in vivo MRI study?

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease. Although postmortem studies have demonstrated mural thickening in leptomeningeal arteries and lenticulostriate perforating arteries, it is unclear whether this also leads to luminal narrowing. High-field MRI scanners enable in vivo imaging of the lumen of the lenticulostriate arteries. The aim of this study is to examine the luminal diameters of lenticulostriate arteries in living patients with CADASIL and to investigate whether luminal narrowing is correlated with the number of lacunar infarcts in the basal ganglia. Twenty-two NOTCH3 mutation carriers and 11 healthy control subjects were examined using high-resolution 3-dimensional time-of-flight MR angiography imaging on a 7-T MRI scanner. Scans were analyzed for the presence of focal stenotic segments. The total number, length, and total cross-sectional area of lenticulostriate arteries were measured and compared between mutation carriers and control subjects. These measurements were correlated with age, disease duration, and number of lacunar infarcts in the basal ganglia. No stenotic segments were observed. No differences between mutation carriers and control subjects were found in total number of end branches (mutation carriers: mean, 14.6; control subjects: mean, 12.8), length of the lenticulostriate system, or total cross-sectional area of lenticulostriate artery lumina. Measurements of lenticulostriate artery lumina were not associated with lacunar infarct load in the basal ganglia area or with basal ganglia hyperintensities.

Three-dimensional time-of-flight MR angiographic on 7 T showed no differences in luminal diameters of lenticulostriate arteries between patients with CADASIL and control subjects.

Are oncogenic PI3K mutations as common as AKT1 and SMO mutations in meningioma?

Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define. We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7. Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base.

This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

Is greater diet quality associated with more optimal glycemic control in a longitudinal study of youth with type 1 diabetes?

Despite the centrality of nutrition in the management of type 1 diabetes, the association of diet quality and macronutrient distribution with glycemic control is ambiguous. This study examined longitudinally the association of dietary intake with multiple indicators of glycemic control in youth with type 1 diabetes participating in a behavioral nutrition intervention study. Participants in a randomized clinical trial of a behavioral nutrition intervention [n = 136; mean ± SD age: 12.8 ± 2.6 y; glycated hemoglobin (HbA1c): 8.1% ± 1.0%; 69.1% using an insulin pump] completed 3-d diet records at baseline and months 3, 6, 9, 12, and 18; masked continuous glucose monitoring (CGM) data were obtained concurrently with the use of the Medtronic iPro CGM system. HbA1c was obtained every 3 mo; 1,5-anhydroglucitol was obtained every 6 mo. Linear mixed-effects regression models estimated associations of time-varying dietary intake variables with time-varying glycemic control indicators, controlling for age, height, weight, sex, Tanner stage, diabetes duration, regimen, frequency of blood glucose monitoring, physical activity, and treatment assignment. HbA1c was associated inversely with carbohydrate and natural sugar, and positively with protein and unsaturated fat. 1,5-Anhydroglucitol was associated positively with fiber intake and natural sugar. Greater glycemic control as indicated by ≥1 CGM variable was associated with higher Healthy Eating Index-2005, whole plant food density, fiber, carbohydrate, and natural sugar and lower glycemic index and unsaturated fat.

Both overall diet quality and macronutrient distribution were associated with more optimal glycemic control. Associations were more consistent for CGM variables obtained concurrently with dietary intake than for biomarkers of longer-term glycemic control. These findings suggest that glycemic control may be improved by increasing intake of high-fiber, low glycemic-index, carbohydrate-containing foods. This trial was registered at clinicaltrials.gov as NCT00999375.

Are extremes of eating associated with reduced neural taste discrimination?

Eating disorders are severe psychiatric disorders of unknown etiology. Understanding how neuronal function affects food choices could help personalize treatment based on brain function. Here we wanted to determine whether disordered eating behavior is associated with alterations in the primary taste cortex's ability to classify taste stimuli, which could interfere with taste reward processing. One-hundred and six women, 27 healthy comparison (age 26.15 ± 6.95 years), 21 with restricting-type anorexia nervosa (AN; age 23.10 ± 6.14 years), 19 recovered from restricting-type AN (recovered AN; age 26.95 ± 5.31 years), 20 with bulimia nervosa (BN; age 25.15 ± 5.31 years), and 19 with obesity (age 28.16 ± 8.13 years), received sucrose, control solution or no taste stimulation during functional magnetic resonance brain imaging. Multivariate Bayesian pattern analysis (decoding) and cross-validation tested taste classification accuracy (adjusted for comorbidity, medication use, taste perception, interoception, and brain activation volume). For sucrose versus control solution, classification accuracy differed (F = 2.53, P < 0.041). Post hoc tests indicated higher classification accuracy in healthy comparison compared to women with AN (P < 0.016) or obesity (P < 0.027), and in recovered AN as compared to AN (P < 0.016) or obesity (P < 0.047) groups. Taste stimulation resulted in sparse insula voxel activation across all groups.

Reduced classification accuracy across stimuli in women with AN or obesity could indicate low brain encoding discrimination of stimulus quality, which could contribute to altered reward activation and eating drive that is not adjusted to nutritional needs. This deficit appears to normalize with recovery from AN, but adjusting food flavor intensity could aid in the treatment of individuals with AN or obesity. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2016; 49:603-612).

Are endocannabinoid type 1 receptor gene (CNR1) polymorphisms associated with obesity and metabolic syndrome in postmenopausal Polish women?

The aim of this study was to determine whether genetic variation at the cannabinoid receptor-1 (CNR1) locus could have an effect on adiposity, fat distribution and obesity-related metabolic disorders in Polish postmenopausal women. The A3813G (rs12720071), G1422A (rs1049353), A4895G (rs806368) and rs806381, rs10485170, rs6454674 and rs2023239 single-nucleotide polymorphisms of CNR1 were genotyped in 348 randomly selected postmenopausal women aged 50-60 years recruited from the Wroclaw city population. CNR1 genotypes, anthropometric measures (body mass index (BMI), waist circumference (WC) and body fat distribution by dual energy X-ray absorptiometry) and metabolic parameters (glucose, lipid profile and Fasting Insulin Resistance Index for insulin resistance) were determined. The 3813G allele was not significantly associated with higher body mass, BMI, WC, total fat or fat percentage, but was associated with higher android fat deposit (2971.78±1655.08 vs 2472.64±1300.53, P=0.007) and percentage of android fat (37.59±8.45 vs 35.66±7.63, P=0.062). No associations for the G1422A, A4895G, rs806381, rs10485170, rs6454674 and rs2023239 variants were observed.

There is an association of the variants of CNR1 with obesity-related phenotypes in Polish postmenopausal women. As cannabinoid receptor type 1 is a drug target for obesity, pharmacogenetic receptor gene analysis of obesity treatment by endocannabinoid blockade may be of interest to identify the best responders.

Try ' I to bother the residents too much ' - the use of capillary blood glucose measurements in nursing homes?

Capillary blood glucose measurements are regularly used for nursing home residents with diabetes. The usefulness of these measurements relies on clear indications for use, correct measurement techniques, proper documentation and clinical use of the resulting blood glucose values. The use of a regular, invasive procedure may also entail additional challenges in a population of older, multimorbid patients who often suffer from cognitive impairment or dementia. The aim of this study was to explore the perspectives of physicians, registered nurses and auxiliary nurses on the use, usefulness and potential challenges of using capillary blood glucose measurements in nursing homes, and the procedures for doing so. This was a qualitative study that used three profession-specific focus group interviews. Interviews were transcribed in modified verbatim form and analysed in accordance with Malterud's principles of systematic text condensation. Five physicians, four registered nurses and three auxiliary nurses participated in the focus groups. All professional groups regarded capillary blood glucose measurements as a necessity in the management of diabetes, the physicians to ensure that the treatment is appropriate, and the nurses to be certain and assured about their caring decisions. Strict glycaemic control and excessive measurements were avoided in order to promote the well-being and safety of the residents. Sufficient knowledge of diabetes symptoms, equivalent practices for glucose measurement, and unambiguous documentation and communication of results were determined to be most helpful. However, all professional groups seldom involved the residents in managing their own measurements and stated that guidelines and training had been inconsistent or lacking.

