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### Question: Is self-reported obstructive sleep apnea associated with nonresponse to antidepressant pharmacotherapy in late-life depression? ### Context: Obstructive sleep apnea (OSA) is frequently comorbid with late-life depression. The purpose of this project was to determine, using a sample of older adults with major depressive disorder, whether patient-reported diagnosis of OSA was associated with rate of response to venlafaxine.Participants from this multisite study were adults ≥60 years old (n = 468) with major depressive disorder and a Montgomery Asberg Depression Rating Scale (MADRS) score of ≥15. Depression response was the outcome variable, defined as a MADRS score of ≤10 for two consecutive assessments at the end of 12 weeks of open-label treatment with venlafaxine 300 mg/day. To assess OSA, participants were asked if they had been diagnosed with OSA using polysomnography.Eighty participants (17.1%) reported a diagnosis of OSA prior to baseline. Participants with OSA were more likely to be male, report greater impairment on measures of health, experience a longer duration of the index episode, and receive an adequate antidepressant trial prior to entering the study. During the 12 weeks of treatment, 40.8% responded to treatment with venlafaxine (43.6%, n = 169/388 of the no OSA group, and 27.5%, n = 22/80 of the OSA group). Participants without OSA were 1.79 times more likely to respond to treatment (HR: 1.79 [95%CI: 1.13-2.86], P < .05) compared to those with OSA. ### Long_Answer: OSA may impair response to antidepressant pharmacotherapy in depressed older adults. Future studies of antidepressant response rates among depressed older adults with OSA should both prospectively diagnose OSA and monitor adherence to treatments such as continuous positive airway pressure. ### Final_Prediction: yes

### Question: Is inflammatory bowel disease associated with an increased risk of lymphoma? ### Context: Previous studies of the risk of lymphoma in inflammatory bowel disease patients have provided conflicting results. This study examines the risk of Hodgkin's and non-Hodgkin's lymphoma among patients with inflammatory bowel disease.The authors performed a retrospective cohort study using the General Practice Research Database. Inflammatory bowel disease patients were matched to randomly selected controls on age, sex, and primary care practice. Lymphoma rates were also compared with published age- and sex-specific rates.The study included 6605 patients with Crohn's disease, 10,391 with ulcerative colitis, and 60,506 controls followed for an average of 3.7, 3.9, and 4.4 years, respectively. The incidence of lymphoma was not increased in patients with inflammatory bowel disease (relative risk = 1.20; 95% CI, 0.67-2.06). In subgroup analyses, an increased risk was not observed among patients with Crohn's disease (relative risk = 1.39; 95% CI, 0.50-3.40) or ulcerative colitis (relative risk = 1.11; 95% CI, 0.51-2.19). Compared with inflammatory bowel disease patients not treated with azathioprine or 6-MP, the relative risk of lymphoma among the 1465 inflammatory bowel disease patients treated with these medications (average, 106 mg/day for 2.0 years) was 1.27 (95% CI 0.03-8.20). ### Long_Answer: Patients with inflammatory bowel disease do not have an increased risk of lymphoma as compared with the general population. Although we cannot completely rule out a modest increased risk of lymphoma with azathioprine or 6-MP therapy, an increased risk was not observed in this cohort. ### Final_Prediction: no

### Question: Is phenoxybenzamine more effective and less harmful than papaverine in the prevention of radial artery vasospasm? ### Context: There is an increasing use of arterial conduits for coronary artery bypass grafting, and the radial artery is commonly used as the third graft. The major drawback of the radial artery is its proclivity to spasm. Both papaverine and phenoxybenzamine have been recommended as topical vasodilators in clinical practice. We compared the efficacy of both drugs to prevent radial artery spasm and their ability to preserve endothelial function.The ability of both drugs to prevent alpha-adrenoreceptor mediated constriction was tested in vitro in an organ bath in radial artery segments obtained from 20 patients. Vessel viability was determined by potassium (K(+)) constriction, and endothelial function was assessed by observing endothelium-dependent relaxation by a synthetic analogue of acetylcholine, carbachol.Papaverine consistently abolished and prevented spasm for up to a maximum of 30 min in all segments. In contrast, phenoxybenzamine consistently abolished and prevented radial artery spasm in all segments for at least 6 h. Whereas papaverine damaged the endothelium of 70% of vessels, there was no evidence of endothelial damage in any arterial segments after exposure to phenoxybenzamine. ### Long_Answer: Phenoxybenzamine more effectively prevents alpha-adrenoreceptor mediated spasm of the human radial artery than papaverine. It is also less harmful to the endothelium. ### Final_Prediction: yes

### Question: Definitive chemoradiation for non-small-cell lung cancer: could a consensus be reached? ### Context: There is currently no consensus as to which chemotherapy to combine with thoracic radiotherapy (TRT) in the setting of definitive chemoradiation for non-small-cell lung cancer (NSCLC). We aimed to retrospectively evaluate the efficacy and report outcome measures of cisplatin/etoposide with conventionally fractionated TRT over a 9-year period.Cisplatin 50 mg/m² on days 1, 8, 29, and 36 and etoposide 50 mg/m² on days 1-5 and 29-33 with conventionally fractionated conformal radiation therapy starting on day 1 was given to 201 eligible patients. Patient records were reviewed for overall survival (OS) and progression-free survival (PFS).The 2-year OS and PFS were 53% and 47%, respectively, while the 3-year OS and PFS were 18% and 17%, respectively. No grade 4 or treatment-related deaths were recorded, and grade 3 hematologic toxicity occurred in only 22 patients (11%) in the form of granulocytopenia and thrombocytopenia. Multivariable analysis showed clinical stage and Eastern Cooperative Oncology Group performance status to statistically significantly affect PFS and OS. ### Long_Answer: Cisplatin and etoposide in these doses with conventionally fractionated TRT is a well-tolerated, effective treatment schedule in the definitive treatment of unresectable or inoperable NSCLC. ### Final_Prediction: nan

### Question: Is lower white matter microstructure in the superior longitudinal fasciculus associated with increased response time variability in adults with attention-deficit/ hyperactivity disorder? ### Context: Response time variability (RTV) is consistently increased in patients with attention-deficit/hyperactivity disorder (ADHD). A right-hemispheric frontoparietal attention network model has been implicated in these patients. The 3 main connecting fibre tracts in this network, the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF) and the cingulum bundle (CB), show microstructural abnormalities in patients with ADHD. We hypothesized that the microstructural integrity of the 3 white matter tracts of this network are associated with ADHD and RTV.We examined RTV in adults with ADHD by modelling the reaction time distribution as an exponentially modified Gaussian (ex-Gaussian) function with the parameters μ, σ and τ, the latter of which has been attributed to lapses of attention. We assessed adults with ADHD and healthy controls using a sustained attention task. Diffusion tensor imaging-derived fractional anisotropy (FA) values were determined to quantify bilateral microstructural integrity of the tracts of interest.We included 100 adults with ADHD and 96 controls in our study. Increased τ was associated with ADHD diagnosis and was linked to symptoms of inattention. An inverse correlation of τ with mean FA was seen in the right SLF of patients with ADHD, but no direct association between the mean FA of the 6 regions of interest with ADHD could be observed. ### Long_Answer: Regions of interest were defined a priori based on the attentional network model for ADHD and thus we might have missed effects in other networks. ### Final_Prediction: yes

### Question: Are cerebral microbleeds a risk factor for warfarin-related intracerebral hemorrhage? ### Context: Cerebral microbleeds are known to be indicative of bleeding-prone microangiopathy and may predict incident intracerebral hemorrhage (ICH). In this study, we investigated whether microbleeds are associated with the incidence of warfarin-related ICH.Twenty-four patients with ICH while on outpatient treatment with warfarin were selected from a consecutive cohort. Control, warfarin-using subjects with no history of ICH were randomly selected during the same time period (n = 48). We compared demographic factors, vascular risk factors, laboratory findings, and radiologic findings including microbleeds between the groups.There were more cases of patients with microbleeds in the ICH than control group (79.2% vs 22.9%: p < 0.001), and the number of microbleeds was much higher for the ICH group (9.0 +/- 26.8 vs 0.5 +/- 1.03: p < 0.001). Moreover, the number of microbleeds was significantly correlated with the presence of warfarin-related ICH (r = 0.299; p < 0.001). Conditional logistic regression analysis showed that increased prothrombin time and the presence of microbleeds were independently related to the incidence of warfarin-related ICH (microbleeds: adjusted OR, 83.12). ### Long_Answer: This study suggests that underlying microbleeds are independently associated with an incidence of warfarin-related intracerebral hemorrhage. Future research should focus on elucidating the risks and benefits of warfarin medication in patients with microbleeds. ### Final_Prediction: yes

### Question: The evolution of faculty development in Canada since the 1980s: coming of age or time for a change? ### Context: The roles and responsibilities of faculty members at Canadian medical schools are changing significantly as a consequence of influences such as the competency dictates outlined in the CanMEDS roles. One result of the changes is an increased need for faculty development to assist faculty members in carrying out their new and expanded roles.The changing climate in medical schools, and the enhanced performance expectations of academic faculty, led us to conduct a survey of current faculty development practices in Canadian medical schools to determine what is being done to address the new and expanded expectations of faculty members. We used an on-line survey instrument based on surveys of faculty development conducted in 1987 and 1997.We received responses from faculty development directors at all 17 Canadian medical schools. Among the principal findings are a continued emphasis on faculty members' teaching roles, increased funding of faculty development activities at most schools, and a broadened emphasis on faculty roles other than teaching. Among these are research and scholarship, and management and administrative roles. The survey revealed a mismatch between what faculty development directors consider to be effective development practices and which practices are actually used in their schools. Another notable finding is the absence of credible faculty development impact studies. ### Long_Answer: The 2007 survey of faculty development practices in Canadian medical schools indicates that teaching is still the number one priority for faculty members and the main focus of faculty development programs. There are notable efforts to help faculty members deal with their newly identified roles including those outlined in the CanMEDS framework. In looking forward, Canadian faculty development directors should continue their efforts to devise credible program evaluation methods. Furthermore, they should expand their thinking beyond Canada's borders. It is time to aggressively explore and understand the approaches and experiences which have proven successful internationally in the United States and Europe. ### Final_Prediction: nan

### Question: Do angiotensin converting enzyme inhibitors attenuate ischemic brain metabolism in hypertensive rats? ### Context: Angiotensin converting enzyme (ACE) inhibitors are expected to modulate neuronal activities. The present study was designed to examine the beneficial effects of ACE inhibitors on microcirculation and metabolism in the ischemic brain.Cerebral ischemia was developed for 60 minutes in spontaneously hypertensive rats (SHR, n = 35) by bilateral carotid artery occlusion. ACE inhibitor (0.1 or 10 mg/kg SQ 29,852 or captopril) were intravenously injected 15 minutes before cerebral ischemia. Cerebral blood flow to the parietal cortex was measured with the H2 clearance technique. Lactate, pyruvate, and ATP in the brain were estimated by the enzymatic method.Before cerebral ischemia, high doses of both SQ 29,852 and captopril significantly decreased mean arterial pressure by 15 to 25 mm Hg and reduced cerebral vascular resistance by 13% to 17% of the resting values. Cerebral blood flow and arterial pressure during ischemia were not altered by these ACE inhibitors. After 60 minutes of cerebral ischemia, tissue lactate in vehicle-treated SHR increased 6.6-fold and ATP decreased to 65% of the control values. Administration of SQ 29,852 or captopril significantly reduced the lactate levels to 1.6- to 3.1-fold and well preserved the ATP levels to 82% to 93% of the control. ### Long_Answer: These results suggest that inhibition of ACE activities may be protective for cerebral metabolism against ischemic insult. ### Final_Prediction: yes

### Question: Is posttransplant nephrocalcinosis associated with poor renal allograft function : a single-center experience? ### Context: Nephrocalcinosis, characterized by intratubular and/or parenchymal deposition of calcium phosphate and calcium oxalate crystals, is frequently seen in renal allograft biopsies; however, the clinical consequence of this histologic finding remains unknown. Kidney transplant recipients with good allograft function usually demonstrate improvement in biochemical parameters; however, persistent hyperparathyroidism remains prevalent in this population of patients. We identified renal allografts with nephrocalcinosis and evaluated the effects on renal allograft function and survival.We conducted a single-center, retrospective review of kidney allograft biopsies performed at our center from December 1, 2006 to November 30, 2012. Biopsies with nephrocalcinosis as the primary diagnosis were included in the final analysis. Biochemical parameters at the time of biopsy included serum creatinine, phosphate, calcium, intact parathyroid hormone (iPTH), 25-hydroxy vitamin D, and albumin. Serum creatinine was measured at 1, 3, 6, and 12 months after nephrocalcinosis was diagnosed. The use of calcimimetics, vitamin D analogs, active vitamin D, and bisphosphonates was also reviewed.We identified 12 patients with nephrocalcinosis as the primary diagnosis on renal biopsy. The average age of these patients was 52.2 ± 11.9 years, and the average time since transplantation was 2.3 ± 2.7 years. The baseline serum creatinine was 1.37 ± 0.4 mg/dL before the onset of acute kidney injury (AKI). Mean iPTH and 25-hydroxy vitamin D at the time of AKI were 495.66 ± 358.9 pg/mL and 19.9 ± 13.3 ng/mL, respectively. Renal function deteriorated in all patients, and mean serum creatinine at 12-month follow up was 2.37 ± 1.3 mg/dL (P=0.028). One patient progressed to end-stage renal disease at the end of the study period. ### Long_Answer: The histologic finding of nephrocalcinosis is associated with poor renal allograft function. Metabolic abnormalities including hyperparathyroidism persist in renal allograft recipients despite normal allograft function and may be associated with the development of nephrocalcinosis in renal transplant recipients. ### Final_Prediction: yes

### Question: Does epidural sufentanil provide better analgesia from 24 h after surgery compared with epidural fentanyl in children? ### Context: Studies comparing epidural fentanyl and sufentanil in adults reported a similar analgesic effect with variable side effects. We hypothesized that epidural fentanyl and sufentanil will have a similar analgesic effect in children undergoing urological surgery.Sixty-four children undergoing urological surgery were randomized into two groups: fentanyl in ropivacaine (fentanyl group, n=32) and sufentanil in ropivacaine (sufentanil group, n=32). After anaesthesia, an epidural catheter was inserted at the L2-3, L3-4 or L4-5 interspace. For post-operative pain relief, a solution consisting of fentanyl 0.1 mcg/kg/ml or sufentanil 0.015 mcg/kg/ml in 1.5 mg/ml ropivacaine was infused at a rate of 2 ml/h. To assess post-operative pain, the faces pain scale and the face, legs, activity, cry, consolability score were recorded at 1, 6, 24, 48 and 72 h after surgery. The incidence of adverse effects such as hypoxia, sedation, pruritus, nausea and/or vomiting was also evaluated.Pain scores demonstrated no significant difference between the groups. The need for rescue analgesia during 24-72 h was higher in the fentanyl group than in the sufentanil group (6/32 vs. 0/32, P=0.012). The incidence of pruritus was higher in the sufentanil group compared with that in the fentanyl group (5/32 vs. 0/32). ### Long_Answer: Epidural sufentanil provides better analgesia from 24 h after surgery compared with epidural fentanyl in infants and children undergoing urological surgery. The incidence of pruritus in the sufentanil group was higher than that in the fentanyl group. ### Final_Prediction: yes

### Question: Do Patients With Chronic Low Back Pain Benefit From Early Intervention Regarding Absence From Work? ### Context: A randomized, controlled, single-center pilot study.The aim of this study was to investigate the feasibility of running a trial to explore if early intervention in individuals with chronic low back pain (CLBP) would lead to an early return to work (RTW) and reduce sick leave during 12 months of follow-up compared with patients on a 3-month waiting list.Back pain is the reason for numerous absent days from work. In Norway, the government initiated a priority program, Earlier Return to Work (ERTW), to reduce work absences through early intervention. However, no proper evaluation has been performed on populations with CLBP. There is no consensus on how RTW should be measured. Only a few studies have examined how waiting time affects RTW.Fifty-eight patients were included in the study. The group with early intervention was examined within 2 weeks, and the group on the waiting list was examined after 12 weeks. The intervention was identical in both groups and consisted of an outpatient, intensive back school. The data were obtained by questionnaire after 3, 6, and 12 months. The primary outcome was absence from work.The sample size in a full-scale study must comprise at least 382 patients on the basis of the assumptions in the pilot. In the pilot study, early intervention directly compared with an ordinary waiting list did not significantly affect the number of sick leave days after 12 months of follow-up. ### Long_Answer: A prerequisite for launching a full-scale clinical trial is a redesign of the intervention, an improvement of procedures concerning inclusion and randomization, and finally a more precise definition of RTW. ### Final_Prediction: nan

### Question: Does undetectable postoperative cortisol always predict long-term remission in Cushing 's disease : a single centre audit? ### Context: An undetectable postoperative serum cortisol has been regarded as a definition of cure in Cushing's disease. However, we noted disease recurrence amongst patients with Cushing's disease despite undetectable postoperative cortisol levels, and this led us to audit our data. We have also previously assessed surgical outcome for acromegaly and microprolactinoma for a single surgeon. The aims of this study were two-fold: (i) to investigate the treatment and surgical outcome of patients with Cushing's disease. In particular, we wished to compare the data with outcome for other pituitary tumours in our centre; and (ii) to determine whether undetectable cortisol following surgery is predictive of long-term cure for Cushing's disease.We performed a retrospective audit of 97 patients; mean age 39.1 (range: 14-82) years, 78/97 (80.4%) female, mean follow-up 92 months (range: 6 months to 29 years), with Cushing's disease seen in our unit between 1969 and 1998. We documented diagnostic investigation, immediate surgical outcome and disease recurrence in these patients.All patients had elevated urinary free cortisol (mean 1270.6 nmol/l, range: 327-3245 nmol/l). In total, 95.5% of patients did not suppress with low-dose dexamethasone suppression testing. Hypokalaemia (K < 3.2 mmol/l) was present in 15.6% of patients; 17.5% of patients did not show cortisol suppression with high-dose dexamethasone and 15.8% of patients did not show an ACTH rise of > 50% following corticotrophic releasing hormone (CRH) administration. There was no significant (> 3) gradient in ACTH or cortisol following CRH during inferior petrosal sinus sampling in 27.3% of patients who had the test. A pituitary tumour was demonstrated on imaging in 55.8% of patients; 10.3% were macroadenomas. Mortality rate following trans-sphenoidal surgery was 1%. Following surgery, the immediate postoperative remission rate (undetectable postoperative cortisol) was 68.5%. However, 11.5% of these patients developed disease recurrence during a mean follow-up period of 36.3 months. Considering microadenomas, Cushing's disease patients had an immediate postoperative remission rate of 63.2% which is significantly lower (P < 0.05) compared to a remission rate of 91.1% in acromegaly. Additionally, new postoperative gonadotrophin deficiency (13.9%) and TSH deficiency (25.8%) was higher in patients with Cushing's disease compared to patients with acromegaly or microprolactinoma. Immediate postoperative remission rates improved from 50% in the first decade of a surgeon's career to consistently above 60% in the second and third decades, demonstrating a trend which may be attributed to surgical experience. ### Long_Answer: (i) Despite strict criteria for immediate postoperative remission and recurrence, undetectable postoperative cortisol is not always predictive of long-term remission. (ii) Despite an aggressive surgical approach, immediate postoperative remission rates for Cushing's disease are lower compared to other microadenomas. The development of new pituitary hormonal deficiency following surgery is also commoner than that seen amongst other microadenomas. These data have important implications for the follow-up of patients with Cushing's disease. ### Final_Prediction: no

