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### Question: Can 'partial' PTSD explain differences in diagnosis of PTSD by questionnaire self-report and interview after head injury? ### Context: Can the concept of 'partial' PTSD explain the disparity between the relatively high incidence of PTSD found using self-report questionnaires and the relatively low incidence using structured interview? It was hypothesized that self-report of greater PTSD symptom severity is associated with increased heart rate and movement when responding to questions about the traumatic event, if 'partial' PTSD is an explanation.A within participants single group design.Twenty-one adults with head injury underwent self-report (Post-traumatic Stress Disorder Scale) and interview (Clinical Assessment of PTSD) assessments of PTSD, the Traumatic Memory Interview, self-report of mood (Hospital Anxiety and Depression Scale) and cognitive assessment (Wechsler Test of Adult Reading, Auditory Verbal Learning Test, Hayling Test, Digit Symbol Test), during which heart rate and motor activity were recorded.Self-report of greater PTSD symptom severity was not associated with increases in heart rate or movement during questions about the traumatic event. In fact, heart rate decreased from baseline in those with higher self-report scores for PTSD, consistent with curiosity about the traumatic event and not 'partial' PTSD. ### Long_Answer: These preliminary findings agree with an emerging theme suggesting that, although PTSD can occur after head injury, it is easily over-diagnosed. ### Final_Prediction: nan

### Question: Does polymorphism -116C/G of human X-box-binding protein 1 promoter is associate with risk of Alzheimer 's disease? ### Context: Alzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with endoplasmic reticulum (ER) stress response. In the response, the regulator factor human X-box-binding protein 1 (XBP1) has been shown to facilitate the refolding and degradation of misfolded proteins, prevent neurotoxicity of amyloid-beta (Aβ) and tau, and play an important role in the survival of neurons. The aim in the study was to analyze the potential association between the -116C/G polymorphism of XBP1 and the risk of AD.The association between -116C/G polymorphism of XBP1 promoter and possible risk of AD was assessed among 276 patients with AD and 254 matched healthy individuals in a case-control study.Overall, there was a significantly statistical difference in genotype (P = 0.0354) and allele frequencies (P = 0.0150, OR = 1.3642, 95% CI = 1.0618-1.7528) between the AD subjects and control subjects, showing that the -116C/G polymorphism of XBP1 might lead to increased susceptibility for AD in a Chinese Han population. In addition, the -116CG and -116GG genotypes were significantly associated with increased AD risk in female (P = 0.0217) and in subjects with APOE є4 (-) (P = 0.0070) in stratified analyses, and the -116CC genotype was significantly associated with fast cognitive deterioration in the AD patients (P = 0.0270). ### Long_Answer: The study supports a role for the -116C/G polymorphism of XBP1 gene in the pathogenesis of AD, and further studies with a larger sample size and detailed data should be performed in other populations. ### Final_Prediction: yes

### Question: Does the effect of discordance among violence and general recidivism risk estimate on predictive accuracy? ### Context: Previous research has shown that the prediction of short-term inpatient violence is negatively affected when clinicians' inter-rater agreement is low and when confidence in the estimate of risk is low. This study examined the effect of discordance between risk assessment instruments used to predict long-term general and violence risk in offenders.The Psychopathy Checklist - Revised (PCL-R), Level of Service Inventory - Revised (LSI-R), Violence Risk Appraisal Guide (VRAG), and the General Statistical Information on Recidivism (GSIR) were the four risk-prediction instruments used to predict post-release general and violent recidivism within a sample of 209 offenders.The findings lend empirical support to the assumption that predictive accuracy is threatened where there is discordance between risk estimates. Discordance between instruments had the impact of reducing predictive accuracy for all instruments except the GSIR. Further, the influence of discordance was shown to be greater on certain instruments over others. Discordance had a moderating effect on both the PCL-R and LSI-R but not on the VRAG and GSIR. ### Long_Answer: There is a distinct advantage when attempting to predict recidivism to employing measures such as the LSI-R, which includes dynamic variables and intervention-related criminogenic domains, over a measure purely of fixed characteristics, such as the GSIR; however, if there is discordance between the risk estimates, caution should be exercised and more reliance on the more static historically based instrument may be indicated. ### Final_Prediction: yes