Inadequate procedures and training in diabetes care may compromise the rationale for capillary blood glucose measurements in nursing homes, and hence the residents' safety. These concerns should be addressed together with the possibility of involving and empowering residents by exploring their ability and wish to manage their own disease.

Does preoperative oral immune-enhancing nutritional supplementation correct TH1/TH2 imbalance in patients undergoing elective surgery for colorectal cancer?

Recent studies have shown that the type 1/2 CD4+ T cell (Th1/Th2) balance shifts toward Th2 dominance in cancer-bearing state or by surgical stress. Perioperative immunonutrition is reported to improve the outcome in patients with gastrointestinal cancer. This study was designed to investigate whether preoperative immunonutrition corrects the impaired Th1/Th2 balance in the perioperative period. Thirty-six patients with colorectal cancer were prospectively divided into two groups as follows: preoperative oral intake supplementation with a formula enriched with arginine, omega-3 fatty acids and ribonucleic acid for five days (supplemented group; n = 19); and (control group; n = 17). Blood sampling was performed before supplementation, on the morning of surgery, and 3, 7, and 14 days postoperatively. The proportions of CD4+ T cells producing intracellular cytokines (interferon-gamma and interleukin-4) were measured by flow cytometry. In the preoperative period, the proportions of CD4+ T cells producing interleukin-4 significantly decreased and Th1/Th2 ratio significantly increased on the morning of surgery compared with those before supplementation. In the postoperative period, the proportions of CD4+ T cells producing interferon-gamma in both groups maintained the preoperative level. The proportions of CD4+ T cells producing interleukin-4 in the control group showed a gradual increase from the preoperative level, which implies Th2 dominant shift. In contrast, the supplemented group maintained the preoperative level of Th1/Th2 ratio.

Preoperative immunonutrition corrects impaired Th1/Th2 balance in both cancer-bearing state and the postoperative period. This correction may be one of the important determinants of the clinical benefits of immunonutrition.

Does tLE1 modify the effects of NOD2 in the pathogenesis of Crohn 's disease?

The mechanisms by which specific mutations in NOD2/CARD15 increase the risk for Crohn's disease (CD) are unclear. We identified proteins that interact with NOD2 and investigated them by expression, genetic, and functional analyses. By using a yeast 2-hybrid screen of an intestinal epithelial library, we identified proteins that interact with NOD2 and confirmed the interactions in mammalian cells using co-immunoprecipitation. We used microarray analysis to analyze gene expression patterns in 302 intestinal biopsy samples (129 from patients with ulcerative colitis [UC], 106 with CD, and 67 controls). Eighty single-nucleotide polymorphisms within the genes that encoded 6 interacting proteins were genotyped in a discovery cohort (869 cases of inflammatory bowel disease [IBD], 885 controls) and a replication cohort (504 patients with IBD, 713 controls). We investigated interaction between transducin-like enhancer of split 1 (TLE1) and NOD2 in HEK293 cells. We identified 6 NOD2-interacting proteins (TLE1, UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2 [GALNT2], HIV-1 Tat interactive protein [HTATIP], Vimentin, fission 1 (mitochondrial outer membrane) homolog [FIS1], and protein phosphatase 2, regulatory subunit B', epsilon isoform [PPP2R5E]). Of these, expression of GALNT2 (CD, P = .004) and vimentin (CD, P = .006; UC, P = .0025) was altered in patients with IBD compared with controls. Single-nucleotide polymorphisms within TLE1 were associated with susceptibility to CD, specifically with ileal disease (rs6559629, P = 3.1 × 10⁻⁵; odds ratio, 1.45). The TLE1 risk allele is required for susceptibility to CD in carriers of NOD2 mutations. In cells, TLE1 and NOD2 co-localized around the nuclear membrane and TLE1 inhibited activation of nuclear factor-κB by NOD2.

Epistatic and biological interactions between TLE1 and NOD2 are involved in IBD pathogenesis. NOD2 might be involved in a series of pathways such as epigenetic regulation of expression (via TLE1 and HTATIP), biosynthesis of mucin (via GALNT2), apoptosis (via PPP2R5E and FIS1), and integrity of the intracellular cytoskeleton (vimentin).

Do cBCL clinical scales discriminate prepubertal children with structured interview-derived diagnosis of mania from those with ADHD?

To evaluate the discriminative ability of the Child Behavior Checklist (CBCL) to identify children with structured interview-derived diagnosis of bipolar disorder. We evaluated the convergence of CBCL scales with the diagnosis of mania in 31 children with mania, 120 children with attention-deficit hyperactivity disorder, and 77 prepubertal normal control children aged 12 years or younger. We evaluated the strength of association between each CBCL scale and structured interview-derived diagnoses with total predictive value and the odds ratio. Excellent convergence was found between the CBCL scales of Delinquent Behavior, Aggressive Behavior, Somatic Complaints, Anxious/Depressed, and Thought Problems and the diagnosis of mania.

These findings indicate that the CBCL could serve as a rapid and useful screening instrument to identify manic children in clinical settings.

Does cellular FLICE-like inhibitory protein secure intestinal epithelial cell survival and immune homeostasis by regulating caspase-8?

The intestinal epithelium generates a barrier that protects mammals from potentially harmful intestinal contents, such as pathogenic bacteria. Dysregulation of epithelial cell death has been implicated in barrier dysfunction and in the pathogenesis of intestinal inflammation. We investigated mechanisms of cell-death regulation in the intestinal epithelium of mice. Conditional knockout mice (either inducible or permanent) with deletion of cellular FLICE-inhibitory protein (cFlip) or caspase-8 in the intestinal epithelium were analyzed by histology and high-resolution endoscopy. We assessed the effects of cFlip or caspase-8 deficiency on intestinal homeostasis. Expression of cFlip in the intestinal epithelium was required for constitutive activation of caspase-8 under steady-state conditions. Intestinal expression of cFlip was required for development; disruption of the gene encoding cFlip from the intestinal epithelium (cFlip(fl/fl) VillinCre(+) mice) resulted in embryonic lethality. When cFlip was deleted from the intestinal epithelium of adult mice (cFlip(iΔIEC) mice), the animals died within a few days from severe tissue destruction, epithelial cell death, and intestinal inflammation. Death of cFlip-depleted intestinal epithelial cells was regulated extrinsically and required the presence of death receptor ligands, such as tumor necrosis factor-α and CD95 ligand, but was independent of receptor-interacting protein 3. cFlip deficiency was associated with strong up-regulation of caspase-8 and caspase-3 activity and excessive apoptosis in intestinal crypts.

cFlip is required for intestinal tissue homeostasis in mice. It controls the level of activation of caspase-8 to promote survival of intestinal epithelial cells.

Does premorbid cognitive leisure independently contribute to cognitive reserve in multiple sclerosis?