### Question: Does selective COX-2 Inhibition exert No Negative Effects on Peripheral Blood Lymphocytes in Allergic Asthmatics? ### Context: Selective inhibition of cyclooxygenase-2 (COX-2) reduces the production of prostaglandin E2 (PGE2), which can have both pro- and anti-inflammatory effects on allergic inflammation. Moreover, in vitro PGE2 has been shown to affect inflammation through the modulation of lymphocyte responses.Sixteen subjects with mild allergic asthma were recruited to a two-period cross-over study: one treatment period with the selective COX-2 inhibitor etoricoxib and one without. Each treatment period ended with an airway challenge with the patient's relevant allergen. Antigen-specific proliferation with the major cat allergen, Fel d 1, was analysed in PBMCs. CD4+ T cells were phenotyped using flow cytometry, and mRNA expression of FOXP3 in anti-CD3-stimulated CD4+ cells were analysed.No significant impact of in vivo inhibition of COX-2 was detected on the proportion of Th1, Th2, or Treg cells in peripheral blood. Likewise, the treatment had minor effects on the stimulated expression of FOXP3 mRNA in CD4+ T cells. Proliferation of PBMCs to the major cat allergen Fel d 1 was slightly reduced by etoricoxib treatment in cat-allergic patients. ### Long_Answer: Short-term treatment with the COX-2 inhibitor etoricoxib had a minor impact on T-cell responses, supporting its safe use also in subjects exposed to triggers of lymphocyte activation. ### Final_Prediction: yes

### Question: Does toll-like receptor 7 stimulation promote autoimmune diabetes in the NOD mouse? ### Context: The role of Toll-like receptor 7 (TLR7), a sensor of viral and self RNA, in promoting autoimmune diabetes remains unclear. Our goal was to determine the effect of TLR7 stimulation on the priming and activation of diabetogenic CD8(+) T cells.We explored the effects of CL097 (TLR7/8 agonist) and immunoregulatory sequence 661 (IRS661, TLR7 inhibitor) on bone marrow-derived dendritic cells (BMDCs), diabetogenic CD8(+) T cell function and autoimmune diabetes onset in NOD and 8.3 NOD T cell receptor transgenic mice (8.3 NOD mice).TLR7 stimulation of NOD BMDCs increased activation and production of proinflammatory cytokines. In vivo administration of CL097 activated T cells and dendritic cells and increased levels of proinflammatory cytokines and type 1/2 IFNs in NOD mice. In vivo antigen-specific cytotoxicity studies revealed enhanced cytotoxicity against islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP, an islet autoantigen) peptide pulsed targets in NOD mice treated with CL097 plus CD40 agonist. This combination treatment accelerated the onset of autoimmune diabetes in 8.3 NOD mice. Likewise, topical treatment of NOD mice with a TLR7 agonist accelerated diabetes onset. Spontaneous disease in 8.3 NOD mice and accelerated disease in CL097+CD40 agonist-treated 8.3 NOD mice were delayed by IRS661 treatment, which is associated with inhibition of the endogenous upregulation of IFN-α levels within the pancreatic lymph nodes. ### Long_Answer: TLR7 stimulation accelerates the spontaneous onset of autoimmune diabetes in 8.3 NOD and NOD mice. Conversely, TLR7 inhibition prevents the early events associated with diabetogenesis. ### Final_Prediction: yes

### Question: Colorectal cancer screening in women with endometrial cancer: are we following the guidelines? ### Context: Colorectal cancer (CRC) is the most common gastrointestinal malignancy. There is an association between CRC and endometrial cancer (EC). Up to 10% of this linkage may be due to hereditary non-polyposis colorectal cancer but in the majority of patients a genetic disorder is not found. The National Comprehensive Cancer Network (NCCN) guidelines on CRC since 2005 have suggested that women with endometrial or ovarian cancer diagnosed at less than 60 years of age have CRC screening with colonoscopy beginning at age 40 or at time of diagnosis of the gynecologic tumor. We assessed our population of women with EC to determine if women were receiving CRC screening after a diagnosis of EC.Electronic medical records of all women diagnosed at our institution with EC predominantly between 1997 and 2007 were reviewed. We assessed age at diagnosis, tumor type, family history of malignancy, CRC screening, and findings at CRC screening and recorded the information in a database. Patients were evaluated for the Amsterdam and Bethesda criteria. This study was approved by the Institutional Review Board.Two hundred sixty-seven women with EC were evaluated. The median age was 66; 39% were less than age 60 at diagnosis. Family history of CRC was present in 25 (9.4%) of EC patients. Of these women, 125 (46.8%) had CRC screening, with 12 (9.6%) being screened for CRC within 1 year of diagnosis and 33 (26.4%) screened for CRC before diagnosis of endometrial cancer. Of the women, 142 (53.2%) did not have CRC screening reported. Of the women screened, ten had adenomatous polyps with one of those polyps being greater than 1 cm, four had tubulovillous histology, and three had CRC. Colonoscopy was performed in 59.2% of women who underwent CRC screening. One woman met criteria for Amsterdam and Bethesda criteria. ### Long_Answer: Less than half of women with EC received screening for CRC. Women who were screened had significant pathology in 13.6% of cases and 2.4% had colon cancer. The NCCN guidelines should be more aggressively followed by physicians who care for women. A prospective colonoscopy screening study on these women with EC to assess the yield and utility in screening in this population is needed. ### Final_Prediction: nan

### Question: Is increased estrogen-dependent expression of calcineurin in female SLE T cells regulated by multiple mechanisms? ### Context: Calcineurin is a key mediator of T cell activation. Previous studies in our laboratory showed a dose-dependent and hormone-specific increase in calcineurin expression in the T cells from females with systemic lupus erythematosus (SLE). This study investigates whether the estrogen-dependent increase in calcineurin expression is due to stabilization of the messenger RNA (mRNA).T cells from female patients with SLE and controls were cultured for 18 hours in a serum-free medium with and without estradiol-17 beta (10(-7) M). Some T cells were activated by further culture on anti-CD3-coated plates. Actinomycin D (25 micrograms/mL) was added to some cultures to inhibit new mRNA synthesis. Calcineurin mRNA stability was assessed by reverse-transcription polymerase chain amplification.Resting SLE (n = 9, P = .59) and normal (n = 5, P = .90) T cells showed no significant differences in mRNA stability in response to estradiol. Calcineurin mRNA was not significantly stabilized in activated SLE (n = 10, P = .12) or activated normal (n = 8, P = .09) T cells in response to estradiol. However, the amount of calcineurin mRNA stabilized in activated normal T cells (n = 8) was significantly greater (P = .02) compared with SLE T cells (n = 10) only after culture in medium without estradiol. ### Long_Answer: These findings highlight the complex gene regulatory mechanisms underlying the differential action of estrogen on SLE T cells. Furthermore, the data indicate that increased calcineurin expression in SLE T cells is not due solely to estrogen-dependent stabilization of the message, and probably involves additional transcriptional regulatory mechanisms. ### Final_Prediction: yes

### Question: Are sleep Problems Associated With Chronic Pain Over and Above Mutual Associations With Depression and Catastrophizing? ### Context: Pain, mood problems, and sleeping difficulties are often comorbid and contribute to reduced physical function and quality of life for those with chronic pain. However, the way in which these factors interact is unclear. Until recently it was thought that the effect of sleep on pain and physical function was simply a result of its common association with mood problems. However, a growing body of research suggests that sleep may have a unique contribution.The aim of this study was to determine whether sleep disturbances were associated with pain and poor physical function independent of psychological distress in patients attending a tertiary pain medicine unit.101 patients with chronic pain completed a set of questionnaires measuring pain, sleep, and mood, and also completed a selection of physical assessments conducted by a physiotherapist.In total, 75.2% of participants had insomnia and 84.3% reported the presence of at least 1 sleep problem. Significant positive correlations with pain were detected for depression, catastrophizing, insomnia, short sleep duration, and poor sleep quality. Sleep duration had a significant independent association with pain after accounting for depression and catastrophizing. Sleep duration also had an independent association with physical function after accounting for pain and catastrophizing. ### Long_Answer: Given that sleep has an important and unique contribution to pain and physical function, it is important that sleep disturbances are addressed both in the assessment and treatment of chronic pain. ### Final_Prediction: yes

### Question: Are children reliable reporters of common symptoms : results from a self-reported symptom diary for primary school children? ### Context: Collecting information on subjective symptoms in children by parental reports or physician's interview is indirect and not suited for prospective data collection over extended time periods.To examine the reliability of a diary for symptom self-reports by primary school children.Children aged 7-8 or 11-12 were recruited from primary school and a paediatric outpatient department. A picture-based symptom diary was completed individually. Children were asked about presence of 10 specified subjective symptoms for five time periods covering the previous 24 h. The diary was completed twice for test-retest and answers were compared with semi structured physician's interviews.Test-retest reliability for reporting a symptom during the previous 24 h gave reliable kappa values of 0.64-0.91. Comparison with physician's interview gave kappas of 0.18-0.68. Requiring correct time of day for each symptom reduced reliability and validity. Kappa values for test-retest and child-physician agreement for the individual symptoms were respectively: sneezing, 0.80 and 0.30; sore throat, 0.89, 0.30; tiredness, 0.88, 0.65; headache, 0.64, 0.66; runny nose, 0.91, 0.68; sore eyes, 0.67, 0.18; cough, 0.73, 0.58; stomach ache, 0.69, 0.45. ### Long_Answer: Our symptom diary gives reliable self-report data from primary school children. It may be used for prospective symptom monitoring. ### Final_Prediction: yes

### Question: Is the severity of nauseogenic effect of cross-coupled rotation proportional to gyroscopic angular acceleration? ### Context: Subjects underwent cross-coupled rotation of the head (i.e., Coriolis stimuli) during which the upper body was tilted from side to side during horizontal rotation of the whole body about the Earth-vertical axis. In Experiment 1, the angle between the two axes of cross-coupled rotation was changed to vary the magnitude of gyroscopic angular acceleration without wide variations in Coriolis linear acceleration. The severity of nausea evoked by cross-coupled rotation stimuli varied relative to the magnitude of gyroscopic angular acceleration. It is noteworthy that nausea was not evoked unless gyroscopic angular acceleration was generated, even though Coriolis linear acceleration was equally induced. In Experiment 2, subjects tilted the upper body with or without restriction of head movement to a vertical plane during Earth-vertical axis rotation of the body at various angular velocities. The severity of evoked nausea was in direct proportion to angular velocity of body rotation irrespective of the restriction. ### Long_Answer: These results indicated that the severity of nauseogenic effect of cross-coupled rotation is directly proportional to gyroscopic angular acceleration. ### Final_Prediction: yes

### Question: Sympathetic ophthalmitis following vitreoretinal surgery: Does antecedent trauma make a difference? ### Context: Sympathetic ophthalmitis (SO) has been reported following vitrectomy; however, there is a lack of data on the role of antecedent penetrating ocular trauma impacting the disease manifestation in eyes developing SO following vitrectomy.AIM: To report differences in the presentation and outcomes of SO in eyes with or without a history of antecedent penetrating trauma; SO being diagnosed after vitreoretinal (VR) surgery.Comparative case series.Seventeen consecutive patients presenting with SO following VR surgery, diagnosed between 1995 and 2011 were included. Eyes with and without prior penetrating injury were included in Group I (n = 7) and Group II (n = 10), respectively. All Group I patients had received systemic steroids prior to presentation. Demographic and clinical parameters were evaluated.Differences were observed between Group I and Group II mainly with regards to time interval between VR surgery and diagnosis of SO (1.5 months vs. 8 months, P = 0.10), presence of neurosensory detachments (100% vs. 30%, P = 0.01), and the inciting eye vision at presentation (nil light perception in 28.5% vs. 80%, P = 0.049). Other differences observed though not statistically significant were optic disc and retinal vessel involvement (42% vs. 70%, P = 0.28), Dalen-Fuchs nodules (localized vs. diffuse) and leaks on fundus fluorescein angiography (pin-head vs. pin-point leak). ### Long_Answer: SO in patients with antecedent penetrating ocular trauma present early with the central serous chorioretinopathy-like picture. Prior use of systemic steroids might have a bearing on the differences in presentation and the visual acuities between the two groups. ### Final_Prediction: nan

### Question: Do synovial concentrations of the angiogenic peptides bFGF and VEGF discriminate rheumatoid arthritis from other forms of inflammatory arthritis? ### Context: To investigate whether concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in aspirated synovial fluid can be used to distinguish rheumatoid arthritis from other forms of inflammatory arthritis.bFGF and VEGF concentrations were measured in aspirated synovial fluid and serum samples from 66 patients with active arthritis (clinical diagnoses: rheumatoid arthritis (35 patients), psoriatic arthritis (9), reactive arthritis (11) and arthritis UNS (11)) utilizing commercial ELISA kits.In comparison with controls, elevated concentrations of VEGF were found in synovial fluid compared with in serum in all forms of arthritis. There were no significant differences in synovial fluid bFGF or VEGF concentrations between rheumatoid arthritis and the other forms of inflammatory arthritis. ### Long_Answer: Both serum bFGF and VEGF concentrations were increased in patients with rheumatoid arthritis. Patients treated with steroids had lower synovial fluid bFGF concentrations. Synovial fluid levels of bFGF and VEGF were elevated but could not be used to distinguish rheumatoid arthritis from other forms of inflammatory arthritis. ### Final_Prediction: no

### Question: Does early statin therapy restore endothelial function in children with familial hypercholesterolemia? ### Context: This study was designed to determine whether simvastatin improves endothelial function in children with familial hypercholesterolemia (FH).Endothelial function measured by flow-mediated dilation of the brachial artery (FMD) is used as a surrogate marker of cardiovascular disease (CVD). Adult studies have shown that statins reverse endothelial dysfunction and therefore reduce the risk for future CVD.The study included 50 children with FH (9 to 18 years) and 19 healthy, non-FH controls. Children with FH were randomized to receive simvastatin or placebo for 28 weeks. The FMD was performed at baseline and at 28 weeks of treatment.At baseline, FMD was impaired in children with FH versus non-FH controls (p < 0.024). In the simvastatin FH group, FMD improved significantly, whereas the FMD remained unaltered in the placebo FH group throughout the study period (absolute increase 3.9% +/- 4.3% vs. 1.2% +/- 3.9%, p < 0.05). In the simvastatin FH group, FMD increased to a level similar to the non-FH controls (15.6% +/- 6.8% vs. 15.5% +/- 5.4%, p = 0.958). Upon treatment, the simvastatin FH group showed significant absolute reductions of total cholesterol (TC) (-2.16 +/- 1.04 mmol/l, 30.1%) and low-density lipoprotein cholesterol (LDL-C) (-2.13 +/- 0.99 mmol/l, 39.8%). The absolute change of FMD after 28 weeks of therapy was inversely correlated to changes of TC (r = -0.31, p < 0.05) and LDL-C (r = -0.31, p < 0.05). ### Long_Answer: Our data show significant improvement of endothelial dysfunction towards normal levels after short-term simvastatin therapy in children with FH. These results emphasize the relevance of statin therapy in patients with FH at an early stage, when the atherosclerotic process is still reversible. ### Final_Prediction: yes

### Question: Does adenosine A1 receptor antagonism hasten the decay in ventricular fibrillation waveform morphology during porcine cardiac arrest? ### Context: Endogenous adenosine (ADO) is known to be cardioprotective during acute myocardial ischemia. Coronary sinus ADO concentration has recently been shown to increase nearly 13-fold over baseline levels after 5 min of untreated ventricular fibrillation (VF). The role of ADO in VF has never been previously examined. The objective of this study was to determine the effect of ADO receptor antagonism, as measured by the scaling exponent (ScE), on the degeneration of VF over time during the circulatory phase of cardiac arrest.A well-established swine model of prolonged VF arrest was used for this experiment. Eighteen domestic mixed-breed swine were assigned by block randomization to receive either DTI-0017 (5mg/kg), a potent ADO A(1) receptor antagonist or placebo in a double-blind fashion. The animals were instrumented under general anesthesia and acclimatized. The assigned solution was infused over 5 min. One minute after the infusion was completed, VF was induced with a 3s, 60 Hz, 100 mA transthoracic shock and left untreated. Lead II ECG was monitored continuously and recorded at 1000 samples/s. It was determined a priori that evaluation of the plots would be limited to a previously observed plateau phase historically occurring between 5 and 8 min corresponding to the circulatory phase of cardiac arrest. The scaling exponent values over this period were calculated for each of the 18 recordings using custom MATLAB routines. Using the Wald statistic to produce the Chi square distributions the null hypothesis, that there was no difference between the two groups, was tested. The Wald statistic calculation based on eight epochs from 300 to 475 s in placebo and DTI groups was significant to reject the null hypothesis of no difference in the groupxtime interaction at the 0.015 level (Chi square distribution for Wald=17.49, d.f.=7). ### Long_Answer: In this swine model, adenosine A(1) receptor antagonism accelerated the natural decay in the ECG VF waveform during the circulatory phase of cardiac arrest. Our findings would suggest that endogenous adenosine has cardioprotective effects during sudden cardiac arrest by slowing the time-dependent degeneration of VF. ### Final_Prediction: yes

### Question: Is upper tract imaging surveillance effective in diagnosing upper tract recurrence in patients followed for nonmuscle invasive bladder cancer? ### Context: We evaluated the usefulness of routine upper tract imaging in patients followed for nonmuscle invasive bladder cancer.A retrospective review of patients treated for nonmuscle invasive bladder cancer between 2000 and 2006 was conducted. Kaplan-Meier curves were calculated to determine upper tract urothelial carcinoma-free probability for stage Ta and T1 disease. Bladder cancer stage was included as a time dependent covariate. Descriptive statistics were used to report rates of imaging studies used and the efficacy in diagnosing upper tract urothelial carcinoma.Of 935 patients treated and followed for nonmuscle invasive bladder cancer 51 were diagnosed with upper tract urothelial carcinoma. Median followup was 5.5 years. The 5-year upper tract urothelial carcinoma-free probability among patients with Ta and T1 disease was 98% and 93%, respectively. The 10-year upper tract urothelial carcinoma-free probability among patients with Ta and T1 disease was 94% and 88%, respectively. Only 15 (29%) patients were diagnosed on routine imaging while the others were diagnosed after symptoms developed. Overall 3,074 routine imaging scans were conducted for an overall efficacy of 0.49%. ### Long_Answer: Upper tract recurrence is a lifelong risk in patients with bladder cancer, but most cases will be missed on routine upper tract imaging. The majority of upper tract urothelial carcinoma can be diagnosed using a combination of thorough history taking, physical examination, urine cytology and sonography, indicating that routine surveillance imaging may not be the most efficient way to detect upper tract recurrence. ### Final_Prediction: no