### Question: Is prostate tumour volume an independent predictor of early biochemical recurrence in a high risk radical prostatectomy subgroup? ### Context: To assess if accurately determined tumour volume variables could serve as independent predictors of early biochemical recurrence in high risk prostate cancer patients who underwent radical prostatectomy.Tumour volume variables were calculated by digital planimetry in 269 prostatectomy specimens of patients with high risk prostate cancer. The associations to biochemical progression of tumour volume and clinicopathological variables, including age, pre-operative prostate specific antigen (PSA) levels, final Gleason score, pathological T stage, and surgical margins, were examined using univariate and multivariate Cox proportional hazards analyses.Median tumour volume was 3.7 ml [interquartile range (IQR) 2.1-6.1 mL] and median follow-up time was 12 months (IQR 6-24 months). Biochemical recurrence occurred in 64 men (24%) during this period, with a median time to recurrence of 7.5 months (IQR 3.0-15.5 months). On univariate analysis all of the tumour volume variables were strongly correlated with the clinicopathological variables, as well as biochemical recurrence (p < 0.001). On multivariate analysis, we found that tumour volume variables served as independent predictors of PSA progression whilst other routinely reported pathological variables did not. ### Long_Answer: Accurately assessing tumour volume in the high risk setting may aid in identifying patients at greatest risk of developing early biochemical recurrence and most in need of adjuvant therapy. ### Final_Prediction: yes

### Question: Does ranitidine effectively relieve symptoms in a subset of patients with functional dyspepsia? ### Context: Acid secretion inhibitors are of dubious value to most patients with functional dyspepsia but might be effective in a subset. The aims of the trial were to compare the effect of ranitidine with that of placebo in selected subsets of patients.Two hundred and twenty-six patients with functional dyspepsia were included in a double-blind multi-crossover (MCO) trial. After 6 weeks an effect score (Xs) with a range of 0-5 was calculated. They were then stratified in accordance with their score and randomized to 4 weeks' double-blind treatment with ranitidine or placebo. Overall symptoms were scored on a 100-mm visual analogue scale, and the change in score (measured in millimetres) was the primary effect measure.Two hundred and six patients completed the study. The effect of ranitidine and placebo in the 'responders' (76 patients with Xs of 4-5 after the MCO period) was 28 mm and 5 mm, respectively (P < 0.001), and in all patients 19 mm and 12 mm, respectively (P < 0.03). No effect was seen in 'nonresponders' (130 patients with Xs of 0-3 after the MCO period). The clinical improvement, as judged by the patients given ranitidine during the last 4-week period was statistically significantly different in favour of responders compared with nonresponders. We were unable to characterize the responders on the basis of demographics, symptoms, and signs. ### Long_Answer: Ranitidine has a good and clinically significant effect in a subset of patients with functional dyspepsia. ### Final_Prediction: yes

### Question: Is fetal cerebral vascular resistance affected by the presence of nuchal cord(s) in the third trimester of pregnancy? ### Context: To assess whether fetal cerebral vascular resistance is affected by the presence of nuchal cord(s) in the third trimester.A set of 115 patients with well-established dates and singleton, appropriate for gestational age (GA), non-anomalous fetuses with nuchal cord(s) diagnosed with prenatal color Doppler imaging, between 28 and 41 weeks and 115 controls matched for GA, were studied. Patients with hypertension, diabetes and autoimmune conditions were excluded. Doppler indices were obtained from the umbilical artery (UA) and the fetal middle cerebral artery (MCA) upon initial diagnosis of the nuchal cord.Of 115 GA-matched pairs of pregnancies, 103 fetuses had a single nuchal cord and 12 a double nuchal cord. No significant differences were noted in patient age, gravidity, parity, sonographically estimated fetal weight (SEFW), and growth centile at ultrasonographic diagnosis. Mean UA systolic/diastolic ratio (S/D) was 2.28 +/- 0.32 and 2.36 +/- 0.33 (P = 0.03) and UA resistance index (RI) 0.55 +/- 0.06 and 0.57 +/- 0.06 (P = 0.02) among study and controls, respectively. Mean fetal MCA S/D and RI did not differ significantly between the two groups (fetal MCA S/D 5.01 +/- 1.28 and 5.04 +/- 1.71 (P = 0.86), and mean fetal MCA RI 0.78 +/- 0.06 and 0.78 +/- 0.05 (P = 0.88)). No significant differences were noted in GA at delivery, incidence of meconium-stained amniotic fluid, birth weight, mode of delivery, neonatal gender, 1 and 5 minute Apgar scores, or UA pH and base excess, between study and control patients. ### Long_Answer: Fetal cerebral vascular resistance is not affected by the presence of nuchal cord(s) in the third trimester of pregnancy. ### Final_Prediction: nan