Consistent with the cognitive reserve hypothesis, higher education and vocabulary help persons with Alzheimer disease (AD) and multiple sclerosis (MS) better withstand neuropathology before developing cognitive impairment. Also, premorbid cognitive leisure (e.g., reading, hobbies) is an independent source of cognitive reserve for elders with AD, but there is no research on the contribution of leisure activity to cognition in MS. We investigated whether premorbid cognitive leisure protects patients with MS from cognitive impairment. Premorbid cognitive leisure was surveyed in 36 patients with MS. Neurologic disease severity was estimated with brain atrophy, measured as third ventricle width on high-resolution MRI. Cognitive status was measured with a composite score of processing speed and memory. Controlling for brain atrophy, premorbid cognitive leisure was positively associated with current cognitive status (r(p) = 0.49, p < 0.01), even when controlling for vocabulary (r(p) = 0.39, p < 0.05) and education (r(p) = 0.47, p < 0.01). Also, premorbid cognitive leisure was unrelated to brain atrophy (r = 0.03, p > 0.5), but a positive partial correlation between leisure and atrophy emerged when controlling for cognitive status (r(p) = 0.37, p < 0.05), which remained when also controlling for vocabulary (r(p) = 0.34, p < 0.05) and education (r(p) = 0.35, p < 0.05).

Premorbid cognitive leisure contributes to cognitive status in patients with MS independently of vocabulary and education. Also, patients with MS who engaged in more cognitive leisure were able to withstand more severe brain atrophy at a given cognitive status. Premorbid cognitive leisure is supported as an independent source of cognitive reserve in patients with MS.

Can follow-up phone calls improve patients self-monitoring of blood glucose?

To evaluate the effectiveness of follow-up phone calls in improving frequency of glucose monitoring over a three month period in two groups of patients with type 2 diabetes with the goal to lower haemoglobin A1C. Telephone intervention has been successfully used in improving adherence to diabetes self-management and other chronic disease conditions. A quality improvement study. Forty one Type 2 diabetic patients with HA1C ≥7·5% were included in the study. The patients were assigned to two groups. The first group of patients received standard diabetic care (Group 1) and the second group of patients (Group 2) received standard diabetic care plus follow-up phone calls within two weeks after a monthly clinic visit over a three month period. A haemoglobin A1C if indicated was done at the initial study visit. There were no statistically significant differences in the baseline haemoglobin A1C between the two groups or the three month haemoglobin A1C of the two groups. There were no statistically significant differences in mean haemoglobin A1C change between Group 1 and Group 2. The analysis revealed that there were no statistically significant differences between groups in the number of patients who kept logs of their blood glucose readings throughout the study.

The intervention using telephone follow-up calls did not show a statistically significant improvement in overall HA1C, but there was a clinically significant change in HA1C in the group of patients that received follow-up phone calls.

Does local allocation of lung donors result in transplanting lungs in lower priority transplant recipients?

Under the current lung allocation system, if organs are accepted for a candidate within the local donor service area (DSA), they are never offered to candidates at the broader regional level who are potentially more severely ill, even if the nonlocal candidate has a higher lung allocation score (LAS). The purpose of this study was to determine the frequency with which organs were allocated to a local lung recipient while a blood group-matched and size-matched candidate with a higher LAS existed in the same region. United Network for Organ Sharing (UNOS) provided deidentified patient-level data. The study population included all locally allocated organs for double-lung transplants (DLTs) performed in 2009 in the United States (n=580). All occurrences of an ABO blood group-matched, height-matched (±10 cm), double-lung candidate in the same region, with a higher LAS than the local candidate who actually received the organs, were calculated; these occurrences were termed events. In 2009, 3,454 events occurred when a local DLT recipient candidate received a DLT while a DLT candidate in the same region had a higher LAS. With a mean of 5.96 events per transplant, this impacted 480 (82.8%) of the 580 DLTs. Further, 555 (16.1%) of these events involved 1 (or more) of the 185 regional candidates who ultimately did not receive transplants and died while on the waiting list.

This analysis suggests that the locally based lung allocation system results in a high frequency of events whereby an organ is allocated to a lower-priority candidate while an appropriately matched higher priority candidate exists regionally.

Does the effect of telephone appointment-reminder call on outpatient absenteeism in a pulmonary function laboratory?

Absenteeism from outpatient appointments is common. Telephone appointment-reminder calls reduce outpatient-appointment absenteeism in many clinic settings. To determine if telephone appointment-reminder calls reduce outpatient absenteeism at a hospital-based pulmonary function laboratory. We conducted a retrospective review of our pulmonary function laboratory's outpatient appointment records from April to November 2004. Data were collected from consecutive outpatient appointments, including patient age, sex, whether a telephone appointment-reminder call was successfully made, and whether the patient showed up for the scheduled test. We performed 3 analyses. Differences in absenteeism between the groups was the primary outcome measure. First, appointments were separated into 2 groups: (1) appointments for which a reminder call was attempted ("called" group) and (2) appointments for which a reminder call was not attempted ("not-called" group). The appointments were then separated into 2 further groups: (1) the reminder call was successfully achieved ("contacted" group) and (2) the patient either was not called or was called but could not be reached ("not-contacted" group). Finally, the contacted group was separated into 2 further groups: (1) reminder calls that resulted in direct conversation with an appropriate person at the patient's listed telephone number, and (2) reminder message left on an answering machine. Data were collected from 515 consecutive outpatient appointments; 45 (8.7%) of these patients did not show up for testing. The absentee rate was 4.7% (n = 10) in the called group and 11.6% (n = 35) in the not-called group (p = 0.0066). In the called group, 6.5% (n = 14) could not be reached. The absentee rate was 4% (n = 8) in the contacted group and 11.7% (n = 37) in the not-contacted group (p = 0.0021). We found no difference in absenteeism between patients who received reminders via direct conversation (4.2%) and those who had a reminder message left on an answering machine (3.7%) (p > 0.05).

A policy of reminding outpatients of their appointments via telephone reduces absenteeism at a hospital-based pulmonary function laboratory. We found no difference in absenteeism between communicating the reminder via direct conversation versus via leaving a message on an answering machine.

Does modulation of single motor unit discharge using magnetic stimulation of the motor cortex in incomplete spinal cord injury?

Motor evoked potentials (MEPs) and inhibition of voluntary contraction to transcranial magnetic stimulation (TMS) of the motor cortex have longer latencies than normal in patients with incomplete spinal cord injury (iSCI) when assessed using surface EMG. This study now examines the modulation of single motor unit discharges to TMS with the aim of improving resolution of the excitatory and inhibitory responses seen previously in surface EMG recordings. A group of five patients with iSCI (motor level C4-C7) was compared with a group of five healthy control subjects. Single motor unit discharges were recorded with concentric needle electrodes from the first dorsal interosseus muscle during weak voluntary contraction (2%-5% maximum). TMS was applied with a 9 cm circular stimulating coil centred over the vertex. Modulation of single motor unit discharges was assessed using peristimulus time histograms (PSTHs). Mean (SEM) threshold (expressed as percentage of maximum stimulator output (%MSO)) for the excitatory peak (excitation) or inhibitory trough (inhibition) in the PSTHs was higher (p<0.05) in the patients (excitation = 47.1 (5.9) %MSO; inhibition = 44.3 (3.2) %MSO) than in controls (excitation=31.6 (1.2) %MSO; inhibition = 27.4 (1.0) %MSO). Mean latencies of excitation and inhibition were longer (p<0.05) in the patients (excitation=35 (1.8) ms; inhibition = 47.1 (1.8) ms) than in the controls (excitation = 21.1 (1.6) ms; inhibition = 27 (0.4) ms). Furthermore, the latency difference (inhibition-excitation) was longer (p<0.05) in the patients (10.4 (2.1) ms) than in the controls (6.2 (0.6) ms).