### Question: Do lactobacillus ruminis strains cluster according to their mammalian gut source? ### Context: Lactobacillus ruminis is a motile Lactobacillus that is autochthonous to the human gut, and which may also be isolated from other mammals. Detailed characterization of L. ruminis has previously been restricted to strains of human and bovine origin. We therefore sought to expand our bio-bank of strains to identify and characterise isolates of porcine and equine origin by comparative genomics.We isolated five strains from the faeces of horses and two strains from pigs, and compared their motility, biochemistry and genetic relatedness to six human isolates and three bovine isolates including the type strain 27780(T). Multilocus sequence typing analysis based on concatenated sequence data for six individual loci separated the 16 L. ruminis strains into three clades concordant with human, bovine or porcine, and equine sources. Sequencing the genomes of four additional strains of human, bovine, equine and porcine origin revealed a high level of genome synteny, independent of the source animal. Analysis of carbohydrate utilization, stress survival and technological robustness in a combined panel of sixteen L. ruminis isolates identified strains with optimal survival characteristics suitable for future investigation as candidate probiotics. Under laboratory conditions, six human isolates of L. ruminis tested were aflagellate and non-motile, whereas all 10 strains of bovine, equine and porcine origin were motile. Interestingly the equine and porcine strains were hyper-flagellated compared to bovine isolates, and this hyper-flagellate phenotype correlated with the ability to swarm on solid medium containing up to 1.8% agar. Analysis by RNA sequencing and qRT-PCR identified genes for the biosynthesis of flagella, genes for carbohydrate metabolism and genes of unknown function that were differentially expressed in swarming cells of an equine isolate of L. ruminis. ### Long_Answer: We suggest that Lactobacillus ruminis isolates have potential to be used in the functional food industry. We have also identified a MLST scheme able to distinguish between strains of L. ruminis of different origin. Genes for non-digestible oligosaccharide metabolism were identified with a putative role in swarming behaviour. ### Final_Prediction: yes

### Question: Are gastrointestinal cell proliferation and crypt fission separate but complementary means of increasing tissue mass following infusion of epidermal growth factor in rats? ### Context: Epidermal growth factor (EGF) is a potent mitogen for the gastrointestinal tract and also influences the number of new crypts formed by crypt fission. The time course of these events and possible linkage between these two complementary mechanisms is however poorly understood. We therefore examined the temporal relationship of proliferation and fission in rats treated with EGF.Osmotic minipumps were implanted subcutaneously into male Wistar rats to infuse EGF continuously (60 microg/rat/day) for periods of 1-14 days. Proliferation and crypt branching were quantified following vincristine induced metaphase arrest and morphometric assessment of microdissected tissue.In the small intestine, EGF significantly increased epithelial cell proliferation and crypt and villus area after 24 hours of EGF, although maximal effects were only reached following six days of infusion. EGF also resulted in an approximate 30% reduction in crypt fission in the small bowel. In the colon, EGF caused a twofold increase in epithelial cell proliferation one day after infusion, from 15.3 (2.3) to 29.6 (3.5) metaphases per crypt (p<0.01). Maximal effects were seen in rats receiving EGF for seven days. For all time points, colonic crypt size increased in response to EGF. The amount of branching increased following one day of infusion with EGF (from 15.3 (1.9) to 32.4 (5.5)%; p<0.001) but was significantly lower (approximately 25% of control values) following longer periods of infusion. Crypt fission did not correlate with crypt area. ### Long_Answer: EGF has profound effects on cell proliferation and also altered crypt fission, with its actions on crypt fission most pronounced in the colon where it first increased and then decreased fission. EGF can thus be a potent stimulus for crypt fission during short term infusion and may reduce the number of branched crypts present in a resting or quiescent stage. Growth factors can alter cell mass by two separate but linked mechanisms, namely altered cell production and crypt fission. ### Final_Prediction: yes

### Question: Is cD10 useful in demonstrating endometrial stroma at ectopic sites and in confirming a diagnosis of endometriosis? ### Context: Recent studies have shown that CD10 is a useful immunohistochemical marker of normal endometrial stroma and of endometrial stromal neoplasms. The aim of this study was to investigate whether CD10 immunoreactivity is present in ectopic endometrial stroma and whether staining is of value in confirming a diagnosis of endometriosis.Twenty five cases of endometriosis were stained with a commercially available antibody against CD10. Endometrial stromal cells were positive in 22 of 25 cases. There was little or no staining of other tissues. ### Long_Answer: CD10 immunoreactivity is largely maintained in endometrial stromal cells located outside the uterus. Immunohistochemical staining with CD10 may be of value in confirming a diagnosis of endometriosis when there is morphological doubt. ### Final_Prediction: yes

### Question: Do high-density lipoproteins suppress chemokines and chemokine receptors in vitro and in vivo? ### Context: To investigate whether high-density lipoproteins (HDLs) suppress chemokine (CCL2, CCL5, and CX(3)CL1) and chemokine receptor (CCR2 and CX(3)CR1) expression, a mechanism for the atheroprotective properties of HDLs.Apolipoprotein (apo) E(-/-) mice were fed a high-fat diet for 12 weeks. Before being euthanized, the mice received 5 consecutive daily injections of lipid-free apoA-I, 40 mg/kg, or saline (control). The injection of apoA-I reduced CCR2 and CX(3)CR1 expression in plaques compared with controls (P<0.05). ApoA-I-injected mice had lower plasma CCL2 and CCL5 levels. Hepatic CCL2, CCL5, and CX(3)CL1 levels were also reduced (P<0.05). In vitro studies found that reconstituted HDL (rHDL) reduced monocyte CCR2 and CX(3)CR1 expression and inhibited their migration toward CCL2 and CX(3)CL1 (P<0.05). Preincubation with rHDL reduced CCL2, CCL5, and CX(3)CL1 expression in monocytes and human coronary artery endothelial cells. The stimulation of CX(3)CR1 with peroxisome proliferator-activated receptor gamma agonist CAY10410 was suppressed by preincubation with rHDL but did not affect the peroxisome proliferator-activated receptor gamma antagonist (GW9664)-mediated increase in CCR2. In monocytes and human coronary artery endothelial cells, rHDL reduced the expression of the nuclear p65 subunit, IkappaB kinase activity, and the phosphorylation of IkappaBalpha (P<0.05). ### Long_Answer: Lipid-free apoA-I and rHDL reduce the expression of chemokines and chemokine receptors in vivo and in vitro via modulation of nuclear factor kappaB and peroxisome proliferator-activated receptor gamma. ### Final_Prediction: yes

### Question: Does misexpression of the constitutive Rpgr ( ex1-19 ) variant lead to severe photoreceptor degeneration? ### Context: Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene are a frequent cause of X-linked retinitis pigmentosa. The RPGR transcript undergoes complex alternative splicing to express both constitutive (Rpgr(ex1-19)) and Rpgr(ORF15) variants. Both variants localize to photoreceptor connecting cilia and are believed to play roles in ciliary function. This study examined variability in isoform expression and tested whether the constitutive variant could substitute for Rpgr function in photoreceptors.Rpgr(ex1-19) and Rpgr(ORF15) expression during retinal development were compared using immunoblot analysis and immunohistochemistry, and ciliary affinity in adult photoreceptors was assessed by protein fractionation. Transgenic mice expressing either the full-length Rpgr(ex1-19) or Rpgr(ORF15) variant were studied using light and electron microscopy and immunofluorescence imaging. The results were compared with those of wild-type and Rpgr(-/-) mice.Rpgr expression undergoes dynamic temporal regulation during retinal development, and variants exhibit variability for ciliary localization in adult photoreceptors. Transgenic expression of both variants grossly exceeded endogenous Rpgr expression in photoreceptors. Although both variants exhibited normal ciliary localization, overexpression of the Rpgr(ex1-19) variant resulted in atypical accumulation of Rpgr in photoreceptor outer segments, abnormal photoreceptor morphology, and severe retinal degeneration. ### Long_Answer: The Rpgr isoform ratio in the adult retina is critical to photoreceptor integrity. The utilization of distinct Rpgr variants at different stages of photoreceptor maturation suggests independent roles in photoreceptor function. Finally, misexpression of Rpgr(ex1-19) causes retinal degeneration that is considerably more severe than that caused by Rpgr knockout but photoreceptors tolerate overexpression of Rpgr(ORF15) without evidence of degeneration. ### Final_Prediction: yes

### Question: Is clinically localised prostate cancer microsatellite stable? ### Context: To determine the frequency of microsatellite instability (MSI) change with mono-, di- and tetranucleotide markers in clinically localized prostate cancer, and to correlate those markers with clinical and pathological variables.Two forms of MSI have been described in human cancer: MSI typical of hereditary nonpolyposis colon cancer, defined with mono- and dinucleotide repeat MS; and a second variety of MSI is best seen at selective tetranucleotide repeats, i.e. elevated microsatellite alterations at select tetranucleotides (EMAST). Prostate specimens were taken from 50 patients. The MS analysis used the Bethesda consensus panel (BCP) and four tetranucleotide loci shown to detect the presence of EMAST.All but four tumours were stable for the 14 loci investigated. There were two (4%) cases with adenomatous polyposis coli (APC) instability among the BCP markers and the same instability rate (4%) amongst the EMAST markers. These four tumours were all unstable at one locus of the 10 markers of the BCP that classified them as MS stable. ### Long_Answer: The MSI related to a mismatch repair deficiency or to the EMAST does not seem to be important in prostate cancer in the early stages of the disease. ### Final_Prediction: yes

### Question: Intraoperative defibrillation threshold testing during implantable cardioverter-defibrillator insertion: do we really need it? ### Context: The assessment of defibrillation efficacy using a safety margin of 10 J has long been the standard of care for insertion of implantable cardioverter-defibrillator (ICD), but physicians are concerned about complications related to induction test. Therefore, the need for testing has been recently questioned. The aim of our study was to assess the impact of defibrillation threshold (DFT) testing of ICD on the efficacy of ICD therapy.We analyzed data obtained from follow-up visits of 122 consecutive patients who underwent ICD implantation at our institute from April 1996 to June 2008, with (n = 42) or without (n = 80) DFT testing. Patients in the DFT group were less likely to be men (83.3% vs 96.3%, P<.031) than those in the non-DFT group. Conversely, the 2 groups were similar in age, left ventricular ejection fraction at baseline, functional class, and underlying cardiovascular disease. Results during a 12-month follow-up, 13 (31.0%) and 30 (37.5%) ventricular tachyarrhythmic episodes were recorded in the DFT and non-DFT groups, respectively (P = .472). Antitachycardia pacing (ATP) terminated most of episodes, reducing the need of defibrillation at 7.7% in the DFT group and 3.3% in the non-DFT group (P = .533). Similar percentages of inappropriate ATP interventions (7.1% vs 3.8%, P = .413) and shock deliveries (2.4% vs 5.0%, P = .659) were recorded between DFT and non-DFT groups. ### Long_Answer: At 1-year follow-up, the performance of DFT testing does not seem to add any significant efficacy advantage in patients undergoing ICD implantation. Prospective randomized trials and long-term follow-up are warranted to clarify whether routine DFT testing may be safely abandoned leading to a revision of current guidelines. ### Final_Prediction: nan

### Question: Do mitochondria-derived reactive oxygen species mediate sympathoexcitation induced by angiotensin II in the rostral ventrolateral medulla? ### Context: Reactive oxygen species (ROS) in the central nervous system are thought to contribute to sympathoexcitation in cardiovascular diseases such as hypertension and heart failure. Nicotinamide adenine dinucleotide phosphate oxidase is a major source of ROS in the central nervous system, which acts as a key mediator (mediators) of angiotensin II (AngII). It is not clear, however, whether mitochondria-derived ROS in the central nervous system also participate in sympathoexcitation.In an in-vivo study, we investigated whether the AngII-elicited pressor response in the rostral ventrolateral medulla, which controls sympathetic nerve activity, is attenuated by adenovirus-mediated gene transfer of a mitochondria-derived antioxidant (Mn-SOD). In an in-vitro study, using differentiated PC-12 cells with characteristics similar to those of sympathetic neurons, we examined whether AngII increases mitochondrial ROS production.Overexpression of Mn-SOD attenuated the AngII-induced pressor response and also suppressed AngII-induced ROS production, as evaluated by microdialysis in the rostral ventrolateral medulla. Using reduced MitoTracker red, we showed that AngII increased mitochondrial ROS production in differentiated PC-12 cells in vitro. Overexpression of Mn-SOD and rotenone, a mitochondrial respiratory complex I inhibitor, suppressed AngII-induced ROS production. Depletion of extracellular Ca2+ with ethylene glycol bis-N,N,N',N'-tetraacetate (EGTA) and administration of p-trifluoromethoxycarbonylcyanide phenylhydrazone, which prevents further Ca2+ uptake into the mitochondria, blocked AngII-elicited mitochondrial ROS production. ### Long_Answer: These results indicate that AngII increases the intracellular Ca2+ concentration and that the increase in mitochondrial Ca2+ uptake leads to mitochondrial ROS production. ### Final_Prediction: yes

### Question: Community-acquired pneumonia (CAP) hospitalizations and deaths: is there a role for quality improvement through inter-hospital comparisons? ### Context: To assess between-hospital variations in standardized in-hospital mortality ratios of community-acquired pneumonia (CAP), and identify possible leads for quality improvement.We used an administrative database to estimate standardized in-hospital mortality ratios for 111 Belgian hospitals, by carrying out a set of hierarchical logistic regression models, intended to disentangle therapeutic attitudes and biases. To facilitate the detection of false-negative/positive results, we added an inconclusive zone to the funnel plots, derived from the results of the study. Data quality was validated by comparison with (i) alternative data from the largest Belgian Sickness Fund, (ii) published German hospital data and (iii) the results of an on-site audit.All Belgian hospital discharge records from 2004 to 2007.A total of 111 776 adult patients were admitted for CAP.Risk-adjusted standardized in-hospital mortality ratios.Out of the 111 hospitals, we identified five and six outlying hospitals, with standardized mortality ratios of CAP consistently on the extremes of the distribution, as providing possibly better or worse care, respectively, and 18 other hospitals as having possible quality weaknesses/strengths. At the individuals' level of the analysis, adjusted odds ratios showed the paramount importance of old age, comorbidity and mechanical ventilation. The data compared well with the different validation sources. ### Long_Answer: Despite the limitations inherent to administrative data, it seemed possible to establish inter-hospital differences in standardized in-hospital mortality ratios of CAP and to identify leads for quality improvement. Monitoring is needed to assess progress in quality. ### Final_Prediction: nan

### Question: Does inflamed pouch mucosa possess altered tight junctions indicating recurrence of inflammatory bowel disease? ### Context: The etiology of pouchitis after coloproctomucosectomy with ileal pouch-anal anastomosis in patients with ulcerative colitis is still unknown. Beside changes in luminal antigens, the immunological predisposition is assumed to be responsible. In previous electrophysiological studies, we showed that mucosal barrier and transport function in pouchitis is markedly reduced. Thus, the aim of the present study was to analyze barrier function on the molecular level.Pouch biopsies of 36 ulcerative colitis patients were analyzed. Time points were (1) intraoperative immediately prior to ileal pouch-anal anastomosis (n = 13), (2) >1 year after ileostomy closure (pouch, n = 12), and (3) during pouchitis (n = 11). Control terminal ileum biopsies were obtained from eight patients undergoing hemicolectomy due to carcinoma. Expression of tight junction proteins was analyzed by Western blotting and confocal laser-scanning microscopy. To elucidate effects on epithelial barrier properties, impedance spectroscopy was performed in miniaturized Ussing chambers.In pouchitis, epithelial resistance was markedly reduced compared to non-inflamed pouch and control ileum. Expression of tight junction proteins claudin-1, 3, 4, 5, and 7 and occludin revealed differential expression regulation with the tightening tight junction protein claudin-1 being decreased and an increase of the pore-forming claudin-2, whereas other claudins remained constant. Morphometry indicated the mucosal surface to be unchanged. ### Long_Answer: Pouchitis is characterized by a selective change of tight junction proteins in favor of opening the epithelial tight junction and, thus, the paracellular pathway, which contributes to the inflammatory process. This resembles changes in inflammatory bowel disease (IBD) and indicates IBD recurrence in pouchitis. ### Final_Prediction: yes

### Question: Does genome-wide identification of transcriptional targets of RORA reveal direct regulation of multiple genes associated with autism spectrum disorder? ### Context: We have recently identified the nuclear hormone receptor RORA (retinoic acid-related orphan receptor-alpha) as a novel candidate gene for autism spectrum disorder (ASD). Our independent cohort studies have consistently demonstrated the reduction of RORA transcript and/or protein levels in blood-derived lymphoblasts as well as in the postmortem prefrontal cortex and cerebellum of individuals with ASD. Moreover, we have also shown that RORA has the potential to be under negative and positive regulation by androgen and estrogen, respectively, suggesting the possibility that RORA may contribute to the male bias of ASD. However, little is known about transcriptional targets of this nuclear receptor, particularly in humans.Here we identify transcriptional targets of RORA in human neuronal cells on a genome-wide level using chromatin immunoprecipitation (ChIP) with an anti-RORA antibody followed by whole-genome promoter array (chip) analysis. Selected potential targets of RORA were then validated by an independent ChIP followed by quantitative PCR analysis. To further demonstrate that reduced RORA expression results in reduced transcription of RORA targets, we determined the expression levels of the selected transcriptional targets in RORA-deficient human neuronal cells, as well as in postmortem brain tissues from individuals with ASD who exhibit reduced RORA expression.The ChIP-on-chip analysis reveals that RORA1, a major isoform of RORA protein in human brain, can be recruited to as many as 2,764 genomic locations corresponding to promoter regions of 2,544 genes across the human genome. Gene ontology analysis of this dataset of genes that are potentially directly regulated by RORA1 reveals statistically significant enrichment in biological functions negatively impacted in individuals with ASD, including neuronal differentiation, adhesion and survival, synaptogenesis, synaptic transmission and plasticity, and axonogenesis, as well as higher level functions such as development of the cortex and cerebellum, cognition, memory, and spatial learning. Independent ChIP-quantitative PCR analyses confirm binding of RORA1 to promoter regions of selected ASD-associated genes, including A2BP1, CYP19A1, ITPR1, NLGN1, and NTRK2, whose expression levels (in addition to HSD17B10) are also decreased in RORA1-repressed human neuronal cells and in prefrontal cortex tissues from individuals with ASD. ### Long_Answer: Findings from this study indicate that RORA transcriptionally regulates A2BP1, CYP19A1, HSD17B10, ITPR1, NLGN1, and NTRK2, and strongly suggest that reduction of this sex hormone-sensitive nuclear receptor in the brain causes dysregulated expression of these ASD-relevant genes as well as their associated pathways and functions which, in turn, may contribute to the underlying pathobiology of ASD. ### Final_Prediction: yes

### Question: Do selectins mediate macrophage infiltration in obstructive nephropathy in newborn mice? ### Context: Urinary tract obstruction during development leads to tubular atrophy and causes interstitial fibrosis. Macrophage infiltration into the interstitium plays a central role in this process. Selectins, a family of three adhesion molecules, are involved in leukocyte recruitment to sites of inflammation and immune activity. We investigated the role of selectins in obstructive nephropathy in newborn mice.Triple selectin-deficient mice (EPL-/-), L-selectin deficient mice (L-/-) and wild type mice (WT) were subjected to complete unilateral ureteral obstruction (UUO) or sham operation within the first 48 hours of life, and were sacrificed 5 and 12 days later. Kidneys were removed, and sections were stained for macrophage infiltration (mAb F4/80), apoptosis (TUNEL), tubular atrophy (periodic acid-Schiff) and interstitial fibrosis (Masson trichrome).Selectin deficient mice showed a marked reduction in macrophage infiltration into the obstructed kidney compared to WT at day 5 and day 12 after UUO. Tubular apoptosis was strongly reduced in EPL-/- at day 5 after UUO, and in EPL-/- and L-/- at day 12 after UUO when compared to WT. The number of apoptotic tubular cells was correlated with macrophage infiltration, suggesting that macrophages stimulate tubular apoptosis in obstructive nephropathy. In addition, tubular atrophy and interstitial fibrosis were significantly diminished in EPL-/- and L-/- compared to WT at day 12 after UUO. ### Long_Answer: Following UUO, selectins mediate macrophage infiltration into the obstructed kidney, which in turn may induce tubular apoptosis, tubular atrophy and interstitial fibrosis. ### Final_Prediction: yes