### Question: Are psychiatric and psychosomatic symptoms increasing problems among Swedish schoolchildren? ### Context: Paediatricians and other professionals in Sweden note that the amount of children with psychiatric and psychosomatic symptoms is growing in number. Suicide attempts among the young (15-24 y) increased by more than 30% from 1998-2003. The Swedish National Board for Health and Welfare's 2004 guidelines for school healthcare shed light on this increasing problem among schoolchildren. An article in this issue of Acta Paediatrica, "Living conditions and psychosomatic complaints in Swedish schoolchildren", analyses economic stress as a causative factor leading to psychosomatic symptoms such as headache, abdominal pain and difficulty in falling asleep. Living conditions, however, most likely include other factors related to our modern and ever-changing society that also have an impact on the growing child. ### Long_Answer: Psychiatric health is changing for the worse among Swedish schoolchildren. The cause is multifactorial. Economic stress is one factor, but there are also other possible causes related to modern society that correlate to the increase of psychosomatic problems among schoolchildren. Three major problems are among those suspected: impaired education and deficient working environment in Swedish schools, a general lack of adult contact and guidance, and excessive computer and TV use. ### Final_Prediction: yes

### Question: EuroSCORE: useful in directing preoperative intra-aortic balloon pump placement in cardiac surgery? ### Context: The placement of preoperative intra-aortic balloon pumps (IABP) in high-risk patients has been described, although controversy remains regarding the appropriate selection of these patients. The EuroSCORE is a proven predictor of operative mortality for coronary artery bypass surgery (CABG). Our objective was to assess whether patients with a preoperative IABP had a 30-day mortality consistent with their predicted mortality.Sixty-sis patients who had had an IABP sited while undergoing CABG were retrospectively identified. The additive EuroSCORE was calculated with omission of the IABP preoperative placement score of 3 points. Patients with a EuroSCORE<5 were considered low risk, and those>or = m5 as high risk.High-risk patients with preoperative IABP placement had a significantly lower mortality (1/16, 6.25%) than predicted. The predicted versus actual mortality was 12.6% versus 6.25%. ### Long_Answer: Correct identification of appropriate patients who would benefit from pre-emptive placement of IABP could potentially be performed using the EuroSCORE. ### Final_Prediction: nan

### Question: Does exercise intensity affect blood pressure and heart rate in obese adolescents? ### Context: Aerobic exercise improves cardiovascular health in general, but whether the impact varies with exercise intensity is not clear.The aim of the current study was to compare the effects of a high-intensity aerobic exercise training (HIT) vs. a low-intensity aerobic exercise training (LIT) on blood pressure (BP), heart rate (HR) and heart rate variability (HRV) in obese adolescents.Forty-three (13-18 years) Tanner stage (III-IV) matched obese adolescents were studied in a randomized trial of either HIT (corresponding to the ventilatory threshold I; n = 20) or LIT (corresponding to 20% below the ventilatory threshold I; n = 23) programme for a period of 6 months. All participants also received a multidisciplinary therapy that included nutritional, psychological and clinical counselling. Both HIT and LIT sessions were isocaloric, with energy expenditure set at 350 kcal. BP, HR and HRV were measured along with markers of body adiposity and insulin resistance before and after the respective interventions.The participants in both groups had similar physical and clinical characteristics. After the 6-month intervention, systolic, diastolic and mean BP decreased (P < 0.05, for all) similarly in both groups, whereas waist circumference, HR and HRV showed beneficial changes only in the HIT group (P < 0.05). ### Long_Answer: Aerobic exercise training set at a high intensity compared with the low intensity appears to have additional benefits on abdominal obesity and cardiovascular health in that it enhances the parasympathetic and autonomic modulation of the heart in obese adolescents. ### Final_Prediction: nan