Increased thresholds and latencies of excitation and inhibition may reflect degraded corticospinal transmission in the spinal cord. However, the relatively greater increase in the latency of inhibition compared with excitation in the patients with iSCI may reflect a weak or absent early component of cortical inhibition. Such a change in cortical inhibition may relate to the restoration of useful motor function after iSCI.

Is coronary flow reserve impaired in patients with nonalcoholic fatty liver disease : association with liver fibrosis?

Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of cardiovascular disease. Coronary flow reserve (CFR) is widely used to examine the integrity of coronary microvascular circulation. We evaluated the prevalence of impaired CFR in patients with biopsy-proven NAFLD. We also investigated the independent clinical, biochemical, and liver histology predictors of CFR in the setting of NAFLD. Fifty-nine consecutive patients with NAFLD and 77 age- and gender-matched controls were evaluated. CFR recordings were performed by transthoracic Doppler harmonic echocardiography. CFR>or=2.0 was considered normal. CFR was significantly lower in patients with NAFLD than in controls (2.11+/-0.45 vs. 2.52+/-0.62, P<0.001). An impaired CFR (i.e. <2) was found in 25 NAFLD patients (42.4%) whereas all controls had normal CFR values (P<0.001). A stepwise linear regression analysis in NAFLD patients identified liver fibrosis scores as the only independent predictor of CFR values (beta=-0.60; t=-2.44, P=0.021).

Our findings indicate that in patients with biopsy-proven NAFLD: (a) an abnormal CFR is found in approximately 42.4% of cases, and (b) liver fibrosis scores are an independent predictor of depressed CFR.

Do symptoms of ADHD at ages 7 and 10 predict academic outcome at age 16 in the general population?

To examine the value of the Conners 10-item scale to predict academic outcomes at age 16 years in schoolchildren aged 7 and 10 years. A cohort study of N = 544 children in a municipality of Stockholm County was conducted. Using the parent and teacher version of the Conners 10-item scale, 7- and 10-year-olds were screened for ADHD symptoms and followed-up for school outcome at age 16 years. The best predictors for school outcome at age 16 years were the Conners items, "child failing to finish tasks" and "being inattentive, easily distracted," with a high specificity (90%-97%) but low sensitivity (18%-39%).

This study indicates a considerable association between certain symptoms of inattentiveness in young schoolchildren and academic underachievement at age 16 years. Screening for one to two symptoms of inattention in schoolchildren identifies 30% to 40% of participants at risk for later poor school attainment.

Does torcetrapib differentially modulate the biological activities of HDL2 and HDL3 particles in the reverse cholesterol transport pathway?

Therapeutic strategies to raise low plasma HDL-cholesterol levels, with concomitant normalization of the intravascular metabolism, physicochemical properties, and antiatherogenic function of HDL particles, are a major focus in atherosclerosis prevention. Patients displaying Type IIB hyperlipidemia (n=14) and healthy controls (n=11) were recruited. After drug washout, dyslipidemic patients first received atorvastatin (10 mg/d) for 6 weeks and subsequently torcetrapib/atorvastatin (60/10 mg/d) for the same period. Partial CETP inhibition markedly reduced supranormal CE transfer rates to normal levels from HDL3 (-58%; P<0.0001) to apoB-lipoproteins; endogenous CE transfer rates from HDL2 to apoB-lipoproteins were markedly subnormal as compared to those in control subjects (10.7+/-0.9 versus 29.3+/-4.8 microg CE/h/mL plasma, respectively). Torcetrapib enhanced the subnormal capacity of HDL2 particles from dyslipidemic patients to mediate free cholesterol efflux via both SR-BI and ABCG1 pathways (+38%; P<0.003 and +35%; P<0.03, respectively) as compared to baseline. In vitro observations and in vivo studies in mice demonstrated that CETP inhibition was associated with an enhanced selective hepatic uptake of CE from HDL particles (1.7-fold; P<0.0003).

CETP inhibition partially corrected the abnormal physicochemical and functional properties of HDL2 and HDL3 particles in type IIB hyperlipidemia. Enhanced hepatic selective uptake of HDL-CE may compensate for attenuated indirect CE transfer to apoB-containing lipoproteins via CETP attributable to torcetrapib.

Does transbronchial needle aspiration improve the diagnostic yield of bronchoscopy in sarcoidosis?

Transbronchial needle aspiration (TBNA) is a minimally invasive bronchoscopic procedure that allows sampling of hilar and mediastinal lymph nodes in close contact with the airways. We undertook this study to assess the value of TBNA in the diagnosis of sarcoidosis manifesting with intrathoracic lymphadenopathies (stages I and II), and to compare its yield with that of transbronchial lung biopsy (TBLB). The results of bronchoscopy with combined TBNA and TBLB in 32 patients with stage I or II sarcoidosis were retrospectively analyzed. Sensitivity was 65.6% for TBNA (stage I, 82.3 %; stage II, 46.6%), and 62.5% for TBLB (stage 1, 52.9%; stage II, 73.3%). The combination of the two methods was associated with the highest diagnostic yield (93.7% overall sensitivity), and allowed significantly better results over both TBNA alone (93.7% vs 65.6%; p = 0.011) and TBLB alone (93.7% vs 62.5%; p = 0.005).

The results of our study suggest that a diagnostic approach combining TBNA and TBLB is safe and effective in the setting of stage I and II sarcoidosis. It also confirmed the value of TBNA, with excellent diagnostic yields especially in stage I of the disease.

Does leptin promote epithelial-mesenchymal transition of breast cancer via the upregulation of pyruvate kinase M2?

Accumulating researches have shown that epithelial-mesenchymal transition (EMT) contributes to tumor metastasis. Leptin, a key adipokine secreted from adipocytes, shapes the tumor microenvironment, potentiates the migration of breast cancer cells and angiogenesis, and is also involved in EMT. However, the potential mechanism remains unknown. This study aims to explore the effect of leptin on EMT in breast cancer cells and the underlying mechanism. With the assessment of EMT-associated marker expression in MCF-7, SK-BR-3, and MDA-MB-468 cells, the effect of leptin on breast cancer cells was analyzed. Besides, an array of pathway inhibitors as well as RNA interference targeting pyruvate kinase M2 (PKM2) were used to clarify the underlying mechanism of leptin-mediated EMT in vitro and in vivo. The results demonstrated that leptin promoted breast cancer cells EMT, visibly activated the PI3K/AKT signaling pathway, and upregulated PKM2 expression. An antibody against the leptin receptor (anti-ObR) and the PI3K/AKT signaling pathway inhibitor LY294002 significantly abolished leptin-induced PKM2 expression and EMT-associated marker expression. SiRNA targeting PKM2 partially abolished leptin-induced migration, invasion, and EMT-associated marker expression. In vivo xenograft experiments indicated that RNA interference against PKM2 suppressed breast cancer growth and metastasis.

Our data suggest that leptin promotes EMT in breast cancer cells via the upregulation of PKM2 expression as well as activation of PI3K/AKT signaling pathway, and PKM2 might be one of the key points and potential targets for breast cancer therapy.

Is fatty liver a good indicator of subclinical atherosclerosis risk in obese children and adolescents regardless of liver enzyme elevation?