### Question: Is lower serum calcium level associated with hemorrhagic transformation after thrombolysis? ### Context: We aim to investigate whether lower admission serum calcium levels are associated with hemorrhagic transformation (HT) after intravenous thrombolysis (IVT).A total of 362 patients treated with IVT was divided into 4 quartiles based on admission serum calcium levels (Q1[<2.16], Q2[2.16, 2.23], Q3[2.24, 2.31], and Q4[>2.31] mmol/L). HT was classified as hemorrhagic infarction and parenchymal hemorrhage. Logistic regression was applied to assess the association between serum calcium levels and the incidence of HT.Compared with Q4, HT was more common in Q1 (odds ratio, 2.580; 95% CI, [1.258-5.292]; P=0.010), Q2 (odds ratio, 2.382; 95% CI, [1.163-4.877]; P=0.018), and Q3 (odds ratio, 2.293; 95% CI, [1.133-4.637]; P=0.021). Hemorrhagic infarction was more common in Q1 (P=0.037), and Q2 (P=0.018), compared with Q4, and parenchymal hemorrhage was more common in Q1 (P=0.029) than Q4. ### Long_Answer: Lower admission serum calcium level is independently associated with HT after IVT, and this hypothesis needs larger confirmatory trials. ### Final_Prediction: yes

### Question: Long-term results of endobronchial brachytherapy: A curative treatment? ### Context: To evaluate outcomes after high-dose-rate endobronchial brachytherapy (HDR-EBBT) for limited lung carcinoma.A total of 106 patients with endobronchial lung cancer and not eligible for surgery or external beam radiotherapy, without nodal or visceral metastases, were treated with HDR-EBBT. They had developed disease relapse after surgery (n = 43) or external beam radiotherapy (n = 27) or had early lung cancer with respiratory insufficiency (n = 36). Treatment consisted of six fractions of 5 or 7 Gy, usually delivered 1 cm from the source.The complete histologic response rate, evaluated at 3 months after HDR-EBBT, was 59.4%. At 3 and 5 years, the local control, overall survival, and cause-specific survival rates were 60.3% and 51.6%, 47.4 and 24%, and 67.9 and 48.5%, respectively. Factors significantly associated with local failure were high tumor volume (tumor length>2 cm, bronchial obstruction>25%, tumor visibility on CT scan) and previous endoscopic treatment. Cause-specific survival, but not overall survival, was significantly associated with local control, probably because of the high rate of deaths not related to lung cancer. Five deaths were attributed to the HDR-EBBT procedure (two from fatal hemoptysis and three from bronchial necrosis). ### Long_Answer: High-dose-rate-EBBT achieved a long-term cause-specific survival rate of 50% of the patients with localized endobronchial carcinoma and could be considered curative. ### Final_Prediction: nan

### Question: The evolution of floral nectaries in Disa (Orchidaceae: Disinae): recapitulation or diversifying innovation? ### Context: The Orchidaceae have a history of recurring convergent evolution in floral function as nectar production has evolved repeatedly from an ancestral nectarless state. However, orchids exhibit considerable diversity in nectary type, position and morphology, indicating that this convergence arose from alternative adaptive solutions. Using the genus Disa, this study asks whether repeated evolution of floral nectaries involved recapitulation of the same nectary type or diversifying innovation. Epidermis morphology of closely related nectar-producing and nectarless species is also compared in order to identify histological changes that accompanied the gain or loss of nectar production.The micromorphology of nectaries and positionally equivalent tissues in nectarless species was examined with light and scanning electron microscopy. This information was subjected to phylogenetic analyses to reconstruct nectary evolution and compare characteristics of nectar-producing and nectarless species.Two nectary types evolved in Disa. Nectar exudation by modified stomata in floral spurs evolved twice, whereas exudation by a secretory epidermis evolved six times in different perianth segments. The spur epidermis of nectarless species exhibited considerable micromorphological variation, including strongly textured surfaces and non-secreting stomata in some species. Epidermis morphology of nectar-producing species did not differ consistently from that of rewardless species at the magnifications used in this study, suggesting that transitions from rewardlessness to nectar production are not necessarily accompanied by visible morphological changes but only require sub-cellular modification. ### Long_Answer: Independent nectary evolution in Disa involved both repeated recapitulation of secretory epidermis, which is present in the sister genus Brownleea, and innovation of stomatal nectaries. These contrasting nectary types and positional diversity within types imply weak genetic, developmental or physiological constraints in ancestral, nectarless Disa. Such functional convergence generated by morphologically diverse solutions probably also underlies the extensive diversity of nectary types and positions in the Orchidaceae. ### Final_Prediction: nan

### Question: Does keratinocyte growth factor pretreatment prevent radiation-induced intestinal damage in a mouse model? ### Context: Radiation-induced gastrointestinal syndrome is usually severe in clinical practice. Keratinocyte growth factor (KGF) plays an important role in the intestinal mucosal growth and repair of intestinal injury. This study was to investigate the effects of KGF on radiation-induced intestinal damage, especially the barrier dysfunction, in a mouse model.Adult C57BL/6J mice were randomized into three groups: normal control, irradiation group, and KGF-treated group. Mice in the later two groups received irradiation with a dose of 6 Gy from Co-60 source. In the KGF-treated group, KGF was intraperitoneally given once daily (5 mg/kg/day) for 5 consecutive days before irradiation. Mice were killed at 3 days after irradiation and the small bowel was collected for histology. Epithelial cell proliferation was studied by immunohistochemistry for proliferating cell nuclear antigen. Claudin-1 and ZO-1 expressions were determined by western blot assay and immunohistochemistry. Epithelial barrier function was assessed with transepithelial resistance.KGF significantly promoted the recovery of mucosa from radiation-induced injury demonstrated by mucosal histology, villus height, crypt depth, and crypt cell proliferation. KGF also improved the disrupted distribution of tight junction proteins and the epithelial barrier dysfunction after irradiation. ### Long_Answer: KGF pretreatment could improve radiation-induced intestinal injury including the epithelial structure and function in a mouse model. ### Final_Prediction: yes

### Question: Do we need to maximize the knowledge and attitude level of physicians and nurses toward organ donation and transplant? ### Context: We sought to assess the knowledge level, attitudes, and personal views of physicians and nurses toward organ donation and transplant.This is a cross-sectional survey, carried out from November 2007 to June 2008 in the intensive care units and accident and emergency departments of the hospitals of the Hamad Medical Corporation. A representative sample of 685 health care professionals working in the hospitals was approached; 521 agreed to participate in the study (76.1%). Face-to-face interviews were based on a questionnaire that included sociodemographic information, knowledge level, and personal views toward organ donation and transplant.Of the 521 participants, there were 268 physicians (51.4%) and 253 nurses (48.6%). The knowledge level of nurses was significantly lower for most of the questions related to organ donation, compared with physicians. Mean -/+ standard deviation for the score reflecting knowledge level was higher for physicians (4.9 -/+ 1.9) than it was for nurses (4.4 -/+ 2.0). The majority of the nurses believed, more than physicians, that brain-dead persons are eligible for organ donation (71.5% vs 63.1%), and that certain organs can be donated while the person is living, including kidneys, lobes of livers, and lungs (71.5% vs 62.3%). Many physicians (72.4%) and nurses (74.7%) did not know that brain death can be described as death. Most physicians and nurses supported organ donation (91.8% vs 79.8%), although a lower proportion of physicians and nurses were willing to donate a kidney to a family member in need (64.6% vs 68.0%). More than physicians (23.9%), nurses (61.3%) agreed that they lacked sufficient information about organ donation. ### Long_Answer: Although the physicians and nurses had an acceptable level of knowledge about organ donation, the mean knowledge score for physicians showed significantly better understanding of the criteria for organ donation and procurement. ### Final_Prediction: nan

### Question: Repeat Cardiovascular Risk Assessment after Four Years: Is There Improvement in Risk Prediction? ### Context: Framingham risk equations are widely used to predict cardiovascular disease based on health information from a single time point. Little is known regarding use of information from repeat risk assessments and temporal change in estimated cardiovascular risk for prediction of future cardiovascular events. This study was aimed to compare the discrimination and risk reclassification of approaches using estimated cardiovascular risk at single and repeat risk assessments.Using data on 12,197 individuals enrolled in EPIC-Norfolk cohort, with 12 years of follow-up, we examined rates of cardiovascular events by levels of estimated absolute risk (Framingham risk score) at the first and second health examination four years later. We calculated the area under the receiver operating characteristic curve (aROC) and risk reclassification, comparing approaches using information from single and repeat risk assessments (i.e., estimated risk at different time points).The mean Framingham risk score increased from 15.5% to 17.5% over a mean of 3.7 years from the first to second health examination. Individuals with high estimated risk (≥20%) at both health examinations had considerably higher rates of cardiovascular events than those who remained in the lowest risk category (<10%) in both health examinations (34.0 [95%CI 31.7-36.6] and 2.7 [2.2-3.3]per 1,000 person-years respectively). Using information from the most up-to-date risk assessment resulted in a small non-significant change in risk classification over the previous risk assessment (net reclassification improvement of -4.8%, p>0.05). Using information from both risk assessments slightly improved discrimination compared to information from a single risk assessment (aROC 0.76 and 0.75 respectively, p<0.001). ### Long_Answer: Using information from repeat risk assessments over a period of four years modestly improved prediction, compared to using data from a single risk assessment. However, this approach did not improve risk classification. ### Final_Prediction: nan

### Question: Does identification and early treatment of dehydration in home parenteral nutrition and home intravenous fluid patients prevent hospital admissions? ### Context: Early identification and treatment of dehydration is prudent in patients requiring home parenteral nutrition (HPN) or home intravenous fluids (HIVF) to prevent hospital admissions for dehydration. Our home nutrition support service (HNS) developed a protocol in 2010 to provide additional bags of HIVF to be kept on hand for immediate use in patients identified at risk of developing dehydration.A retrospective review was performed on all HPN and HIVF patients from a clinical database who received additional HIVF during 2010. Standard treatment for dehydration was 1 L HIVF daily for 3 days in addition to prescribed infusions.Of 308 HNS patients in 2010, additional HIVF were ordered in 161 patients with malabsorption, fistula, or obstruction. Of the 161 patients, 63% (n = 102) required additional HIVF and had 201 episodes of dehydration recorded. Increased enterostomy output (P = .021), negative intake and output (I/O data) (P = .014), and age (P = .021) were predictors of multiple dehydration episodes. I/O data were consistent with signs and symptoms of dehydration 80% of the time. One hundred seventy episodes (84.5%) of dehydration were successfully treated at home compared with 9 emergency room (ER) admissions (4.5%) and 22 hospital admissions (11%) for dehydration. ### Long_Answer: We demonstrate 84.5% of episodes of dehydration successfully treated in the home in patients initially identified at risk by our protocol. Education of patients at risk of dehydration prior to discharge and providing additional HIVF on hand for immediate use may avoid ER treatment or hospitalization and potentially save healthcare costs. ### Final_Prediction: yes

### Question: Is aPOEε2 associated with milder clinical and pathological Alzheimer disease? ### Context: The Alzheimer disease (AD) APOEε4 risk allele associates with an earlier age at onset and increased amyloid-β deposition, whereas the protective APOEε2 allele delays the onset and appears to prevent amyloid-β deposition. Yet the clinical and pathological effects of APOEε2 remain uncertain because of its relative rarity. We investigated the effects of APOEε2 and ε4 alleles on AD pathology and cognition in a large US data set of well-characterized AD patients.We studied individuals from the National Alzheimer's Coordinating Center autopsy cohort across the entire clinicopathological continuum of AD. Multivariate models were built to examine the associations between APOE alleles and AD neuropathological changes, using the APOEε3/ε3 group as comparator. Mediation analysis was used to estimate the direct and indirect effects of APOE alleles on AD pathology and cognition (Clinical Dementia Rating Sum of Boxes and Mini-Mental State Examination).Compared to APOEε3/ε3, APOEε2 is independently associated with lower Braak neurofibrillary tangle (NFT) stages and possibly fewer neuritic plaques, but has no direct effect on cerebral amyloid angiopathy (CAA) severity, whereas APOEε4 is associated with more neuritic plaques and CAA, but has no independent effect on Braak NFT stage. Unadjusted analyses showed marked differences among APOE genotypes with respect to cognitive performance (ε2 > ε3 > ε4). Mediation analysis suggests that this is largely explained through effects on pathology. ### Long_Answer: Even when adjusted for age at onset, symptom duration, and other demographic variables, APOEε2 is associated with milder AD pathology and less severe antemortem cognitive impairment compared to APOEε3 and ε4 alleles, suggesting a relative neuroprotective effect of APOEε2 in AD. ### Final_Prediction: yes

### Question: Mesh repair for postoperative wound dehiscence in the presence of infection: is absorbable mesh safer than non-absorbable mesh? ### Context: In patients with postoperative wound dehiscence in the presence of infection, extensive visceral oedema often necessitates mechanical containment of bowel. Prosthetic mesh is often used for this purpose. The aim of the present study was to assess the safety of the use of non-absorbable and absorbable meshes for this purpose.All patients that had undergone mesh repair of abdominal wound dehiscence between January 1988 and January 1998 in the presence of intra-abdominal infection were included in a retrospective cohort study. All surviving patients had physical follow-up in February 2001.Eighteen patients were included in the study. Meshes consisted of polyglactin (n = 6), polypropylene (n = 8), polyester (n = 1), or a combination of a polypropylene mesh with a polyglactin mesh on the visceral side (n = 3). All patients developed complications, consisting mainly of mesh infection (77%), intra-abdominal abscess (17%), enterocutaneous fistula (17%), or mesh migration through the bowel (11%). Mesh removal was necessary in eight patients (44%). Within four months postoperatively, six patients (33%) had died because of progressive abdominal sepsis. The incidence of progressive abdominal sepsis was significantly higher in the group with absorbable polyglactin mesh than in the group with nonabsorbable mesh (67 vs. 11%, p = 0.02) After a mean follow-up of 49 months, 63% of the surviving patients had developed incisional hernia. Absorbable meshes did not yield better outcomes than nonabsorbable meshes in terms of complications and mortality rate. ### Long_Answer: Synthetic graft placement in the presence of intra-abdominal infection has a high risk of complications, regardless of whether absorbable (polyglactin) or non-absorbable mesh material (polypropylene or polyester) is used, and should be avoided if possible. ### Final_Prediction: nan

### Question: Does autologous platelet-poor plasma decrease the bronchial stump necrosis in rat? ### Context: Necrosis of the bronchial stump is a very important trigger for bronchopleural fistula. The administration of local autologous platelet-poor plasma (PPP) could protect the bronchial stump.Left pneumonectomy was performed in 25 Sprague-Dawley rats. Animals were randomly assigned to a control group (n=13) and PPP group (n=12). PPP was locally administered on the bronchial stump after pneumonectomy. We analyzed histologic changes in the bronchial stump and messenger RNA expression changes of genes involved in wound repair at 10 and 20 d.Local PPP treatment produced a mass of fibrous tissue surrounding the bronchial stump and significantly decreased the presence of necrosis at 20 d. PPP increased the expression of insulin like growth factor 1 at 10 d although it did not reach statistical significance. ### Long_Answer: Our findings indicate that local PPP treatment of the bronchial stump after pneumonectomy decreased necrosis and could have a protective effect on the bronchial stump. ### Final_Prediction: yes

### Question: Does semaphorin 5A promote gastric cancer invasion/metastasis via urokinase-type plasminogen activator/phosphoinositide 3-kinase/protein kinase B? ### Context: Semaphorin 5A, a member of the semaphorin family, was originally identified as an axonal guidance factor functioning during neuronal development. Previously, we showed that the expression of semaphorin 5A might contribute to the metastasis of gastric cancer. However, less information is currently available as to the involvement of uPA in the semaphorin 5A-induced metastasis and invasion of gastric cancer cells.The present study was designed to test whether semaphorin 5A mediates the invasion and metastasis of gastric cancer via PI3K/Akt/uPA signaling.The semaphorin 5A-overexpressing cell was established from the gastric cancer cell line AGS. The effect of semaphorin 5A on the expression of uPA was evaluated by ELISA and Western blotting as well as RT-PCR assays, respectively. Synthetic or natural inhibitors and dominant-negative mutants were used to determine the hierarchical relationship between semaphorin 5A, PI3K/Akt and uPA in the invasion and metastasis of gastric cancer.Overpression of semaphorin 5A enhanced the expression of uPA, and synthetic or natural inhibitors of uPA abolished semaphorin 5A-induced cell migration and invasion. Semaphorin 5A overexpression promoted the phosphorylation of Akt. Blocking effects of PI3K/Akt using pharmacologic inhibitors, dominant-negative mutants abolished the ability of semaphorin 5A to induce uPA expression and cell invasion and migration. ### Long_Answer: Semaphorin 5A could promote invasion and metastasis of gastric cancer through the PI3K/Akt/uPA signal transduction pathway. Semaphorin 5A and its regulated molecules could be the potential targets for cancer therapy. ### Final_Prediction: yes

### Question: Does three-month exercise and weight loss program improve heart rate recovery in obese persons along with cardiopulmonary function? ### Context: Heart rate recovery (HRR) after exercise is an independent risk factor for cardiovascular disease and mortality, and it is well known to be modifiable by weight loss. We investigated whether HRR was mainly improved by better cardiopulmonary function or by alteration of the metabolic profile.The weight loss program included 2h of group exercise per week and individual dietary instruction by a qualified dietician every week. Clinical assessment (including HRR) was done before and after the 3-month program.The subjects were 125 obese persons without a past history of stroke, cardiovascular events, or use of medications who participated in and completed our exercise plus weight loss program.HRR (35.61+/-12.83 to 45.34+/-13.6 beats/min, p<0.0001) was significantly faster after the program. The change in HRR was significantly correlated (p<0.05) with the changes in body weight, body mass index, percent body fat, waist circumference, hip circumference, resting heart rate, peak exercise heart rate, exercise time, maximal work load, physical working capacity divided by body weight (PWC75%HRmax/weight), subcutaneous fat area, visceral fat area, low-density lipoprotein cholesterol, and leptin. Multivariate analysis showed that the change in HRR was significantly correlated (p<0.05) with the changes in resting heart rate, peak exercise heart rate, and PWC75%HRmax/weight. ### Long_Answer: Our data demonstrated that HRR can be improved in obese subjects by a 3-month exercise and weight loss program. Improvement in cardiopulmonary function by exercise seems to be the main contributor to the increment of HRR. ### Final_Prediction: yes

### Question: Does the cholecystokinin antagonist proglumide enhance the analgesic effect of dihydrocodeine? ### Context: To investigate the potential pro-analgesic effect of the non-specific CCK antagonist proglumide on the analgesia produced by dihydrocodeine.A double-blind, placebo-controlled crossover study of 30 adult subjects.Mean pain scores fell from a baseline of 8.12-7.89 during the placebo phase (N.S.) and to 6.82 during the proglumide phase (P < 0.05). Side effects were minor. ### Long_Answer: The CCK antagonist proglumide enhances the analgesic effect of dihydrocodeine. ### Final_Prediction: yes

### Question: Is connective tissue growth factor expression in endocrine tumors associated with high stromal expression of alpha-smooth muscle actin? ### Context: Complications due to fibrosis development are common in patients with well-differentiated endocrine carcinomas in the small intestine (ileal carcinoids). Connective tissue growth factor (CTGF) expression in ileal carcinoids may be related to this fibrosis development. This study aimed to examine CTGF expression in relation to local myofibroblast differentiation in a large series of ileal carcinoids and in different types of endocrine tumors.Immunoreactivity (IR) for CTGF and α-smooth muscle actin (α-SMA), a marker for myofibroblasts, was compared in serial tumor tissue sections from 42 patients with ileal carcinoids and from 80 patients with other endocrine tumors. Western blot was performed on an additional 21 patients with ileal carcinoids.CTGF IR was present in >50% of tumor cells in all 42 ileal carcinoids and in 2 out of 14 endocrine pancreatic tumors, 4 out of 6 rectal carcinoids, and 1 out of 5 lung carcinoids. Tumors with abundant CTGF expression also displayed α-SMA IR in stromal fibroblast-like cells, whereas other endocrine tumors displayed less or no CTGF and α-SMA IR. Protein bands corresponding to full-length CTGF (36-42 kDa) were detected in protein lysates from ileal carcinoids. ### Long_Answer: CTGF is uniquely prevalent in ileal carcinoids when compared with most other endocrine tumor types. Immunoreactive cells are adjacent areas with increased fibrovascular stroma that express α-SMA. This supports a potential role for CTGF in myofibroblast-mediated fibrosis associated with ileal carcinoids, and indicates that CTGF should be investigated as a target for future therapy. ### Final_Prediction: yes

### Question: Is hyperchloremia associated with mortality in critically ill patients? ### Context: The aim of the study was to determine if acid-base variables are associated with hospital mortality.This prospective cohort study took place in a university-affiliated hospital intensive care unit (ICU). One hundred seventy-five patients admitted to the ICU during the period of February to May 2007 were included in the study. We recorded clinical data and acid-base variables from all patients at ICU admission. A logistic regression model was constructed using Sepsis-related Organ Failure Assessment (SOFA) score, age, and the acid-base variables.Individually, none of the variables appear to be good predictors of hospital mortality. However, using the multivariate stepwise logistic regression, we had a model with good discrimination containing SOFA score, age, chloride, and albumin (area under receiver operating characteristic curve, 0.80; 95% confidence interval, 0.73-0.87). ### Long_Answer: Hypoalbuminemia and hyperchloremia were associated with mortality. This result involving chloride is something new and should be tested in future studies. ### Final_Prediction: nan

### Question: Clusters according to patient need in a long-stay inpatient population with schizophrenia: does executive dysfunction underpin needs-directed care? ### Context: To identify the external validators of patient clusters according to need in a long-stay inpatient population with schizophrenia.We recruited without exclusion 112 in-patients with chronic schizophrenia in a long-stay rehabilitation facility of a major psychiatric hospital in Perth, Western Australia. Case managers completed a number of measures for participants, including The Camberwell Assessment of Need-Short Appraisal Schedule, which evaluates health and social needs. Latent class analysis according to patient need was performed to identify clusters within the cohort. One way analysis of variance was used to identify the external validators of these clusters, using variables obtained from the additional study measures (Social Behaviour Schedule, Global Assessment of Function, Basic Everyday Living Skills, Behaviour Rating Inventory of Executive Function-Adult version).Three distinct needs-based clusters with different external profiles were identified. A "low unmet needs" group (n = 50) with relatively intact executive function, with the least problematic behaviour and most independent functioning; a "high unmet need (drug abstinent)" group (n = 43) with greatest executive dysfunction, most problematic behaviour and least independent function; a "high unmet need (drug using)" group (n = 19), with less severe executive dysfunction, and intermediate relative to the other groups on measures of social behaviour and independent functioning. ### Long_Answer: The clinical heterogeneity we have identified, which may well be explained by executive dysfunction, suggests further exploration of appropriate assessment and streams of care for those in the rehabilitation setting is warranted. ### Final_Prediction: nan

### Question: Does obesity lead to declines in motor skills across childhood? ### Context: Poor motor skills have been consistently linked with a higher body weight in childhood, but the causal direction of this association is not fully understood. This study investigated the temporal ordering between children's motor skills and weight status at 5 and 10 years.Participants were 668 children (54% male) who were studied from infancy as part of an iron deficiency anaemia preventive trial and follow-up study in Santiago, Chile. All were healthy, full-term and weighing 3 kg or more at birth. Cross-lagged panel modelling was conducted to understand the temporal precedence between children's weight status and motor proficiency. Analyses also examined differences in gross and fine motor skills among healthy weight, overweight, and obese children.A higher BMI at 5 years contributed to declines in motor proficiency from 5 to 10 years. There was no support for the reverse, that is, poor motor skills at 5 years did not predict increases in relative weight from 5 to 10 years. Obesity at 5 years also predicted declines in motor proficiency. When compared with normal weight children, obese children had significantly poorer total and gross motor skills at both 5 and 10 years. Overweight children had poorer total and gross motor skills at 10 years only. The differences in total and gross motor skills among normal weight, overweight and obese children appear to increase with age. There were small differences in fine motor skill between obese and non-obese children at 5 years only. ### Long_Answer: Obesity preceded declines in motor skills and not the reverse. Study findings suggest that early childhood obesity intervention efforts might help prevent declines in motor proficiency that, in turn, may positively impact children's physical activity and overall fitness levels. ### Final_Prediction: yes

### Question: Does phenotype-stratified genetic linkage study demonstrate that IBD2 is an extensive ulcerative colitis locus? ### Context: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci.This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis.We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. ### Long_Answer: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD. ### Final_Prediction: yes

### Question: Does autophagy facilitate antibody-enhanced dengue virus infection in human pre-basophil/mast cells? ### Context: Dengue virus (DENV) infection can cause severe hemorrhagic disease in humans. Although the pathogenic mechanisms underlying severe DENV disease remain unclear, one of the possible contributing factors is antibody-dependent enhancement (ADE) which occurs when sub-neutralizing antibodies derived from a previous DENV infection enhance viral infection through interaction between virus-antibody complexes and FcR-bearing cells, such as macrophages and basophil/mast cells. Although recent reports showed that DENV induces autophagy, the relationship between antibody-enhanced DENV infection and autophagy is not clear.We showed that sub-neutralizing antibodies derived from dengue patient sera enhanced DENV infection and autophagy in the KU812 pre-basophil-like cell line as well as the HMC-1 immature mast cell line. Antibody-enhanced DENV infection of KU812 cells increased the number of autophagosome vesicles, LC3 punctation, LC3-II accumulation, and p62 degradation over that seen in cells infected with DENV alone. The percentages of DENV envelope (E) protein-positive cells and LC3 puncta following antibody-enhanced DENV infection of KU812 cells were reduced by the autophagy inhibitor 3-MA. Antibody-enhanced DENV infection of HMC-1 cells showed co-localization of DENV E protein and dsRNA with autophagosomes, which was inhibited by 3-MA treatment. Furthermore, DENV infection and replication were reduced when KU812 cells were transfected with the autophagy-inhibiting Atg4BC74A mutant. ### Long_Answer: Our results demonstrate a significant induction of autophagy in antibody-enhanced DENV infection of pre-basophil-like KU812 and immature mast cell-like HMC-1 cells. Also, autophagy plays an important role in DENV infection and replication in these cells. Given the importance of ADE and FcR-bearing cells such as monocytes, macrophages and basophil/mast cells in dengue disease, the results provide insights into dengue pathogenesis and therapeutic means of control. ### Final_Prediction: yes

### Question: Right ventricular ejection fraction during orthotopic liver transplantation: does anesthetic technique make a difference? ### Context: The objective of this study is to evaluate the right ventricular ejection fraction (RVEF) during orthotopic liver transplantation (OLT) under 2 different anesthetic regimens: propofol vs isoflurane anesthesia.We retrospectively analyzed the hemodynamic data of 25 (n = 25) patients who underwent OLT during the last year (2008). All patients were monitored with a modified pulmonary artery catheter, which continuously measured the RVEF. Anesthetic technique consisted of either isoflurane or total intravenous anesthesia with propofol. Surgical technique was similar between groups.Ten (n = 10) patients comprised the isoflurane group (I), whereas 15 (n = 15) patients received propofol anesthesia (P). The RVEF was not significantly different between groups (I vs P, baseline: 41% ± 9% vs 40% ± 6%; anhepatic phase: 36% ± 8% vs 35% ± 6%; postreperfusion: 41% ± 6% vs 41% ± 8%; P = not significant). ### Long_Answer: The choice between propofol and isoflurane seems to have minimal influence on the RVEF during OLT, which followed similar trends regardless of the anesthetic technique. ### Final_Prediction: nan

### Question: Is surgical intervention and accommodative responses , II : forward ciliary body accommodative movement facilitated by zonular attachments to the lens capsule? ### Context: To determine the role of the lens and the lens capsule in the three-dimensional architecture of the ciliary muscle at rest and during accommodation, in live rhesus monkeys and in histologic sections, by removing the entire lens, or only the lens nucleus and cortex, while leaving the posterior capsule in place.In 15 rhesus monkey eyes, aged 6 to 27 years, accommodation was induced by central stimulation of the Edinger-Westphal nucleus before and after intra- or extracapsular lens extraction (ICLE, ECLE). Forward ciliary body movement and ciliary body width were measured by ultrasound biomicroscopy (UBM, 50 MHz). The monkeys were then killed, the eyes were examined morphologically in 1-microm sections, and the shape of the ciliary muscle was compared with that obtained from UBM images.The shape of the ciliary muscle in eyes undergoing ECLE (n = 5) did not differ from that in control eyes. In contrast, after ICLE (n = 10), accommodative forward ciliary body movement (P < 0.01) and thickness were decreased (P < 0.001), length was increased (P = 0.058), and the inner apex was located more posteriorly than in control eyes (P < 0.005). Histologic and in vivo data were similar and showed that the ciliary muscle maintained its triangular shape only if the lens capsule (with or without the lens substance) was present. ### Long_Answer: The posterior lens capsule and anterior zonular attachments facilitate forward accommodative ciliary body movement. Lens substance extraction procedures that leave the posterior capsule intact, similar to those used clinically, do not affect the capsule/zonular/muscular system movements, an important finding for accommodating intraocular lens development. ### Final_Prediction: yes

### Question: Is birch pollen immunotherapy in mice : inhibition of Th2 inflammation sufficient to decrease airway hyper-reactivity? ### Context: Suppression of Th2 cytokine production by allergen-specific Th2 cells is considered to be critical for the suppression of allergic symptoms by subcutaneous immunotherapy. The aim of this study was to develop a mouse model for birch pollen (BP) immunotherapy to elucidate the underlying mechanisms that contribute to the improvement of clinical symptoms.Mice with BP-induced allergic airway inflammation received weekly subcutaneous immunotherapy (SCIT) injections with BP extract (BPE) adsorbed to alum. The effect of an increasing dose of BPE adsorbed to a fixed concentration of alum on the suppression of airway inflammation and airway hyper-responsiveness (AHR) was determined. After 2, 4, 6 or 8 immunotherapy injections, the mice were rechallenged with the same allergen and all hallmarks of allergic asthma were evaluated.Suppression of the immunological parameters by immunotherapy was dependent on the BPE dose. Two injections were sufficient to suppress IL-4, IL-5, IL-13, IL-10 and IFN-γ production, eosinophil recruitment and peribronchial inflammatory infiltrates. BP-specific immunoglobulins were upregulated, but this was not sufficient to reduce AHR. Eight injections were needed to suppress AHR. The gradual reduction in AHR was inversely associated with the increase of BP IgG2a. ### Long_Answer: BP SCIT induces an early suppression of Th2-mediated eosinophilic airway inflammation, but AHR is only effectively reduced after continued SCIT conceivably by allowing IgG2a antibody titres to build up. ### Final_Prediction: no

### Question: The impact of intraoperative neuromonitoring (IONM) on surgical strategy in bilateral thyroid diseases: is it worth the effort? ### Context: Intraoperative nerve monitoring (IONM) of the recurrent laryngeal nerve and the vagal nerve can detect nonfunctioning nerves (recurrent laryngeal nerve palsy, RLNP) that are visibly intact. The use of IONM is questionable, however, as we still lack evidence that it reduces the rate of postoperative nerve injuries. Since negative IONM results after thyroid dissection of the first side could change our surgical strategy and thus could prevent patients from bilateral RLNP, we questioned whether IONM results are reliable enough to base changes in surgical strategy and whether this has any effect on surgical outcome.We retrospectively analyzed the data of 1333 consecutive patients with suggested benign bilateral thyroid disease who had been operated on under a defined protocol, including the use of a specific IONM technique (tube electrodes and stimulation of the vagal nerve and the inferior recurrent nerve before and after thyroid resection), between January 1, 2006 and December 31, 2008.In four patients the IONM system did not work, two nerves had not been found, and in eight patients the tube had to be readjusted. Of five permanent nerve injuries, four were visible during surgery and one was suspected. Sensitivity of IONM in detecting temporary nerve injuries of macroscopically normal-appearing nerves was 93%. Specificity was 75-83% at first side of dissection and 55-67% at the second side, with an overall specificity of 77%. In 11 of 13 patients (85%) with known nerve injury (preexisting or visible) and in 20 of 36 patients (56%) with negative IONM stimulation at the first side of dissection, the surgical strategy was changed (specific surgeon or restricted resection) with no postoperative bilateral RLNP. This was in contrast to 3 of 18 (17%) bilateral RLNP (p<0.05), when surgeons were not aware of a preexisting or highly likely nerve injury at the first side of thyroid dissection. ### Long_Answer: Failed IONM stimulation of the vagal or recurrent laryngeal nerve after resection of the first thyroid lobe is specific enough to reconsider the surgical strategy in patients with bilateral thyroid disease to surely prevent bilateral RLNP. ### Final_Prediction: nan

### Question: A prospective trial of systematic nodal dissection for lung cancer by video-assisted thoracic surgery: can it be perfect? ### Context: There have been no reports evaluating the completeness of systematic nodal dissection with video-assisted thoracic surgery (VATS). In order to elucidate the completeness of the dissection, we have conducted a prospective trial with patients having primary lung cancer.Patients with clinical stage I lung cancer were the candidates for this study. Thoracotomy was performed with a small skin incision of 7 cm to 8 cm in length. Through these small wounds and two trocars, pulmonary resection was performed and then hilar and mediastinal lymph nodes were dissected. After that, a standard thoracotomy was carried out by another surgeon to complete systematic nodal dissection.Video-assisted thoracic surgery lobectomy with lymph node dissection was accomplished in 17 right lung cancer patients and 12 left lung cancer patients. On the right side, the average numbers of resected lymph nodes by VATS and remnant lymph nodes were 40.3 and 1.2, respectively. The average weights of dissected tissues by VATS and remnant tissues were 10.0 g and 0.2 g, respectively. On the left side, there were 37.1 and 1.2 lymph nodes and 8.3 g and 0.2 g of weight of dissected tissues. No nodal involvement was observed in the remnant lymph nodes. ### Long_Answer: The lymph node dissection with VATS was technically feasible and the remnant ("missed" by VATS) lymph nodes and tissues were 2% to 3%, which seems acceptable for clinical stage I lung cancer. ### Final_Prediction: nan

### Question: Do needle age and season influence photosynthetic temperature response and total annual carbon uptake in mature Picea mariana trees? ### Context: The carbon (C) balance of boreal terrestrial ecosystems is sensitive to increasing temperature, but the direction and thresholds of responses are uncertain. Annual C uptake in Picea and other evergreen boreal conifers is dependent on seasonal- and cohort-specific photosynthetic and respiratory temperature response functions, so this study examined the physiological significance of maintaining multiple foliar cohorts for Picea mariana trees within an ombrotrophic bog ecosystem in Minnesota, USA.Measurements were taken on multiple cohorts of needles for photosynthetic capacity, foliar respiration (Rd) and leaf biochemistry and morphology of mature trees from April to October over 4 years. The results were applied to a simple model of canopy photosynthesis in order to simulate annual C uptake by cohort age under ambient and elevated temperature scenarios.Temperature responses of key photosynthetic parameters [i.e. light-saturated rate of CO2 assimilation (Asat), rate of Rubisco carboxylation (Vcmax) and electron transport rate (Jmax)] were dependent on season and generally less responsive in the developing current-year (Y0) needles compared with 1-year-old (Y1) or 2-year-old (Y2) foliage. Temperature optimums ranged from 18·7 to 23·7, 31·3 to 38·3 and 28·7 to 36·7 °C for Asat, Vcmax and Jmax, respectively. Foliar cohorts differed in their morphology and photosynthetic capacity, which resulted in 64 % of modelled annual stand C uptake from Y1&2 cohorts (LAI 0·67 m(2 )m(-2)) and just 36 % from Y0 cohorts (LAI 0·52 m(2 )m(-2)). Under warmer climate change scenarios, the contribution of Y0 cohorts was even less; e.g. 31 % of annual C uptake for a modelled 9 °C rise in mean summer temperatures. Results suggest that net annual C uptake by P. mariana could increase under elevated temperature, and become more dependent on older foliar cohorts. ### Long_Answer: Collectively, this study illustrates the physiological and ecological significance of different foliar cohorts, and indicates the need for seasonal- and cohort-specific model parameterization when estimating C uptake capacity of boreal forest ecosystems under ambient or future temperature scenarios. ### Final_Prediction: yes

### Question: Does curcumin induce apoptosis in human neuroblastoma cells via inhibition of NFkappaB? ### Context: Metastasised neuroblastoma is a largely incurable neoplasia in children over one year of age using current treatment protocols. After dissemination to the bone, the survival rate is <7%, indicating an urgent need for novel therapeutic regimes. As curcumin (diferuloylmethane) had been shown to exert strong anticancer effects against diverse human malignancies different from neurblastoma, the antiproliferative effect of curcumin on the growth of human neuroblastoma cell lines was tested.Proliferation of neuroblastoma cell lines Lan-5, SK-N-SH and Kelly under the treatment of curcumin over a broad concentration range (1 x 10(-5) to 1 x 10(2) microM) was assessed using XTT cell proliferation assays. Possible induction of apoptosis through curcumin treatment was assessed by detection of DNA fragmentation. To investigate the effect of curcumin on NFkappaB activation, the protein levels of the NFkappaB subunit p65 of curcumin-treated cells were compared to untreated cells using Western blots.Curcumin showed a significant dose-dependent antiproliferative effect on all three neuroblastoma cell lines starting at a concentration of 1 x 10(-3) microM. The highest concentration of 1 x 10(2) microM significantly reduced the viable cell count to 8-48% depending on the cell line. This antiproliferative effect was mediated through an increased induction of apoptosis by inhibition of NFkappaB, corroborating earlier findings indicating an antiapoptotic effect of NFkappaB. ### Long_Answer: Our results suggest that curcumin might hold promise in the treatment of patients suffering from neuroblastoma. ### Final_Prediction: yes

### Question: Are outcomes Worse in US Patients Undergoing Surgery on Weekends Compared With Weekdays? ### Context: Increasing surgical access to previously underserved populations in the United States may require a major expansion of the use of operating rooms on weekends to take advantage of unused capacity. Although the so-called weekend effect for surgery has been described in other countries, it is unknown whether US patients undergoing moderate-to-high risk surgery on weekends are more likely to experience worse outcomes than patients undergoing surgery on weekdays.The aim of this study was to determine whether patients undergoing surgery on weekends are more likely to die or experience a major complication compared with patients undergoing surgery on a weekday.Using all-payer data, we conducted a retrospective cohort study of 305,853 patients undergoing isolated coronary artery bypass graft surgery, colorectal surgery, open repair of abdominal aortic aneurysm, endovascular repair of abdominal aortic aneurysm, and lower extremity revascularization. We compared in-hospital mortality and major complications for weekday versus weekend surgery using multivariable logistic regression analysis.After controlling for patient risk and surgery type, weekend elective surgery [adjusted odds ratio (AOR)=3.18; 95% confidence interval (CI), 2.26-4.49; P<0.001] and weekend urgent surgery (AOR=2.11; 95% CI, 1.68-2.66; P<0.001) were associated with a higher risk of death compared with weekday surgery. Weekend elective (AOR=1.58; 95% CI, 1.29-1.93; P<0.001) and weekend urgent surgery (AOR=1.61; 95% CI, 1.42-1.82; P<0.001) were also associated with a higher risk of major complications compared with weekday surgery. ### Long_Answer: Patients undergoing nonemergent major cardiac and noncardiac surgery on the weekends have a clinically significantly increased risk of death and major complications compared with patients undergoing surgery on weekdays. These findings should prompt decision makers to seek to better understand factors, such physician and nurse staffing, which may contribute to the weekend effect. ### Final_Prediction: yes