To investigate the presence of association between nonalcoholic fatty liver disease (NAFLD) and subclinical atherosclerosis using carotid intima media thickness (c-IMT) in obese children and adolescents. Additionally, we wished to investigate the relationship between fatty liver and elevated liver enzymes. A total of 157 obese patients (78 boys and 79 girls, mean age: 11.3 ± 2.6 years, age range: 6-16 years) were enrolled in the study. Aminotransferase, fasting glucose and lipid levels were determined. An oral glucose tolerance test was performed. The c-IMT was measured. Infectious and metabolic causes of elevated liver enzymes were excluded. The diagnosis of NAFLD was based on ultrasound scan. Obese patients with NAFLD had markedly increased carotid IMT (mean: 0.48 mm, 95% CI: 0.47-0.49) than those without NAFLD (mean: 0.45 mm 95% CI: 0.44-0.45, p < 0.001). The presence of NAFLD significantly increased c-IMT whether the patient had elevated liver enzyme or not (ANOVA, p < 0.001). In a multiple-regression model, only the presence of NAFLD was associated with increased c-IMT (β = 0.031, SE (β) = 0.008, p < 0.001).

Obese children and adolescents with NAFLD are at risk of early atherosclerotic changes. As liver function tests are not sufficient to identify patients with fatty liver, ultrasonographic evaluation of NAFLD might be considered in all obese children and adolescents.

Are trophoblast cells able to regulate monocyte activity to control Toxoplasma gondii infection?

Toxoplasma gondii is an intracellular parasite that causes severe disease when the infection occurs during pregnancy. Trophoblast cells constitute an important maternal-fetal barrier, with monocytes concentrating around them. Thus, interactions between trophoblasts and monocytes are important for maintaining a successful pregnancy, especially in cases of infection. This study aimed to evaluate the role of trophoblast cells (BeWo line) on monocyte (THP-1 line) activity in the presence or absence of T. gondii infection. THP-1 cells were stimulated with supernatants of BeWo cells, previously infected or not with T. gondii, and then infected with parasites. The supernatant of both cells were collected and analyzed for cytokine production and T. gondii proliferation in THP-1 cells was determined. The results showed that after infection, the pattern of cytokines secreted by THP-1 and BeWo cells was characterized as a pro-inflammatory profile. Furthermore, supernatant of BeWo cells infected or not, was able to change the cytokine profile secreted by infected THP-1 cells, and this supernatant became THP-1 cells more able to control T. gondii proliferation than those that had not been stimulated.

This effect was associated with secretion of interleukin (IL)-6 by the THP-1 cells and soluble factors secreted by BeWo cells, such as IL-6 and MIF.

Do two intravenous iron sucrose preparations have the same efficacy?

Intravenous (i.v.) iron sucrose similar (ISS) preparations are available but clinical comparisons with the originator iron sucrose (IS) are lacking. The impact of switching from IS to ISS on anaemia and iron parameters was assessed in a sequential observational study comparing two periods of 27 weeks each in 75 stable haemodialysis (HD) patients receiving i.v. iron weekly and an i.v. erythropoiesis-stimulating agent (ESA) once every 2 weeks. Patients received IS in the first period (P1) and ISS in the second period (P2). Mean haemoglobin value was 11.78 ± 0.99 g/dL during P1 and 11.48 ± 0.98 g/dL during P2 (P = 0.01). Mean serum ferritin was similar for both treatment periods (P1, 534 ± 328 μg/L; P2, 495 ± 280 μg/L, P = 0.25) but mean TSAT during P1 (49.3 ± 10.9%) was significantly higher than during P2 (24.5 ± 9.4%, P<0.0001). The mean dose of i.v. iron per patient per week was 45.58 ± 32.55 mg in P1 and 61.36 ± 30.98 mg in P2 (+34.6%), while the mean ESA dose was 0.58 ± 0.52 and 0.66 ± 0.64 μg/kg/week, respectively (+13.8%). Total mean anaemia drug costs increased in P2 by 11.9% compared to P1.

The switch from the originator IS to an ISS preparation led to destabilization of a well-controlled population of HD patients and incurred an increase in total anaemia drug costs. Prospective comparative clinical studies are required to prove that ISS are as efficacious and safe as the originator i.v. IS.

Does tumor necrosis factor-α predict response to cardiac resynchronization therapy in patients with chronic heart failure?

Pro-inflammatory cytokines contribute to the pathophysiology of heart failure (HF) and are up-regulated in affected patients. We investigated whether pro-inflammatory cytokines might predict the response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Plasma levels of tumor necrosis factor-α (TNF-α) and interleukin-6 were assessed in 91 patients before CRT. Response to CRT was defined as a decrease ≥15% in left ventricular end-systolic volume (LVESV) at 6 months. Baseline TNF-α did correlate with LVESV reduction (P=0.001) after CRT. The subject group was divided according to tertiles of TNF-α. From the lower to the upper tertile LVESV (-31±28%, -17±17%, -9±22%) and LV end-diastolic volume (-23±25%, -14±16%, -4±18%) were progressively less reduced after CRT (P<0.001). The proportion of responders to CRT was 70%, 42% and 33%, according to the lower, intermediate and upper tertile of TNF-α distribution (P=0.01). Serious cardiac events (cardiac death, HF hospitalization or urgent heart transplantation) occurred in 63% of patients in the upper tertile vs. 32% and 17% in the intermediate and lower tertiles, respectively, during a median follow-up of 47 months (P<0.001).

Circulating TNF-α predicts the degree of LV reverse remodeling after CRT and may contribute to the early identification of those patients at higher risk of events after device implantation.

Does pyrrole-imidazole polyamide targeting transforming growth factor β1 ameliorate encapsulating peritoneal sclerosis?

Encapsulating peritoneal sclerosis (EPS) is a devastating fibrotic complication in patients treated with peritoneal dialysis (PD). Transforming growth factor β1 (TGF-β1) is a pivotal factor in the induction of EPS. To develop pyrrole-imidazole (PI) polyamide, a novel gene silencer, targeted to the TGF-β1 promoter (Polyamide) for EPS, we examined the effects of Polyamide on messenger RNA (mRNA) expression of TGF-β1, vascular endothelial growth factor (VEGF), and extracellular matrix (ECM) in mesothelial cells in vitro, and on the thickness of injured peritoneum evaluated by histology and high-resolution regional elasticity mapping in rats in vivo. Polyamide significantly lowered mRNA expression of TGF-β1 and ECM in vitro. Polyamide labeled with fluorescein isothiocyanate was taken up into the injured peritoneum and was strongly localized in the nuclei of most cells. Polyamide 1 mg was injected intraperitoneally 1 or 3 times in rats receiving a daily intraperitoneal injection of chlorhexidine gluconate and ethanol (CHX) for 14 days. Polyamide significantly suppressed peritoneal thickening and the abundance of TGF-β1 and fibronectin mRNA, but did not affect expression of VEGF mRNA in the injured peritoneum. Elasticity distribution mapping showed that average elasticity was significantly lower in Polyamide-treated rats than in rats treated solely with CHX.

Polyamide suppressed the stiffness, ECM formation, and thickening of the injured peritoneum that occurs during EPS pathogenesis. These data suggest that PI polyamide targeted to the TGF-β1 promoter will be a specific and feasible therapeutic strategy for patients with EPS.

Is posterior aspect of the orbital septum reinforced by ligaments?

To investigate the ligaments reinforcing the posterior aspect of the orbital septum. Sixteen upper eyelids of eight cadavers of Asians were dissected. Ten were subjected to gross dissections to investigate the ligaments attached to the posterior aspect of the orbital septum and to investigate the relationships with the associated ligamentous structures, and six were used for histological sections to elucidate the ligament anchoring sites in the septum. The ligaments were attached to the posterior aspect of the orbital septum in both upper and lower eyelids in all cases. Some septa in the upper eyelids were supported by the lower-positioned transverse ligament in the lateral area. In all cases, part of the Lockwood ligament was attached to the posterior aspect of the orbital septum in the lower eyelids. Histologically, the ligaments were anchored to the posterior aspect of the orbital septum.