### Question: Does a missense mutation ( S3660L ) in MLL3 gene influence risk of gastric cancer? ### Context: Several studies indicated that the expression level of MLL3 gene in gastric cancer tissue was associated with prognosis, and previous studies also suggested that genetic polymorphisms of MLL3 were related to the risk for gastric cancer. The present study aimed to investigate the association of a missense mutation (S3660L) in the MLL3 gene with gastric cancer risk in a Chinese population.In the present study, we identified a novel missense mutation in MLL3 gene (S3660L) by directly sequencing method in 48 gastric cancer patients. To further explore the relation between gastric cancer and this mutation, we selected 354 gastric cancer patients and 377 healthy control subjects and designed a case-control study.We found that the AG genotype (14.9 vs 6.40%, odds ratio/OR=2.58, 95% CI: 1.33-4.54, p<0.001) and A allele (7.5 vs 3.2%, OR=2.46, 95% CI: 1.55~5.34, p<0.001) were common in the gastric cancer patients than in the control subjects. ### Long_Answer: We concluded that this novel missense (S3660L) mutation in MLL3 gene is likely to increase the gastric cancer risk. ### Final_Prediction: yes

### Question: Are higher levels of advanced glycation endproducts in human carotid atherosclerotic plaques associated with a rupture-prone phenotype? ### Context: Rupture-prone atherosclerotic plaques are characterized by inflammation and a large necrotic core. Inflammation is linked to high metabolic activity. Advanced glycation endproducts (AGEs) and their major precursor methylglyoxal are formed during high metabolic activity and can have detrimental effects on cellular function and may induce cell death. Therefore, we investigated whether plaque AGEs are increased in human carotid rupture-prone plaques and are associated with plaque inflammation and necrotic core formation.The protein-bound major methylglyoxal-derived AGE 5-hydro-5-methylimidazolone (MG-H1) and N(ε)-(carboxymethyl)lysine (CML) were measured in human carotid endarterectomy specimens (n = 75) with tandem mass spectrometry. MG-H1 and CML levels were associated with rupture-prone plaques, increased protein levels of the inflammatory mediators IL-8 and MCP-1 and with higher MMP-9 activity. Immunohistochemistry showed that AGEs accumulated predominantly in macrophages surrounding the necrotic core and co-localized with cleaved caspase-3. Intra-plaque comparison revealed that glyoxalase-1 (GLO-1), the major methylglyoxal-detoxifying enzyme, mRNA was decreased (-13%, P < 0.05) in ruptured compared with stable plaque segments. In line, in U937 monoctyes, we found reduced (GLO-1) activity (-38%, P < 0.05) and increased MGO (346%, P < 0.05) production after stimulation with the inflammatory mediator TNF. Direct incubation with methylglyoxal increased apoptosis up to two-fold. ### Long_Answer: This is the first study showing that AGEs are associated with human rupture-prone plaques. Furthermore, this study suggests a cascade linking inflammation, reduced GLO-1, methylglyoxal- and AGE-accumulation, and subsequent apoptosis. Thereby, AGEs may act as mediators of the progression of stable to rupture-prone plaques, opening a window towards novel treatments and biomarkers to treat cardiovascular diseases. ### Final_Prediction: yes

### Question: Does 16S rDNA sequencing of valve tissue improve microbiological diagnosis in surgically treated patients with infective endocarditis? ### Context: The aim was to evaluate 16S rDNA sequencing in heart valves in patients with infective endocarditis undergoing surgery.Fifty-seven patients with infective endocarditis were examined in this prospective study by analysing heart valves with 16S rDNA sequencing and culturing methods and comparing the results to blood cultures. As controls, heart valves from 61 patients without any signs of endocarditis were examined.All together 77% of the endocarditis patients were positive for 16S rDNA, 84% had positive blood cultures and 23% had positive cultures from heart valves, whereas only 16% of the cultures from heart valves were concordant with results from blood cultures or 16S rDNA. Concordant results between 16S rDNA sequencing and blood cultures were found in 75% patients. All controls were negative for 16S rDNA. In 4 out of 9 patients with negative blood cultures, the aetiology was established by 16S rDNA alone, i.e. viridans group streptococci. ### Long_Answer: In this Swedish study, 16S rDNA sequencing of valve material was shown to be a valuable addition in blood culture-negative cases. The value of heart valve culture was low. Molecular diagnosis using 16S rDNA sequencing should be recommended in patients undergoing valve replacement for infective endocarditis. ### Final_Prediction: yes

### Question: Does dietary selenium augment sarcoplasmic calcium release and mechanical performance in mice? ### Context: As an essential trace element selenium plays a significant role in many physiological functions of the organs. It is found within muscles as selenocystein in selenoprotein N, which is involved in redox-modulated calcium homeostasis and in protection against oxidative stress.The effects of two different selenium compounds (selenate and NanoSe in 0.5 and 5 ppm concentration for two weeks) on muscle properties of mice were examined by measuring While the grip force did not change, 5 ppm selenium diets significantly increased the speed of voluntary running and the daily distance covered. Both forms of selenium increased significantly the amplitude of single twitches in EDL and SOL muscle in a concentration dependent manner. Selenate increased fatigue resistance in SOL. The amplitude of the calcium transients evoked by KCl depolarization increased significantly from the control of 343 ± 44 nM to 671 ± 51 nM in the presence of 0.5 ppm selenate in FDB fibers. In parallel, the rate of calcium release during short depolarizations increased significantly from 28.4 ± 2.2 to 45.5 ± 3.8 and 52.1 ± 1.9 μM/ms in the presence of 0.5 ppm NanoSe and selenate, respectively. In 0.5 ppm concentration both selenium compounds increased significantly the selenoprotein N expression only in EDL muscle. ### Long_Answer: Selenium supplementation augments calcium release from the sarcoplasmic reticulum thus improves skeletal muscle performance. These effects are accompanied by the increased selenoprotein N expression in the muscles which could result in increased oxidative stress tolerance in case of long lasting contraction. ### Final_Prediction: yes

### Question: Are drug-free chitosan coated poly ( isobutylcyanoacrylate ) nanoparticles active against trichomonas vaginalis and non-toxic towards pig vaginal mucosa? ### Context: The present work reports a non-conventional therapeutic strategy based on the use of vaginally-applied formulations for the treatment of trichomoniasis due to Trichomonas vaginalis without adding a drug.The formulations were based on a thermosensitive pluronic® F127 hydrogel containing mucoadhesive poly(isobutylcyanoacrylate) nanoparticles coated with a mixture of chitosan and thiolated chitosan (75/25 wt%). The nanoparticles were obtained by anionic emulsion polymerization of isobutylcyanoacrylate. The anti-T. vaginalis activity of the formulations was evaluated in vitro.Chitosan-coated nanoparticles showed a strong anti-T. vaginalis activity at 100 μg/mL independently on the proportion of thiolated chitosan. No anti-T. vaginalis activity was reported neither with chitosan-uncoated poly(isobutylcyanoacrylate) nanoparticles nor with chitosan used as a solution. These results suggest that the anti-T. vaginalis activity was related to poly(isobutylcyanoacrylate) nanoparticles but only when they are coated with chitosan. Histological analysis of ex vivo pig vaginal mucosa in contact with pluronic® F127 hydrogel containing poly(isobutylcyanoacrylate) nanoparticles coated with the mixture chitosan/thiolated chitosan (75/25 wt%) did not reveal any toxicity. ### Long_Answer: This study demonstrated that poly(isobutylcyanoacrylate) nanoparticles coated with chitosan were active against T. vaginalis without adding a drug. Besides their anti-T. vaginalis activity, the formulations are non-toxic towards pig vaginal mucosa. ### Final_Prediction: yes

### Question: Is minor neurological dysfunction in five year old very preterm children associated with lower processing speed? ### Context: Minor neurological dysfunction (MND) is present in one quarter to one third of children born very preterm (VP). The more severe form, complex (c)-MND has been associated with learning disabilities, behavioural and motor problems.To study the association between c-MND and neurocognitive and motor disabilities at age five in VP children without CP.Ninety-four children born with gestational age<30weeks and/or a birth weight<1000g were assessed at five years corrected age. MND was classified according to Touwen. The Wechsler Preschool and Primary School Scale of Intelligence (WPPSI-III-NL) was used to measure intelligence. Simple reaction time, focused attention and visuomotor coordination were measured using the Amsterdam Neuropsychological Tasks, and working memory using a Digit Span Task. For motor skills the Movement Assessment Battery for children (M-ABC2) was used.Eighty-one percent was classified as 'normal' (no or simple (s-)-MND) and 19% as 'abnormal'(c-MND or mild CP). The abnormal group had a significantly lower processing speed quotient (PSQ), M-ABC percentile score and slower simple Reaction Time than the normal group. Verbal IQ, Performance IQ, working memory, focused attention and visuomotor coordination did not differ between groups. Exclusion of the mild CP cases (n=4) led to similar results. ### Long_Answer: Five year old VP children with c-MND have lower PSQ, slower reaction time, and poorer motor skills, than those without c-MND. Neurological examination should include identification of MND to help identify children at risk for neurocognitive disabilities. ### Final_Prediction: yes

### Question: Is catastrophic thinking about pain independently associated with pain severity , disability , and somatic complaints in school children and children with chronic pain? ### Context: To investigate the value of pain catastrophizing in explaining pain, disability, and somatic complaints, beyond negative affectivity (NA).Two cross-sectional studies, one in a sample of school children (n = 193) and a second in a clinical sample of children with recurrent or chronic pain (n = 43), were conducted. In both studies, measures of pain catastrophizing and NA were examined for their ability to explain pain, disability, and somatic complaints.In both studies, pain catastrophizing significantly accounted for the variance of pain, disability, and somatic complaints, beyond the effects of age, sex, and NA. Furthermore, pain catastrophizing significantly mediated the relationship between NA and somatic complaints in both studies and between NA and functional disability in study 1. ### Long_Answer: Results suggest the importance of assessing for pain catastrophizing in children. Pain catastrophizing is further discussed in terms of communicating distress to significant others. ### Final_Prediction: yes

### Question: Does deletion of Prkcz increase intermittent ethanol consumption in mice? ### Context: Prkcz has been identified as a gene whose expression is positively correlated with ethanol (EtOH) consumption in mice and is also induced by EtOH. Two proteins are produced from Prkcz: protein kinase M zeta (PKMζ), which is expressed in the nervous system and protein kinase C zeta (PKCζ), which is expressed in other tissues. We examined Prkcz(-/-) mice that lack PKCζ and PKMζ to investigate the role of this gene in behavioral responses to EtOH.Male Prkcz(-/-) and wild-type littermates were tested for EtOH consumption using 4 procedures: 24-hour intermittent access, 4-hour limited intermittent access, 4-day drinking-in-the-dark, and 24-hour continuous access. We also assessed the acute hypnotic effect of EtOH, EtOH reward, and taste preference for sweet-, bitter-, salty-, and umami-flavored solutions. Finally, we determined whether EtOH could increase PKMζ and PKCζ transcripts and protein expression in wild-type mice using quantitative PCR and Western blot analysis.Prkcz(-/-) mice consumed more EtOH than their wild-type littermates in both intermittent access procedures, but not in the drinking-in-the-dark or 24-hour continuous access procedures. EtOH exposure increased Prkcz transcripts in cultured PC12 cells, and intermittent EtOH consumption increased PKMζ protein in the ventral striatum of wild-type mice. ### Long_Answer: Absence of PKMζ in the brain is associated with increased EtOH intake during procedures that incorporate intermittent consumption sessions every other day. Our data suggest that EtOH induces PKMζ, which acts in a negative feedback loop to limit binge-like EtOH consumption. ### Final_Prediction: yes

### Question: Is rheumatoid arthritis a risk factor for a high-riding vertebral artery? ### Context: A retrospective comparative study on the morphologic characteristics of the axis in patients with or without rheumatoid arthritis (RA).To compare the morphologic risk of vertebral artery (VA) injury during atlantoaxial transarticular screw fixation between patients with or without RA.VA injury is a potentially serious complication during atlantoaxial transarticular screw fixation. Although this operation is frequently performed on RA patients, there have been few comparative studies on the morphologic risk of VA injury between RA and non-RA patients.A total of 107 three-dimensional computed tomography images of the cervical spine including the C1-C2 complex were evaluated. Forty-seven RA patients and 60 non-RA patients were included in the study. The maximum atlantoaxial transarticular screw diameter (MSD) that could be inserted without breaching the cortex was measured 3-dimensionally using a computer- assisted navigation system. A high-riding-VA carrier was defined as a patient with either MSD of 4 mm or less. In RA patients, the space available for the spinal cord in flexion (SAC in flexion), duration of disease, RA stage, and type of disease were examined.In the RA group, 45 of 94 MSDs (47.9%) were 4 mm or less, and 33 of 47 patients (70.2%) were high-riding-VA carriers. In the non-RA group, 11 of 120 MSDs (9.2%) were 4 mm or less, and 9 of 60 (15.0%) patients were high-riding-VA carriers. MSD, C3 A-P diameter, and the ratio of MSD to C3 A-P diameter were significantly smaller in the RA group than in the non-RA group. Multiple logistic regression analysis showed that SAC in flexion was a significant risk factor for a high-riding-VA carrier in the RA group. ### Long_Answer: RA was a significant risk factor for the presence of a high-riding VA. When performing atlantoaxial transarticular screw fixation, particularly on RA patients, thorough preoperative evaluation of the bony architecture is of great importance to avoid inadvertent VA injury. ### Final_Prediction: nan

### Question: Does pupil dilation influence subfoveal choroidal laser Doppler flowmetry? ### Context: The aim of this study was to assess (i) whether pupil dilation with tropicamide influences subfoveal choroidal blood flow, as assessed by continuous laser Doppler flowmetry (LDF) and (ii) if this is the case, whether the effect is due to a haemodynamic response of the drug-induced dilation.Following the instillation of one drop of 1% tropicamide in one eye of 18 healthy, nonsmoking volunteers (age 20-25 years), the subfoveal choroidal LDF parameters (Vel, Vol and ChBF) were recorded during 30 min, at 3-min intervals under two paradigms: through an artificial pupil (4 mm diameter) placed in front of the cornea (P1) and without this artificial pupil (P2).Tropicamide increased the pupil diameter from 3.3 ± 0.4 mm (mean ± SD) to 8.3 ± .4 mm. Full dilation was reached at ~24 min. During this period of time, linear regression analysis demonstrated that none of the LDF parameters varied significantly (p>0.05), either under P1 or P2. Based on a group of 12 subjects, the smallest (%) change in the mean value of ChBF (ChBFm ) that would be detectable (sensitivity of the method, S) was found to be 2% for P1 and 6% for P2. The average coefficient of variation of ChBFm based on eight measurements during dilation was greater for P2 than for P1 by a factor of approximately 2. ### Long_Answer: Tropicamide had no significant influence on the subfoveal choroidal LDF parameters measured by continuous LDF during pupil dilation. Furthermore, pupil dilation did not affect ChBFm by more than the calculated minimum percentage change of 6% detectable with our method. ### Final_Prediction: nan

### Question: Does profiling of Vascular Endothelial Growth Factor Receptor Heterogeneity identify Protein Expression-defined Subclasses of Human Non-small Cell Lung Carcinoma? ### Context: the vascular endothelial growth factor (VEGF) pathway plays a prominent role in the growth and progression of human cancer, including non-small cell lung carcinoma (NSCLC). The key mediators of VEGF signaling are a family of related receptor tyrosine kinases that include VEGFR1, VEGFR2, and VEGFR3. The relative expression levels, activity, and cross-talk among these receptors may contribute to response of NSCLC to anti-angiogenic therapies, and a better systematic, translatable approach to categorizing tumors is needed.We comparatively evaluated immunohistochemical expression of the three VEGFRs in archival primary NSCLC tissues (n=96).VEGFR1 and VEGFR2 were localized both in vessels and tumor cells, while VEGFR3 was only localized in tumor vessels. A set of eight VEGFR staining subclasses were identified: Triple VEGFR positive (n=11, 11.5%), VEGFR1 predominant (n=22, 22.9%), VEGFR2 predominant (n=9, 9.4%), VEGFR3 predominant (n=3, 3.1%), VEGFR1/2 predominant (13, 13.5%), VEGFR1/3 predominant (2, 2.1%), VEGFR2/3 predominant (n=8, 8.3%), and triple VEGFR negative (n=28, 29.2%). An objective categorization based on K-means clustering revealed four clusters, three of which showed high VEGFR2 compared to VEGFR3 (30.7% of cases), cases high in both VEGFR2 and VEGFR3 (18.2%), and cases that were negative/low for both VEGFR2 and VEGFR3 (45.4%). A positive association between VEGFR2 and VEGFR3 was found, however no associations were observed between VEGFR1 and VEGFR2, nor VEGFR1 and VEGFR3. ### Long_Answer: The proposed subclasses of NSCLC are an approach for complementing lines of investigation of anti-angiogenic therapies beginning with systematic characterization of the disease. ### Final_Prediction: yes

### Question: Do urinary & serum oxalate determination by oxalate oxidase immobilized on to affixed arylamine glass beads? ### Context: Although the measurement of oxalate in urine and serum by Amaranthus leaf oxalate oxidase immobilized on free arylamine glass beads is highly sensitive and specific, the handling of glass beads is tedious and cumbersome. The present study was undertaken to overcome this problem.Partially purified Amaranthus spinosus leaf oxalate oxidase was immobilized through diazotization onto arylamine glass beads affixed on the surface of a plastic strip by a non reactive fixative and employed for oxalate determination in urine and serum samples collected from healthy individuals and urinary stone formers.The immobilized enzyme retained 56 per cent of its initial activity with a conjugation yield of 40 mg/g support. The strip bound enzyme showed maximum activity at pH 3.5 when incubated at 40 degrees C for 15 min. The minimum detection limit of the method was 0.01 mM/l in the urine and 2.5 microM/l in the serum. The analytical recovery of added oxalate was 97.7+/-1.2 per cent in urine and 92.0+/-2.4 per cent in serum. Within and between assay coefficient of variation (CV) were 4.6 and 5.2 per cent in urine and 7.4 and 5.8 per cent in serum respectively. A good correlation for oxalate in urine (r1= 0.99) and in serum (r2= 0.92) was obtained between Sigma kit method and the present method. The strip could be reused 150 times over a period of 2 months, when stored at 4 degrees C in reaction buffer. ### Long_Answer: Immobilization of Amaranthus leaf oxalate oxidase on to affixed glass beads provided enormous ease in its reuse for determination of oxalate in urinary and serum samples. ### Final_Prediction: yes

### Question: Do newly induced beta-galactosidase molecules have a higher activity than the basally expressed enzyme? ### Context: The objective of this study was to compare the activities of individual molecules of induced and basally expressed Escherichia coli beta-galactosidase.Single-molecule assays of enzymes have determined that individual molecules are not identical. They differ with respect to catalytic rate. The structural cause and cellular role of this microheterogeneity is as yet unknown.E. coli were grown and induced to produce beta-galactosidase by treatment with isopropyl-beta-D-thiogalactopyranoside. Cells were lysed and the beta-galactosidase assayed with capillary electrophoresis instrumentation utilizing post-column, laser-induced fluorescence detection. The enzyme obtained from treated cells were compared to that from untreated cells.The activity of newly induced beta-galactosidase was found to be approximately 20% greater than that of the basally expressed enzyme. This measured difference is statistically significant. ### Long_Answer: Production of beta-galactosidase in E. coli under differing conditions results in differences in the activities of the individual enzyme molecules. ### Final_Prediction: yes

### Question: Is stathmin a highly sensitive and specific biomarker for vulvar high-grade squamous intraepithelial lesions? ### Context: Differentiating between human papilloma virus-dependent vulvar low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) remains difficult in selected cases. Stathmin, a protein involved in cell cycle progression, might be a useful additional marker for this differentiation. The aim of this study was to investigate the additional diagnostic value of stathmin expression in vulvar intraepithelial neoplastic (VIN) lesions.Immunohistochemical analysis was used to evaluate stathmin, P16 and Ki67 expression in 91 samples, including LSILs (n=16), HSILs (n=50), differentiated VIN (dVIN; n=10), lichen sclerosis (LS; n=10) and normal vulvar tissue (n=5).Stathmin was expressed in more than one-third of the epithelium in all HSILs and in 20% of LSILs. P16 and Ki67 were expressed in more than one-third of the epithelium in 94% of HSILs and in 13% and 40% of LSILs, respectively. Stathmin was expressed in more than one-third of the epithelium in 10% of the dVIN and in none of the LS or normal lesions. P16 and Ki67 expression was not present in more than one-third of the epithelium in any of these lesions. The sensitivity of stathmin for differentiating between LSILs and HSILs was 100% compared with a sensitivity of 94% for both p16 and Ki67. The specificity of stathmin, p16 and Ki67 was 80%, 87% and 60%, respectively. ### Long_Answer: Stathmin is a highly sensitive and specific biomarker for the diagnosis of vulvar HSIL. In addition to the more commonly used immunohistochemical markers p16 and Ki67, stathmin can be a useful diagnostic tool for identifying HSILs, especially in cases in which differentiating between LSIL and HSIL is difficult. ### Final_Prediction: yes

### Question: Does [ Pulchinenoside inhibit the fibroblast-like synoviocytes apoptosis in adjuvant arthritis rats ]? ### Context: To explore the eff ect of pulchinenoside (PULC) on fi broblast-like synoviocytes (FLS) apoptosis in adjuvant arthritis (AA) rats.A total of 60 SD rats were randomly divided into 8 groups: A normal control group, an AA group, a low PULC group (50 mg/kg), a middle PULC group (100 mg/kg) or a high PULC group (150 mg/kg) and an ibuprofen (8 mg/kg) group (n=10 per group). FLS from the AA rats was cultured. The expression of Bcl-2, Bax, caspase-3 and the FLS proliferation were detected by the real time qPCR and MTT, respectively. The expression of IL-6 and IL-8 in culture medium was detected by ELISA.Compared with the AA group, the Bcl-2 expression was down-regulated (all P<0.05), the Bax and caspase-3 expression was up-regulated (all P<0.05), and the FLS proliferation was inhibited (all P<0.05). The IL-6 and IL-8 expression was suppressed in the FLS in the PULC groups at different dosages (all P<0.05) as well as in the ibuprofen group (P<0.05). ### Long_Answer: PULC may inhibit the FLS proliferation in AA rats by increase in FLS apoptosis. ### Final_Prediction: yes

### Question: Posterior tibial nerve stimulation: is the once-a-week protocol the best option? ### Context: Thirty-five patients (28 females, 7 males) with overactive bladder syndrome not responding to antimuscarinic therapy were enrolled in a prospective study. A total of 17 out of 35 patients were randomly assigned to group A and treated with a PTNS protocol based on weekly stimulation sessions; 18 out of 35 patients were randomly assigned to group B and treated with a PTNS protocol based on stimulation sessions performed 3 times per week. All subjects were evaluated by means of 24 h bladder diaries, quality of life questionnaires (I-QoL, SF36) and urodynamic evaluation before and after treatment. Patients were asked after each stimulation session to give their opinion on the efficacy of the treatment. We have considered ''success'' those patients who presented a reduction>50% of the micturition episodes/24 h (ME/24) or (if incontinent) of the incontinence episodes/24 h (IE/24). Results before and after treatments in both groups were collected and statistically compared.As a whole, 11/17 patients (63%) in group A and 12/18 patients (67%) in group B were considered ''success''; 4/11 (36%) incontinent patients in group A and 5/11 (45%) incontinent patients in group B were completely cured after treatment. In both groups, patients reported subjective improvement after 6-8 stimulation sessions. ### Long_Answer: Our findings seem to show that the periodicity of stimulation does not effect the results of PTNS treatment. The advantage of more frequent stimulation sessions is to achieve earlier a clinical improvement. ### Final_Prediction: nan

### Question: Does human recombinant apyrase therapy protect against canine pulmonary ischemia-reperfusion injury? ### Context: There is accumulating evidence that extracellular adenosine triphosphate (eATP) promotes many of the underlying mechanisms that exacerbate acute lung injury. However, much of these data are from inbred rodent models, indicating the need for further investigation in higher vertebrates to better establish clinical relevance. To this end we evaluated a human recombinant apyrase therapy in a canine warm pulmonary ischemia-reperfusion injury (IRI) model and measured eATP levels in human lung recipients with or without primary lung graft dysfunction (PGD).Warm ischemia was induced for 90 minutes in the left lung of 14 mongrel dogs. Seven minutes after reperfusion, the apyrase APT102 (1 mg/kg, n = 7) or saline vehicle (n = 7) was injected into the pulmonary artery. Arterial blood gases were obtained every 30 minutes up to 180 minutes after reperfusion. Bronchioalveolar lavage fluid (BALF) was analyzed for eATP concentration, cellularity, and inflammatory mediator accumulation. Thirty bilateral human lung transplant recipients were graded for immediate early PGD and assessed for BALF eATP levels.APT102-treated dogs had progressively better lung function and less pulmonary edema during the 3-hour reperfusion period compared with vehicle-treated controls. Protection from IRI was observed, with lower BALF eATP levels, fewer airway leukocytes, and blunted inflammatory mediator expression. Human lung recipients with moderate to severe PGD had significantly higher eATP levels compared with recipients without this injury. ### Long_Answer: Extracellular ATP accumulates in acutely injured canine and human lungs. Strategies that target eATP reduction may help protect lung recipients from IRI. ### Final_Prediction: yes

### Question: Is off-pump technique a safer procedure for coronary revascularization? ### Context: We aim to describe our experience in coronary artery bypass grafting (CABG) with or without cardiopulmonary bypass by comparing intraoperative and postoperative outcomes.From January 1993 to June 2013, 3097 patients underwent consecutive emergency and scheduled CABG surgery. A total of 1770 patients underwent on-pump CABG (ONCABG) and 1327 off-pump CABG (OPCABG). A propensity score matching was performed to identify appropriate matched-pair patients; univariable and multivariable logistic regression analyses were performed to assess significant predictors of hospital and 30-day morbidity and mortality composite end-points. Morbidity composite end-point was defined as any renal, pulmonary, cardiovascular and neurological complication that occurred during hospital stay. We collected all-cause mortality data during the study period.We identified 1004 patients in each group. There were no significant differences in thirty day mortality, 2.8 vs 3.8%, in OPCABG and ONCABG, respectively (P = 0.21). Cardiovascular, neurological, respiratory and renal complications were more frequent in the ONCABG group: 13.9 vs 8.7% (P<0.001), 3.9 vs 2.2% (P = 0.03), 13.5 vs 7.5% (P<0.001), 7.1 vs 5.3% (P = 0.095), respectively. The long-term all-cause mortality rate was 12.3 vs 12.9% in the OPCABG versus ONCABG group (P = 0.42), respectively. In both uni- and multivariable analysis preoperative renal failure, chronic obstructive pulmonary disease and ONCABG were independent predictors of mortality and morbidity composite end-points. ### Long_Answer: OPCABG is associated with less postoperative morbimortality and shorter hospital and intensive care unit length of stay. ONCABG resulted as an independent predictor of morbidity and mortality composite end-point. No statistically significant differences were observed in long-term all-cause mortality between groups. ### Final_Prediction: nan

### Question: Is low subcutaneous thigh fat a risk factor for unfavourable glucose and lipid levels , independently of high abdominal fat . The Health ABC Study? ### Context: We investigated whether low subcutaneous thigh fat is an independent risk factor for unfavourable glucose and lipid levels, and whether these associations differ between sexes, and between white and black adults. Our secondary aim was to investigate which body composition characteristics (lean tissue, fat tissue) are reflected by anthropometric measures (waist and thigh circumference).Anthropometric measurements and computed tomography of the abdomen and of the thigh were performed for all participants of the Health, Aging and Body Composition Study, who were aged 70-79 years. Fasting glucose, triglycerides and HDL-cholesterol, and 2-h postload glucose were determined.After excluding those already diagnosed with diabetes or dyslipidaemia, we analysed data from 2,106 participants. After adjustment for abdominal subcutaneous and visceral fat, and intermuscular thigh fat, larger thigh subcutaneous fat area was statistically significantly associated with lower ln-transformed triglycerides [standardised beta (95% CI) -0.12 (-0.20 to -0.04) in men and -0.13 (-0.21 to -0.05) in women] and higher ln-HDL-cholesterol [0.10 (0.02 to 0.19) and 0.09 (0.01 to 0.18), respectively]. The associations with lower glucose levels were strong in men [-0.11 (-0.20 to -0.02) for fasting and -0.14 (-0.23 to -0.05) for postload glucose], but not statistically significant in women [-0.02 (-0.10 to 0.07) and -0.04 (-0.13 to 0.05), respectively]. There were no differences in the associations between white and black persons. Waist circumference was more strongly associated with abdominal subcutaneous fat, and this association became stronger with increasing BMI, whereas the association with visceral fat became weaker. Thigh circumference was equally dependent on thigh fat and thigh muscle in men, whereas in women the fat component was the main contributor. ### Long_Answer: Larger subcutaneous thigh fat is independently associated with more favourable glucose (in men) and lipid levels (in both sexes) after accounting for abdominal fat depots, which are associated with unfavourable glucose and lipid levels. Anthropometric measures reflect different fat depots at different levels of BMI at the abdomen, and reflect both fat and lean tissue at the thigh. These results emphasise the importance of accurate measures of regional body composition when investigating potential health risks. ### Final_Prediction: yes

### Question: Does long non-coding RNA CRNDE promote tumor growth in medulloblastoma? ### Context: Medulloblastoma is the most common malignant brain tumor in children. Despite remarkable advances over the past decades, a novel therapeutic strategy is urgently required to increase long-term survival. This study aimed to understand the role of a long non-coding RNA (lncRNA), colorectal neoplasia differentially expressed (CRNDE), in medulloblastoma tumor growth.The transcript level of CRNDE was initially examined in dissected clinical tissues and cultured cancerous cells. Effects of CRNDE knockdown on cell viability and colony formation in vitro were assessed using the CCK-8 and colony formation assays, respectively. Cell cycle progression and survival were also determined after CRNDE knockdown. A xenograft mouse model of human medulloblastoma was established by injecting nude mice with medulloblastoma cells stably depleted of CRNDE expression.Our data suggest that transcript levels of CRNDE are elevated in clinical medulloblastoma tissues instead of in adjacent non-cancerous tissues. Knockdown of CRNDE significantly slowed cell proliferation rates and inhibited colony formation in Daoy and D341 cells. Tumor growth in vivo was also inhibited after CRNDE knockdown. Moreover, after knockdown of CRNDE, cell cycle progression was arrested in S phase and apoptosis was promoted by 15-20% in Daoy and D341 cells. In vivo data further showed that proliferating cell nuclei antigen (PCNA) was decreased, whereas the apoptosis initiator cleaved-caspase-3 was increased upon CRNDE knockdown in cancerous tissues from the mouse model. ### Long_Answer: All these data suggest that CRNDE promotes tumor growth both in vitro and in vivo. This growth-promotion effect might be achieved via arresting cell cycle progression and inhibiting apoptosis. Therapeutics against CRNDE may be a novel strategy for the treatment of medulloblastoma. ### Final_Prediction: yes

### Question: Are sociodemographic , psychological , and lifestyle characteristics associated with a liking for salty and sweet tastes in French adults? ### Context: Various studies have shown that sensory liking influences dietary behavior and that individual characteristics are related to food intake and weight status, but little is known about individual profiles associated with salt and sweet liking.The aim of the present study was to investigate the association between a liking for salty and sweet tastes (i.e., a liking for foods rich in salt or sugar and preferred amounts of salt or sugar seasoning in foods) and sociodemographic, psychological, and lifestyle characteristics in a large sample.Individual factors and liking scores were collected by validated questionnaires from 37,181 French adults participating in the NutriNet-Santé study, a large web-based observational cohort launched in 2009 that studies relations between nutrition and health. The associations were assessed by multivariable multinomial logistic regression models adjusted for socioeconomic, anthropometric, and health variables.In both genders, with increasing age, individuals were more likely to have a high salt liking (men, OR: 1.24; 95% CI: 1.18, 1.30; women, OR: 1.14, 95% CI: 1.09, 1.19), whereas they were less likely to have a strong sweet liking (men, OR: 0.87; 95% CI: 0.83, 0.91; women, OR: 0.66; 95% CI: 0.64, 0.68). Current smokers (men, OR: 2.30; 95% CI: 1.90, 2.78; women, OR: 1.50; 95% CI: 1.36, 1.66) and heavy drinkers (men, OR: 2.92; 95% CI: 2.37, 3.58; women, OR: 2.57, 95% CI: 2.22, 2.98) were more likely to like salt than nonsmokers and alcohol abstainers. Regarding the sweet taste, women smokers were less likely to like sweets (OR: 0.80; 95% CI: 0.72, 0.89). Highly uncontrolled eaters [men, OR: 2.39; 95% CI: 2.04, 2.80; women, OR: 2.22; 95% CI: 1.99, 2.47) and highly emotional women (OR: 1.35; 95% CI: 1.18, 1.55) were more likely to have a high liking for sweets than slightly uncontrolled eaters and nonemotional eaters, whereas those with high cognitive restraint (men, OR: 0.39; 95% CI: 0.33, 0.46; women, OR: 0.55; 95% CI: 0.50, 0.60) and former weight-loss dieters (men, OR: 0.60; 95% CI: 0.52, 0.70; women, OR: 0.68; 95% CI: 0.62, 0.73) were less likely to have a strong sweet liking compared with those with low cognitive restraint and never-dieters. ### Long_Answer: An unhealthy lifestyle that includes smoking and alcohol consumption may influence salt liking, and eating behavior may have an impact on sweet liking. Further research is needed to study the influence of individual factors and sensory liking on dietary intake and weight status. This study was registered at the European Clinical Trials Database as 2013-000929-31. ### Final_Prediction: yes

### Question: Does tLR-3 receptor activation protect the very immature brain from ischemic injury? ### Context: We have shown that preconditioning by lipopolysaccharide (LPS) will result in 90% reduction in ischemic brain damage in P7 rats. This robust LPS neuroprotection was not observed in P3 or P5 pups (corresponding to human premature infant). LPS is a known Toll-like receptor 4 (TLR-4) ligand. We hypothesized that TLRs other than TLR-4 may mediate preconditioning against cerebral ischemic injury in the developing brain.TLR-2, TLR-3, TLR-4, and TLR-9 expression was detected in brain sections from P3, P5, and P7 rats by immuno-staining. In subsequent experiments, P5 rats were randomly assigned to TLR-3 specific agonist, poly I:C, or saline treated group. At 48 h after the injections, hypoxic-ischemic (HI) injury was induced by unilateral carotid artery ligation followed by hypoxia for 65 min. Brains were removed 1 week after HI injury and infarct volumes were compared in H&E stained sections between the two groups.TLR-2 and TLR-3 were highly expressed in brains of P3 and P5 but not in P7 rats. The number of TLR-4 positive cells was lower in P3 and P5 compared to P7 brains (P <0.05). TLR-3 was predominately expressed in P5 pups (P <0.05). There was no significant difference in TLR-9 expression in the three age groups. There was a significant reduction in infarct volume (P=0.01) in poly I:C compared to saline pre-treated P5 pups. Pre-treatment with poly I:C downregulated NF-κB and upregulated IRF3 expression in P5 rat ischemic brains. Pre-treatment with poly I:C did not offer neuroprotection in P7 rat brains. ### Long_Answer: TLRs expression and function is developmentally determined. Poly I:C-induced preconditioning against ischemic injury may be mediated by modulation of TLR-3 signaling pathways. This is the first study to show that TLR-3 is expressed in the immature brain and mediates preconditioning against ischemic injury. ### Final_Prediction: yes

### Question: Does intervention study show outpatient cardiac rehabilitation to be economically at least as attractive as inpatient rehabilitation? ### Context: Since the late 1990 s, cost pressure has led to a growing interest in outpatient rehabilitation in Germany where predominantly inpatient rehabilitation has been provided. Taking into account the feasibility of a randomized design, the aim of this study was to compare outpatient and inpatient cardiac rehabilitation from a societal perspective.A comprehensive cohort design was applied. Costs during rehabilitation were measured using individual documentation of the rehabilitation centers. Economic end points were quality of life (EQ-5D), and total direct and indirect costs. A propensity score approach, integrated into a simultaneous regression framework for cost and effects, was used to control for selection bias. Bootstrap analysis was applied for assessing uncertainty in cost-effectiveness.A total of 163 patients were included in the study (112 inpatients, 51 outpatients). As randomization was chosen by only 2.5% of participants, the study had to be analyzed as an observational study. Direct costs during inpatient rehabilitation were significantly higher by 600 euro (+/-318; p < 0.001) compared to outpatient rehabilitation (2,016 euro +/- 354 euro vs. 1,416 euro +/- 315), while there was no significant difference in health-related quality of life. Over the 12-month follow-up period, adjusted costs difference in total cost was estimated at -2,895 euro (p = 0.102) and adjusted difference in effects at 0.018 quality-adjusted life years (QALYs) (n.s.) in favor of outpatient treatment. ### Long_Answer: The ratio of mean cost over mean effect difference (incremental cost-effectiveness ratio) indicates dominance of outpatient rehabilitation, but at a considerable statistical uncertainty. However, outpatient rehabilitation cannot be rejected from an economic perspective. ### Final_Prediction: yes

### Question: The distribution of carotid endarterectomy procedures among surgeons and hospitals in New York state: is regionalization of specialized vascular care occurring? ### Context: In a published analysis of all carotid endarterectomies (CEAs) performed in New York state from 1990 to 1995, perioperative mortality rate was inversely correlated with surgeon and hospital CEA volume, was significantly higher when CEAs were performed by surgeons who performed less than five CEAs annually, and was significantly lower in hospitals where surgeons performed more than 100 CEAs annually. The purpose of this study was to determine whether this information has influenced practice patterns in New York state.The database of the Center for Medical Consumers was queried to determine the volume distribution among surgeons and hospitals of all CEAs performed in New York state in 1999 and 2000.During 1999, 695 surgeons in 169 hospitals performed 9458 CEAs (mean, 13.6 per surgeon). Three hundred fifty-three surgeons (51%) performed less than five CEAs, and 180 (26%) performed only one CEA during the year. Only 41 surgeons (6%) performed more than 50 CEAs. Likewise, in only 28 of the hospitals (17%) were more than 100 CEAs performed during 1999, whereas in 73 of the hospitals (43%) 20 or less CEAs were carried out during the year. During 2000, 684 surgeons performed 8196 CEAs in 165 hospitals. Three hundred fifty-three (52%) performed less than five CEAs, and 229 (33%) performed only one CEA during the year. Only 33 surgeons (5%) performed more than 50 CEAs during 2000. In only 26 hospitals (16%) were more than 100 CEAs performed during 2000, whereas in 71 hospitals (43%) 20 or less CEAs were carried out. ### Long_Answer: It appears that published compelling evidence that operator and institutional volume influence outcome has not influenced referral patterns or led to a regionalization of CEA care in New York state. Robust educational programs directed to patients and referring physicians appear indicated. ### Final_Prediction: nan