The ligaments were attached to the posterior aspect of the orbital septum. These ligaments, in cooperation with the associated ligaments, are thought to complement the fragility of the orbital septum.

Is an anal plug useful in the treatment of fecal incontinence in children with spina bifida or anal atresia?

We evaluated the efficacy and tolerance of the Conveen anal plug in children with spina bifida or anal atresia with persistent fecal incontinence necessitating diapers despite bowel management. Seven 4 to 12-year-old patients with high congenital imperforate anus and 9 who were 6 to 13 years old with spina bifida, no mental retardation and no involuntary urine loss on clean intermittent catheterization were included in the study. During a prospective, 6-week crossover descriptive study after a test period to find the most comfortable plug with a diameter of 37 or 45 mm patients and parents completed a diary with the number of soiling episodes, stool frequency, stool consistency and the number of diapers used during 3 weeks without and with the plug, respectively. They provided a final assessment of the device. Two of the 7 patients with congenital imperforate anus discontinued use because of pain and discomfort, 1 had a decrease in soiling episodes and 4 achieved full continence and needed no diapers while using 2 plugs daily (range 1 to 4). All patients preferred the smaller plug. Two of the 9 patients with spina bifida always lost the plug within 1 hour after introduction, 5 had a decrease in soiling episodes but continued to need diapers and 2 achieved full continence using 2 plugs daily (range 1 to 4). All patients preferred the larger plug.

The Conveen anal plug is an adjuvant treatment option for fecal incontinence in children with congenital imperforate anus or spina bifida, enabling a minority to stop using diapers. The Conveen anal plug is not a universal solution for fecal incontinence problems in these patients.

Are circulating leptin levels associated with cardiovascular morbidity and mortality in women with diabetes : a prospective cohort study?

Leptin, an adipocyte-secreted hormone, plays an important role in regulating neuroendocrine and immune function as well as insulin resistance and metabolism. Our objective was to examine the relationship between leptin levels and cardiovascular morbidity and overall mortality in women with type 2 diabetes. This prospective cohort study included 1,194 women with a confirmed diagnosis of type 2 diabetes, who provided a blood sample at baseline in 1989-1990. Participants were followed for 12 years for the development of health outcomes including cardiovascular disease (CVD) events as well as total mortality. There were 218 new CVD events and 228 deaths from all causes. Cox proportional hazards analysis was used to estimate the relative risks (RRs) for each quintile level of leptin compared with the lowest quintile. Leptin levels were positively associated with several CVD risk factors including BMI and inflammatory markers, but were not independently associated with the incidence of CVD or total mortality in women with diabetes. The multivariate RRs (95% CIs) for CVD across the quintiles of leptin were 0.96 (0.61-1.53), 0.99 (0.61-1.61), 1.04 (0.63-1.71), 1.02 (0.59-1.75) (p for trend = 0.83).

Although circulating leptin levels are associated with obesity and inflammatory markers, they are not significantly related to the risk of CVD or mortality in women with diabetes.

Does the necrotrophic effector protein SnTox3 re-programs metabolism and elicit a strong defence response in susceptible wheat leaves?

The fungus Stagonospora nodorum is a necrotrophic pathogen of wheat. It causes disease by secreting proteinaceous effectors which interact with proteins encoded by dominant susceptibility genes in the host. The outcome of these interactions results in necrosis, allowing the fungus to thrive on dead plant material. The mechanisms of these effectors though are poorly understood. In this study, we undertake a comprehensive transcriptomics, proteomic and metabolomic approach to understand how a susceptible wheat cultivar responds to exposure to the Stagonospora nodorum effector protein SnTox3. Microarray and proteomic studies revealed that SnTox3 strongly induced responses consistent with those previously associated with classical host defence pathways including the expression of pathogenicity-related proteins and the induction of cell death. Collapse of the photosynthetic machinery was also apparent at the transcriptional and translational level. SnTox3-infiltrated wheat leaves also showed a strong induction of enzymes involved in primary metabolism consistent with increases in hexoses, amino acids and organic acids as determined by primary metabolite profiling. Methionine and homocysteine metabolism was strongly induced upon exposure to SnTox3. Pathogenicity in the presence of homocysteine was inhibited confirming that the compound has a role in plant defence. Consistent with the strong defence responses observed, secondary metabolite profiling revealed the induction of several compounds associated with plant defence, including the phenylpropanoids chlorogenic acid and feruloylquinic acid, and the cyanogenic glucoside dhurrin. Serotonin did not accumulate subsequent to SnTox3 infiltration.

These data support the theory that the SnTox3 effector protein elicits a host cell death response to facilitate the pathogen's necrotrophic infection cycle. Our data also demonstrate that the mechanism of SnTox3 appears distinct from the previously characterised Stagonospora nodorum effector SnToxA. Collectively, this comprehensive analysis has advanced our understanding of necrotrophic effector biology and highlighted the complexity of effector-triggered susceptibility.

Does carpal tunnel syndrome impair thumb opposition and circumduction motion?

Carpal tunnel syndrome is associated with sensory and motor impairments resulting from the compressed and malfunctioning median nerve. The thumb is critical to hand function, yet the pathokinematics of the thumb associated with carpal tunnel syndrome are not well understood. The purpose of this study was to evaluate thumb motion abnormalities associated with carpal tunnel syndrome. We hypothesized that the ranges of translational and angular motion of the thumb would be reduced as a result of carpal tunnel syndrome. Eleven patients with carpal tunnel syndrome and 11 healthy control subjects voluntarily participated in this study. Translational and angular kinematics of the thumb were obtained using marker-based video motion analysis during thumb opposition and circumduction movements. Motion deficits were observed for patients with carpal tunnel syndrome even though maximum pinch strength was similar. The path length, normalized by palm width of the thumb tip for the patients with carpal tunnel syndrome was less than for control participants (opposition: 2.2 palm width [95% CI, 1.8-2.6 palm width] versus 3.1 palm width [95% CI, 2.8-3.4 palm width], p < 0.001; circumduction: 2.2 palm width [95% CI, 1.9-2.5 palm width] versus 2.9 palm width [95% CI, 2.7-3.2 palm width], p < 0.001). Specifically, patients with carpal tunnel syndrome had a deficit of 0.3 palm width (95% CI, 0.04-0.52 palm width; p = 0.022) in the maximum position of their thumb tip ulnarly across the palm during opposition relative to control participants. The angular ROM also was reduced for the patients with carpal tunnel syndrome compared with the control participants in extension/flexion for the metacarpophalangeal (opposition: 34° versus 58°, p = .004; circumduction: 33° versus 58°, p < 0.001) and interphalangeal (opposition: 37° versus 62°, p = .028; circumduction: 41° versus 63°, p = .025) joints.

Carpal tunnel syndrome disrupts kinematics of the thumb during opposition and circumduction despite normal pinch strength.

Student decisions about lecture attendance: do electronic course materials matter?

This study explored whether first-year medical students make deliberate decisions about attending nonrequired lectures. If so, it sought to identify factors that influence these decisions, specifically addressing the potential impact of electronic materials. Medical students who completed first-year studies between 2004 and 2006 responded to an open-ended survey question about their own lecture-attendance decisions. Responses were coded to capture major themes. Students' ratings of the electronic materials were also examined. Most respondents made deliberate attendance decisions. Decisions were influenced by previous experiences with the lecturer, predictions of what would occur during the session itself, personal learning preferences, and learning needs at that particular time, with the overriding goal of maximizing learning. Access to electronic materials did not influence students' choices.

Fears that the increasing availability of technology-enhanced educational materials has a negative impact on lecture attendance seem unfounded.

Is serum uric acid level associated with all-cause mortality in high-functioning older persons: MacArthur studies of successful aging?

To explore the effect of serum uric acid level on subsequent all-cause mortality in high-functioning community-dwelling older persons. It is controversial whether high serum uric acid level is a true independent risk factor for cardiovascular and total mortality or the association is due to other confounding variables. Furthermore, it remains unclear whether the predictive value of uric acid level on mortality observed in younger cohorts can be extended to older people. Prospective cohort study. A sample of community-dwelling older people. A cohort of 870 participants from the MacArthur Studies of Successful Aging. Baseline information was obtained for serum uric acid level, C-reactive protein (CRP), interleukin-6 (IL-6), prevalent medical conditions, and health behaviors. Crude and multivariate logistic regression analyses were used to examine the association between serum uric acid levels and 7-year all-cause mortality, while adjusting for potential confounders. In men, the multiply adjusted risk ratios for 7-year total mortality were 1.07 (95% CI=0.61-1.88) for the mid tertile of uric acid level and 1.24 (95% CI=0.70-2.20) for the top tertile. In women, the multiply adjusted risk ratios were 0.58 (95% CI=0.29-1.18) and 0.47 (95% CI=0.22-0.99), for the mid and top tertiles respectively. CRP and IL-6 were important confounders in the relationship between serum uric acid and overall mortality.

High serum uric acid level is not independently associated with increased total mortality in high-functioning older men and women. When evaluating the association between serum uric acid and mortality, the potential confounding effect of underlying inflammation and other risk factors must be considered.

Is c5a inhibitory peptide combined with gabexate mesilate a clinically available candidate for preventing the instant blood-mediated inflammatory reaction?

The instant blood-mediated inflammatory reaction, characterized by activation of both the coagulation and complement cascades, is a serious obstacle to successful islet engraftment. No attractive protocol is clinically available as yet. The objective of the present study was to examine whether complementary peptide against an active region of C5a in combination with a clinically available anticoagulant could provide an effective protocol for suppression of the instant blood-mediated inflammatory reaction. Three islet equivalents per gram of syngeneic rat grafts were transplanted intraportally into 6 pairs of rats with streptozotocin-induced diabetes. Islets from the same donor were transplanted into each pair. In each pair, one rat was treated with C5a inhibitory peptide in addition to continuous intravenous infusion of gabexate mesilate and the other rat, injected with equivalent amount of saline solution, served as the control. In addition, 6 rats that received transplants from irrelevant donors were treated with the same dose of gabexate mesilate. We evaluated the cure rate, time to normoglycemia, liver insulin concentration in recipients, and results of in vivo glucose tolerance tests. The cure rate was remarkably improved and the time to normoglycemia in cured animals was significantly shortened with C5a inhibitor plus gabexate treatment. In six rats that received only gabexate mesilate, normoglycemia was not restored during the study.

These data suggest that C5a inhibitory peptide combined with gabexate mesilate could be an attractive drug candidate without adverse effects to control the detrimental innate immune responses induced in clinical islet transplantation.

Does endothelium agree with the concept of idiopathic hepatic vessel thrombosis?

Fibrinogenesis was studied by measuring the activated factor VII, total and free levels of tissue factor pathway inhibitor (TFPI). The fibrinolysis step was investigated by determining the global fibrinolytic capacity. The endothelial function was assessed by measuring the levels of soluble adhesion molecules, namely soluble intercellular adhesion molecule 1 (sICAM-1), soluble vascular cell adhesion molecule 1 (sVCAM-1) and soluble E-selectin molecule. The exclusion criteria from "idiopathic" patient group were abdominal surgery, pregnancy, use of oral contraceptives, anti-phospholipid syndrome, Behçet's disease, cancer, myeloproliferative diseases. The congenital factors like mutations of factor-V Leiden and prothrombin, deficiencies of proteins C and S, antithrombin, hyperhomocysteinemia and hyperfibrinogenemia were ruled out. The total number of patients was reduced from 96 to 9 (7 with portal vein thrombosis, 2 Budd Chiari syndrome) by exclusion criteria. The levels of adhesion molecules sICAM-1, sVCAM-1, free TFPI levels and global fibrinolytic capacity were significantly different (P<0.05) in the patient group indicating an endothelial dysfunction and a lower fibrinolytic activity.

These results show that this patient group should be tested by means of endothelial dysfunction and managed differently.

Does β-Hydroxy-β-methylbutyrate modify human peripheral blood mononuclear cell proliferation and cytokine production in vitro?

The main objective was to investigate the potential immunomodulatory effects of β-hydroxy-β-methylbutyrate (HMB) in human cells. Peripheral blood mononuclear cells were isolated from the blood of eight volunteers and assayed for proliferation, cell cycle progression, surface expression of CD25, intracellular expression of pERK1/2, and cytokine production after in vitro exposure to a range of HMB concentrations (0.1 to 10 mM). Above 1 mM, HMB decreased the extent of proliferation normally observed after stimulation by concanavalin A. The decrease was evident at 10 mM HMB, when the proliferation index was 50% reduced when compared with the absence of HMB. Cell cycle analysis demonstrated an increase in the proportion of cells at the G0-G1 phase at 10 mM HMB. CD25 and pERK1/2 expression were not related to the observed effect on proliferation. HMB affected the concentrations of all five cytokines measured following stimulation. Tumor necrosis factor-α concentration in the culture medium was reduced by ~35% at all HMB concentrations. Th1/Th2 cytokine production was modified toward a Th2 profile when HMB was at 1 or 10 mM. Thus, HMB at 10 mM impairs lymphocyte proliferation and progression through the cell cycle. The lowest concentration used here (0.1 mM) exerted some actions on cytokine production, including decreasing TNF-α production, but not on proliferation and cell cycle progression.

HMB may be a useful agent to consider for modulation of immune function in specific situations.

Is parenting associated with teenagers' early sexual risk-taking, autonomy and relationship with sexual partners?

Extensive research has explored the relationship between parenting and teenagers' sexual risk-taking. Whether parenting is associated with wider aspects of teenagers' capacity to form satisfying sexual relationships is unknown. Self-reported data were collected in 2007 from 1,854 students, whose average age was 15.5 years, in central Scotland. Multivariate analyses examined associations between parenting processes and sexual outcomes (delayed first intercourse, condom use and several measures reflecting the context or anticipated context of first sex). Parental supportiveness was positively associated with all outcomes (betas, 0.1-0.4), and parental values restricting intercourse were positively associated with all outcomes except condom use (0.1-0.5). Parental monitoring was associated only with delayed intercourse (0.2) and condom use (0.2); parental rules about TV content were associated with delayed intercourse (0.7) and expecting sex in a relationship, rather than casually (0.8). Frequency of parental communication about sex and parental values endorsing contraceptive use were negatively associated with teenagers' delayed intercourse (-0.5 and -0.3, respectively), and parents' contraceptive values were negatively associated with teenagers' expecting sex in a relationship (-0.5). Associations were partly mediated by teenagers' attitudes, including value placed on having sex in a relationship.

Parents may develop teenagers' capacity for positive and safe early sex by promoting skills and values that build autonomy and encourage sex only within a relationship. Interventions should promote supportive parenting and transmission of values, avoid mixed messages about abstinence and contraception, and acknowledge that teenagers may learn more indirectly than directly from parents about sex.