### Question: Does chromosomal mosaicism mitigate stigmata and cardiovascular risk factors in Turner syndrome? ### Context: To study genotype-phenotype correlations in Turner syndrome (TS) regarding body composition, cardiovascular risk factors, stigmata and age at diagnosis vs. degree of mosaicism estimated as the percentage of 45,X and 46,XX cells.One hundred and twenty-six TS women, mean age 31 years, were examined by three specialists, who reported stigmata independent of each other. Dual energy X-ray absorptiometry (DXA) was used to measure bone mineral density (BMD). The karyotype was blinded. Fluorescence in situ hybridization (FISH) was performed on buccal cells. A random population sample served as controls.Forty-four per cent exhibited a 45,X karyotype and 56% a second-cell line, while 27% of all had a 45,X/46,XX mosaicism. Five 45,X cases with a conventional karyotype were 45,X/46,XX mosaic according to FISH. At diagnosis, 45,X cases were younger (P < 0.05) and had more stigmata per person (P < 0.01) than the mosaics. TS with marker chromosome X or Y, iso or ring, did not differ from 45,X in this aspect. The mosaics had higher BMD and SHBG and lower total cholesterol and FSH than TS with 45,X and did not differ compared with controls in terms of body mass index (BMI), waist/hip ratio, BMD, blood pressure, cholesterol, triglycerides, SHBG, diabetes or osteoporosis. The number of stigmata correlated positively to BMI, waist/hip ratio, cholesterol and %45,X and inversely to height and %46,XX according to FISH. ### Long_Answer: Mosaicism seems to mitigate the TS phenotype and the cardiovascular risk factor profile. Mosaics were diagnosed 8 years later than 45,X cases. This emphasizes the necessity for a stricter genotype categorization not only in the clinic but also in research on TS than previously adopted. ### Final_Prediction: yes

### Question: Does being easily moved to tears as a response to psychological stress reflect response to treatment and the general prognosis in patients with rheumatoid arthritis? ### Context: Psychological stress affects the condition of patients with rheumatoid arthritis (RA). We evaluated the neuroendocrine and immune responses (NEIRs) in the peripheral blood to psychological stress induced by deep emotion with tears in patients with RA.We compared the levels of plasma cortisol and interleukin-6 (IL-6), the CD4/CD8 ratio, and natural killer (NK) cell activity in peripheral blood between the patients with easily controlled RA (CRP<1.0 mg/dl) and those with difficult-to-control RA (CRP>or = 1.0 mg/dl) before and after the stress session.Psychological stress induced by deep emotion with tears had a greater influence on NEIRs in patients with difficult-to-control RA (CRP>or = 1.0 mg/dl) than in those with easily controlled RA (CRP<1.0 mg/dl). The levels of plasma cortisol, IL-6, and the CD4/CD8 ratio were lower, while NK cell activity in the peripheral blood was higher in those who were not moved to tears than in those who were moved to tears. Patients who were moved to tears were apt to obtain good control of RA (CRP<1.0 mg/dl) within one year. ### Long_Answer: The patients with better RA control are easily moved to tears as an emotional expression; shedding tears is considered to suppress the influence of stress on the NEIRs, thus preventing the buildup of stress. Patients who were moved to tears had a more easily controlled RA compared with those who were emotionally affected but not moved to tears. ### Final_Prediction: nan

### Question: Does hDAC5 promote cell proliferation in human hepatocellular carcinoma by up-regulating Six1 expression? ### Context: Histone deacetylases (HDACs) plays important roles in the regulation of genes expression and contribute to the growth of cancer cells. The present study aimed to investigate the function of HDAC5 in human hepatocellular carcinoma (HCC).The expression of HDAC5 in human hepatocellular carcinoma tissues and cells was detected. MTT assay was used to measure the proliferation of HCC cell lines. siRNA technology was employed to down-regulate the protein expression of HDAC5 and Six1.Western blot showed that the HDAC5 expression was increased in human HCC tissues. The mRNA and protein levels of HDAC5 were up-regulated in human HCC cell lines. MTT assay showed that over-expression of HDAC5 promoted cell proliferation in human HCC cell lines. Down-regulation of HDAC5 caused a significantly inhibition of liver cancer cells proliferation. Furthermore, we found that HDAC5 promoted the Six1 expression both at the mRNA and protein levels in HCC cell lines. ### Long_Answer: The current study demonstrated for the first time that HDAC5 promoted HCC cell proliferation through up-regulation of Six1 expression and might provide novel therapeutic targets in the treatment of HCC. ### Final_Prediction: yes

### Question: Are plasma matrix metalloproteinase-8 concentrations associated with the presence and severity of coronary artery disease? ### Context: Interstitial collagen, especially type I, is a major component of atherosclerotic plaques and the matrix metalloproteinases (MMP) 1, 8 and 13 can initiate collagen breakdown. MMP-8 degrades type I collagen preferentially and more potently than MMP-1 or MMP-13. Although MMP-8 was thought to be produced only by neutrophils, it was recently reported to also be produced by endothelial cells, smooth muscle cells and macrophages in plaques.Plasma MMP-8 concentrations were measured in 250 patients undergoing coronary angiography for coronary artery disease (CAD: >50% stenosis), which was found in 181 patients, of whom 69 had 1-vessel, 66 had 2-vessel, and 46 had 3-vessel disease. Compared with 69 patients without CAD, the 181 with CAD had higher MMP-8 concentrations (3.5 vs 3.0 ng/ml, p < 0.001). There was a stepwise increase in MMP-8 concentration depending on the number of stenotic vessels: 3.2 in 1-vessel, 3.6 in 2-vessel, and 4.3 ng/ml in 3-vessel disease (p < 0.001). Multivariate analysis showed that MMP-8 concentration was independently associated with CAD. The odds ratio for CAD was 1.22 (95%confidence interval = 1.07-1.39) for a 1 ng/ml increase in MMP-8 concentration. ### Long_Answer: Plasma MMP-8 concentration is associated with the presence and severity of CAD. ### Final_Prediction: yes

### Question: Does greater symptom duration predict response to immunomodulatory therapy in dilated cardiomyopathy? ### Context: Persistent inflammation contributes to cardiac dysfunction in chronic dilated cardiomyopathy (DCM). Trials of immunomodulatory therapy for DCM have been limited by small sample size and yielded conflicting results. We hypothesized that clinical response to immunomodulation would be dependent on symptom duration. Pooled immunomodulatory trial data was used to test this hypothesis.Data from 130 subjects in 3 randomized, placebo-controlled trials of immunomodulatory therapy in DCM were combined and prospectively analyzed to evaluate change in left ventricular ejection fraction (LV-EF) at 6 and 12 months after randomization by Wilcoxon Rank-Sum test. Logistic regression analysis evaluated correlations between age, gender, symptom duration and change in LV-EF.Patients >or=6 months of symptoms before immunomodulatory therapy had a greater increase in LV-EF at 6 and 12 months than those receiving placebo (14.4% vs. 4.4%, p<0.001 and 19.5% vs. 5.6%, p<0.001, respectively). Patients with <6 months of symptoms had a similar increase in LV-EF compared to subjects treated with placebo (14.3% vs. 13.3%, p=0.84 and 14.8% vs. 15.2%, p=0.74, respectively). Older age and male gender were not associated with LV-EF change. ### Long_Answer: Immunomodulatory therapy is associated with improved LV-EF in DCM patients with >or=6 or more months of symptom duration. ### Final_Prediction: yes

### Question: Does pancreatitis-associated protein predict disease relapse in inflammatory bowel disease patients? ### Context: The pancreatitis-associated protein (PAP) is increased in the serum of active inflammatory bowel disease (IBD) patients and its levels seem to be correlated with disease activity. Our aim was to evaluate the usefulness of serum and fecal PAP measurements to predict relapse in patients with inactive IBD.We undertook a 12-month prospective study that included 66 Crohn's disease (CD) and 74 ulcerative colitis (UC) patients. At inclusion, patients were in clinical remission, defined by a Harvey-Bradshaw (HB) Index≤4 (CD) or a partial Mayo Score (MS)<3 (UC), along with a normal serum C reactive protein (CRP) and fecal calprotectin. Patients were followed every 3 months. Blood and stool samples were collected and a clinical evaluation was performed at each visit. Serum PAP and CRP levels as well as fecal concentrations of PAP and calprotectin were assessed.Active CD patients had an increased mean serum PAP at the diagnosis of the flare (104.1 ng/ml) and 3 months prior to activity (22.68 ng/ml) compared with patients in remission (13.26 ng/ml), p<0.05. No significant change in serum PAP levels in UC and fecal PAP levels in CD and UC were detected during disease activity. In CD, serum PAP was a poor diagnostic predictor of disease activity, with an AUC of 0.69. In patients in remission, fecal PAP was barely detectable in UC compared with CD patients. ### Long_Answer: Serum PAP is increased only in active CD patients, but this marker does not predict disease activity. Inactive UC patients have marked low levels of PAP in fecal samples compared with CD patients. ### Final_Prediction: no

### Question: Are NBME examination scores useful in selecting radiology residency candidates? ### Context: The quality of the graduates of radiology residency programs is powerfully affected by the quality of the candidates admitted to them, making the evaluation and ranking of residency applicants one of the most important tasks of radiology education. In the applicant evaluation process, evaluators frequently take into account applicants' scores on the National Board of Medical Examiners (NBME) examination, operating on the implicit assumption that these scores help predict future performance as residents. The purpose of this study was to test that assumption.Using a data set consisting of information about 99 residents admitted over a period of 10 residency class years, the authors compared scores for parts I and II of the NBME examination with later results on the American Board of Radiology (ABR) written and oral examinations. Logistic regression was used to model differences in resident performance on the NBME and ABR examinations and to determine whether variance in ABR results could be predicted by variance in NBME examination scores.The authors were unable to demonstrate any statistically significant value of NBME examination scores in predicting eventual performance on the ABR written and oral examinations. ### Long_Answer: The authors' attempt to validate the widespread practice of using NBME examination scores to evaluate and rank applicants to radiology residency programs demonstrated no discernible value for these scores in predicting the success of residents on the ABR examinations. ### Final_Prediction: nan

### Question: Is alprazolam relatively more toxic than other benzodiazepines in overdose? ### Context: To describe alprazolam poisoning and the relative toxicity of alprazolam compared with other benzodiazepines.A database of consecutive poisoning admissions to a regional toxicology service was searched to identify consecutive benzodiazepine deliberate self poisonings, which were coded as alprazolam, diazepam or other benzodiazepine. Major outcomes used were length of stay (LOS), intensive care (ICU) admission, coma (GCS < 9), flumazenil administration and requirement for mechanical ventilation. Prescription data were obtained for benzodiazepines for the study period.There were 2063 single benzodiazepine overdose admissions: 131 alprazolam overdoses, 823 diazepam overdoses and 1109 other benzodiazepine overdoses. The median LOS for alprazolam overdoses was 19 h which was 1.27 (95% CI 1.04, 1.54) times longer compared with other benzodiazepines by multiple linear regression. For patients with alprazolam overdoses, 22% were admitted to ICU which was 2.06 (95% CI 1.27, 3.33) times more likely compared with other benzodiazepines after multivariate analysis adjusting for age, dose, gender, time to ingestion and co-ingested drugs. Flumazenil was administered to 14% of alprazolam patients and 16% were ventilated, which was significantly more than for other benzodiazepine overdoses (8% and 11%, respectively). Twelve percent of alprazolam overdoses had a GCS < 9 compared with 10% for other benzodiazepines. From benzodiazepine prescription data, total alprazolam prescriptions in Australia increased from 0.13 million in 1992 to 0.41 million in 2001. Eighty five percent of prescriptions were for panic disorder, anxiety, depression or mixed anxiety/depression. ### Long_Answer: Alprazolam was significantly more toxic than other benzodiazepines. The increased prescription of alprazolam to groups with an increased risk of deliberate self poisoning is concerning and needs review. ### Final_Prediction: yes

### Question: Is peptidylarginine deiminase type 2 over expressed in the glaucomatous optic nerve? ### Context: To determine levels of Peptidyl arginine deiminase 2 (PAD2) and its product protein-bound citrulline in cadaver eyes that suffered from normal tension glaucoma (NTG) compared to primary open angle glaucoma (POAG), and controls.Western analysis, ELISA, and immunohistochemical analysis were performed with human tissues.We report over expression of PAD2 and higher levels of its product protein-bound citrulline in the optic nerve of normal tension glaucoma patients (NTG). ### Long_Answer: This is the first report demonstrating that like in POAG, NTG also possesses elevated levels of both PAD2 and protein-bound citrulline. ### Final_Prediction: yes

### Question: Does a Multidisciplinary Evaluation help Identify the Antisynthetase Syndrome in Patients Presenting as Idiopathic Interstitial Pneumonia? ### Context: Interstitial lung disease (ILD) is 1 possible manifestation of the idiopathic inflammatory myopathies (IIM). Occasionally, patients presenting with ILD are mistakenly diagnosed with idiopathic interstitial pneumonia (IIP), but after multidisciplinary evaluation, their ILD is determined to be because of antisynthetase syndrome (SynS) or myositis spectrum of disease.We used retrospective analytic methods to identify patients with ILD evaluated at the National Jewish Health between February 2008 and August 2014 and believed initially to have IIP but ultimately diagnosed with SynS or myositis spectrum of disease.The cohort included 33 patients; most were white women with a mean age at presentation of 55 years. Their pulmonary physiologic impairment was moderate. In 31 cases, the ILD pattern by thoracic high-resolution computed tomography scan was nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), or a combination of the 2. Surgical lung biopsy was performed in 21 patients; NSIP was the most common pattern. Less than one-third of the cohort had positive antinuclear antibodies. Two-thirds had positive SSA. All patients had either myositis-specific or myositis-associated autoantibody. Most had subtle extrathoracic symptoms or signs of SynS; 12 had an elevated serum creatine phosphokinase, but none had clinical evidence of myositis. None met the Peter and Bohan classification criteria for polymyositis/dermatomyositis. ### Long_Answer: Among patients who present with presumed IIP, a multidisciplinary evaluation that includes the integration of clinical evaluations by rheumatologists and pulmonologists, morphologic (both histopathologic and radiographic) data, and serologic features is helpful in the detection of occult SynS or the myositis spectrum of disease. ### Final_Prediction: yes

### Question: Is smoking a strong risk factor for non-vertebral fractures in women with diabetes : the Tromsø Study? ### Context: In this longitudinal study of 4,160 postmenopausal women (3,947 without and 213 with self-reported diabetes), smoking was strongly related to fracture risk in those with diabetes.Smoking is related to low bone mass and increased risk of fracture risk in postmenopausal women of the general population. The aim of the present longitudinal population-based study was to examine the effect of smoking on the risk of non-vertebral fractures in women ≥ 55 years of age, with specific focus on its relationship with diabetes.A total of 4,160 women (3,947 without and 213 with self-reported diabetes) from the municipality of Tromsø, Norway, were followed for a mean of 7.6 years. Measurements of height and weight and questionnaire information concerning smoking and alcohol consumption habits, physical activity, prevalent diseases, and use of medication were collected before the start of follow-up. Non-vertebral fractures were registered during follow-up.A total of 1,015 without and 66 with diabetes sustained a new non-vertebral fracture. Smoking status (never, past, and current) was significantly associated with an increased risk of fracture both in women with and without diabetes (p values for trend 0.02 and <0.001, respectively, after adjustments for age), but in women without diabetes, the relationship was no longer significant after multiple adjustments. There was a strong interaction between smoking status and diabetes on fracture risk (p= 0.004). Women with diabetes who were current smokers had a 3.47 (95% CI 1.82-6.62) higher risk of non-vertebral fractures than diabetic women who were never smokers (p value for linear trend = 0.001, after multiple adjustments). ### Long_Answer: We conclude that smoking is strongly related to fracture risk in postmenopausal women with self-reported diabetes. ### Final_Prediction: yes

### Question: Is soluble intercellular adhesion molecule-1 related to endothelial vasodilatory function in healthy individuals? ### Context: To investigate the associations between markers of systemic and vascular inflammation, and indicators of vascular morphology and function.In 59 apparently healthy individuals, we measured serum levels of highly sensitive C-reactive protein (hsCRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin. Endothelium-dependent (EDV) and -independent (EIDV) vasodilatation was evaluated in the forearm by venous occlusion plethysmography and local infusions of methacholine and sodium nitroprussid. Endothelial function index (EFI) was expressed as the EDV/EIDV ratio. The intima-media thickness (IMT) of the common carotid artery was investigated with ultrasound (far wall).EFI was inversely related only to ICAM-1 (r=-0.31, P<0.02) by univariate analysis. This association remained significant after adjustment for age, sex, blood pressure, smoking and serum cholesterol. EFI did not relate to hsCRP, VCAM-1 or E-selectin. Neither hsCRP, nor the adhesion molecules were significantly related to carotid artery IMT. ### Long_Answer: ICAM-1 was related to endothelial vasodilatory function, but not to IMT, suggesting that endothelial inflammatory activation is related to an impaired vascular relaxation in apparently healthy individuals. ### Final_Prediction: yes

### Question: Does orally administered paracetamol act locally in the rat formalin test : evidence for a supraspinal , serotonin-dependent antinociceptive mechanism? ### Context: The mechanism of action of paracetamol (acetaminophen) remains elusive because it is still under discussion as to whether it acts locally and/or centrally. The primary aim of this study was to clarify its site(s) of action (central and/or local) using the rat formalin test.Spontaneous biting and licking of the injected paw following intraplantar injection of formalin 2.5% was monitored during the two phases of nociceptive behavior (0-5 and 20-40 min after injection), and the authors examined the antinociceptive activity of paracetamol following oral, intravenous, intraplantar, and intrathecal administrations as well as the reversion of this effect by an intrathecal injection of WAY 100,635, a selective 5-HT1A receptor antagonist.The oral administration of paracetamol (300, 400 mg/kg) reduced nociceptive behavior in both phases (400 mg/kg: 36.9 +/- 4.6% and 61.5 +/- 5.2% of inhibition in phases I and II, respectively, P <0.05), whereas lower doses reduced primarily the score of the second phase of the test. Only high doses of 10 to 20 mg/kg intraplantarly administered paracetamol, which were ineffective when administered subcutaneously, produced a significant but limited reduction in the early phase of the test and had no effect on the second phase or any antiinflammatory activity. Thus, this local effect did not seem to participate in the antinociceptive action of 400 mg/kg orally given paracetamol, which was totally blocked in both phases by an intrathecal injection of 40 microg WAY 100,635 per rat. Such an inhibition was not observed when paracetamol (200 microg per rat) was intrathecally coinjected with WAY 100,635, whereas the antinociceptive action of 5-HT (50 microg per rat, intrathecally) during both phases of pain was inhibited by WAY 100,635 (intrathecally). ### Long_Answer: Orally administered paracetamol does not seem to exert any relevant local action in the formalin model of tonic pain in rats, but it might activate the serotonergic bulbospinal pathways via a supraspinal site of action that remains to be elucidated. ### Final_Prediction: no