Do common gamma chain-signaling cytokines promote proliferation of T-cell acute lymphoblastic leukemia?

The identification of signals critical for the pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) should contribute to the development of novel, more effective therapeutic strategies. Common gamma-chain signaling cytokines (gammac-cytokines) - interleukins 2, 4, 7, 9 and 15 - differentially regulate T-cell development, survival, proliferation and differentiation. Although studies exist on some individual cytokines, no comprehensive analysis of the effects of the Zc-cytokine family on malignant T cells has been reported. Here, we examined the effect of Zc-cytokines on T-ALL proliferation. Primary leukemic cells were collected at diagnosis from the blood or bone marrow of children with T-ALL. The cells were immunophenotyped and classified according to maturation stage. Proliferative responses to gammac-cytokines were assessed by 3H-thymidine incorporation. All gammac-cytokines promoted proliferation of primary T-ALL cells. Interleukin (IL)-7 was the cytokine that most frequently induced leukemic cell proliferation and promoted the most robust responses. IL-4 preferentially stimulated proliferation of samples with a more mature immunophenotype, whereas CD1a-positive cortical T-ALL cells were less responsive to IL-9. Finally, combinations of two Zc-cytokines showed synergistic or additive proliferative effects.

This study indicates that all the gammac-cytokines tested can stimulate proliferation of leukemic T cells and suggests that synergistic effects may occur in vivo. We present the first demonstration that IL-9 and IL-15 can provide a proliferative signal to T-ALL cells. Importantly, our results support the hypothesis that IL-7 may function as a critical regulator of T-ALL and that its activity may be potentiated by other Zc-cytokines.

Do profilometric and standard error of the mean analysis of rough implant surfaces treated with different instrumentations?

This study evaluated, in vitro, the effects of different instrumentations used in the treatment of peri-implantitis on implant surfaces coated with hydroxyapatite or titanium plasma spray (TPS). There were 14 cylindrical rough implants used, including 7 hydroxyapatite and 7 TPS coated. Split in 2 parts for a total of 24 experimental surfaces, implants were treated with a stainless-steel curette, plastic curette, ultrasonic scaler tip, and air-powder-water spray. There was 1 hydroxyapatite and 1 TPS implant used as controls. Profilometry and scanning electron microscopy were used to examine instrumented surfaces for variations in surface topography. All experimental procedures determined changes on tested rough implant surfaces. Such alterations were related to the implant coating material, and the procedure consisting in coating removal and/or leveling of surface roughness.

Although a plastic curette and air-powder-water spray induced less implant surface alterations, these instrumentations left deposits on the surface that may affect, in vivo, the tissue healing process.

Does a non-smooth tumor margin on preoperative imaging predict microvascular invasion of hepatocellular carcinoma?

Microvascular invasion (mVI) is known to be a risk factor of hepatocellular carcinoma (HCC) recurrence. Several factors such as the tumor grade, tumor size, tumor margin status on imaging studies, fluorine-18 fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) results, and tumor markers have been proposed to predict mVI of HCC. However, the values of these factors have not yet been validated. Among the patients evaluated using enhanced CT/MRI, (18)F-FDG-PET, and tumor markers prior to hepatectomy from 2007 to 2012, 79 HCC patients without apparent macrovascular invasion in preoperative imaging were enrolled in this study. The image tumor margin status (smooth/non-smooth), (18)F-FDG-PET, and tumor markers, which were previously described as predictors for mVI, were evaluated. Fifteen patients had mVI (mVI+ group) and 64 patients had no evidence of mVI (mVI- group) on pathological examinations. A univariate analysis showed that the mVI+ group had a higher SUV and TNR (5.2 vs 3.8, p = 0.02 and 1.8 vs 1.3, p = 0.02, respectively) and a higher portion of non-smooth tumor margin (87 vs 27 %, p = 0.0001). There was no significant difference in the tumor markers. A multivariate analysis showed that non-smooth tumor margin alone could independently predict mVI (odds ratio 18.3, 95 % CI 3.27-102.6, p = 0.0009).

A non-smooth tumor margin on preoperative imaging predicts microvascular invasion of HCC.

Impact of the Surviving Sepsis Campaign on the recognition and management of severe sepsis in the emergency department: are we failing?

Severe sepsis/septic shock (SS/SS) has a high mortality. The past decade lays witness to a concerted international effort to tackle this problem through the Surviving Sepsis Campaign (SSC). However, bundle delivery remains problematic. In 2009, the College of Emergency Medicine (CEM) set out guidelines for the management of SS/SS. These set the standards for this audit. To assess the recognition and management of patients presenting with SS/SS across three emergency departments (EDs) within the West Midlands. Data were collected retrospectively over a 3-month period. Patients in the ED with a diagnostic code of, or presenting complaint suggestive of, sepsis, had their scanned notes assessed for evidence of SS/SS. Compliance with the CEM guidelines, and evidence of referral to the intensive care staff was evaluated. 255 patients with SS/SS were identified. Of these, 17% (44/255) were documented as septic by ED staff. The CEM standard of care was received in 41% of those with a documented diagnosis of severe sepsis in the ED, and 23% of patients with SS/SS overall. 89% of patients received the 'treatment' aspects of care: oxygen, IV antibiotics and IV fluids. Twelve patients with a raised lactate level and normal blood pressure (cryptic shock) failed to receive fluid resuscitation. 71% of patients with SS/SS had no documented discussion or consideration of referral to the intensive care unit.

The SSC has had some impact; however, there is still a long way to go. It is assumed that the picture is similar in EDs across the UK and recommendations are made based on these local findings.

Does initial Surgical Treatment of Humeral Shaft Fracture predict Difficulty Healing when Humeral Shaft Nonunion Occurs?

Although most humeral nonunions are successfully treated with a single procedure, some humeral nonunions are more difficult to heal and require multiple procedures. Current literature does not provide evidence describing how the prognosis for surgical repair in patients who develop humeral diaphyseal nonunions may be affected by initial operative versus nonoperative treatment. The purpose of this study was to assess whether operative versus nonoperative treatment of acute humeral shaft fractures impacts outcome of subsequent repairs of humeral nonunions (NU) including the need for additional surgery and a comparison of pain relief (Visual Analogue Scale for pain) and functional outcome (Short Musculoskeletal Functional Assessment). Thirty-four patients with humeral shaft nonunion were evaluated of which 15 patients had been treated operatively (OF), and 19 patients had been treated nonoperatively (NO) for their initial humerus shaft fracture. All patients underwent plating with autogenous bone graft or allograft ± bone morphogenic protein (BMP) 2 or 7 as their final NU repair surgery prior to healing. We compared functional outcome and pain for both cohorts and determined risk factors for requiring more than 1 nonunion repair surgery. The mean time of final follow-up was 14.7 ± 10.4 months. Thirty-three of 34 NUs (97.1%) healed. Patients who underwent OF of their original fracture were more likely to require more than 1 NU repair surgery (66.7 vs. 0%, p < 0.01). Of the 15 patients who underwent initial OF, 33.0% required 1 NU surgery, 33.0% required 2 NU surgeries, and 33.0% required 3 NU surgeries. Patients who underwent initial OF were more likely to require >6 months to achieve union (40.0 vs. 10.5%, p = 0.04). At final follow-up, there was no difference in functional outcome or pain scores. Initial OF was the only independent predictor of needing more than 1 NU repair surgery (OR 70.1 CI 2.8-1762.3) to achieve healing.

Humeral shaft nonunions following initial operative fixation of the index fracture is more resistant to achieving union when compared to nonunions forming after initial nonoperative treatment. When final healing is achieved, there is no difference in function or pain.