### Question: Does nF-κB potentiate caspase independent hydrogen peroxide induced cell death? ### Context: The pro-survival activity of NF-κB in response to a variety of stimuli has been extensively characterized. Although there have been a few reports addressing the pro-cell death role of NF-κB, the precise mechanism of NF-κB's pro-cell death function still remains elusive.In the present study, we investigated the role of NF-κB in cell death induced by chronic insult with hydrogen peroxide (H(2)O(2)). Here, we show that NF-κB promotes H(2)O(2) induced caspase independent but PARP dependent fibroblast cell death. The pro-death activity of NF-κB is due to the DNA binding activity of RelA, which is induced through IKK- mediated IκBα degradation. NF-κB dependent pro-survival genes, Bcl-2 and XIAP, were significantly repressed, while NF-κB dependent pro-death genes, TNFα and Fas Ligand, were induced in response to H(2)O(2). ### Long_Answer: We discovered an unexpected function of NF-κB, in that it potentiates chronic H(2)O(2) exposure induced cell death, and suggest that NF-κB mediates cell death through the repression of pro-survival genes and induction of pro-death genes. Since unremitting exposure of tissues to H(2)O(2) and other reactive oxygen species can lead to several degenerative disorders and diseases, our results have important implications for the use of NF-κB inhibitors in therapeutic drug design. ### Final_Prediction: yes

### Question: Does ropivacaine attenuate endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling? ### Context: Acute lung injury (ALI) is associated with high mortality due to the lack of effective therapeutic strategies. Mechanical ventilation itself can cause ventilator-induced lung injury. Pulmonary vascular barrier function, regulated in part by Src kinase-dependent phosphorylation of caveolin-1 and intercellular adhesion molecule-1 (ICAM-1), plays a crucial role in the development of protein-/neutrophil-rich pulmonary edema, the hallmark of ALI. Amide-linked local anesthetics, such as ropivacaine, have anti-inflammatory properties in experimental ALI. We hypothesized ropivacaine may attenuate inflammation in a "double-hit" model of ALI triggered by bacterial endotoxin plus hyperinflation via inhibition of Src-dependent signaling.C57BL/6 (WT) and ICAM-1 (-/-) mice were exposed to either nebulized normal saline (NS) or lipopolysaccharide (LPS, 10 mg) for 1 hour. An intravenous bolus of 0.33 mg/kg ropivacaine or vehicle was followed by mechanical ventilation with normal (7 ml/kg, NTV) or high tidal volume (28 ml/kg, HTV) for 2 hours. Measures of ALI (excess lung water (ELW), extravascular plasma equivalents, permeability index, myeloperoxidase activity) were assessed and lungs were homogenized for Western blot analysis of phosphorylated and total Src, ICAM-1 and caveolin-1. Additional experiments evaluated effects of ropivacaine on LPS-induced phosphorylation/expression of Src, ICAM-1 and caveolin-1 in human lung microvascular endothelial cells (HLMVEC).WT mice treated with LPS alone showed a 49% increase in ELW compared to control animals (p = 0.001), which was attenuated by ropivacaine (p = 0.001). HTV ventilation alone increased measures of ALI even more than LPS, an effect which was not altered by ropivacaine. LPS plus hyperinflation ("double-hit") increased all ALI parameters (ELW, EVPE, permeability index, MPO activity) by 3-4 fold compared to control, which were again decreased by ropivacaine. Western blot analyses of lung homogenates as well as HLMVEC treated in culture with LPS alone showed a reduction in Src activation/expression, as well as ICAM-1 expression and caveolin-1 phosphorylation. In ICAM-1 (-/-) mice, neither addition of LPS to HTV ventilation alone nor ropivacaine had an effect on the development of ALI. ### Long_Answer: Ropivacaine may be a promising therapeutic agent for treating the cause of pulmonary edema by blocking inflammatory Src signaling, ICAM-1 expression, leukocyte infiltration, and vascular hyperpermeability. ### Final_Prediction: yes

### Question: Is cholesterol , not just cardiovascular risk , important in deciding who should receive statin treatment? ### Context: Guidelines for primary prevention of cardiovascular disease (CVD) with statins, including the most recent, fail to make the best use of the evidence from clinical trials by concentrating on absolute CVD risk as a statin indication and not also considering that a major determinant of therapeutic benefit is the magnitude of the low-density lipoprotein (LDL) (or non-HDL) cholesterol reduction achieved. This decrease is proportional to the pretreatment concentration. We set out to apply this knowledge to the calculation of the number needed to treat to prevent one event (NNT) and to assess critically how current guidelines performed at different degrees of CVD risk across a range of LDL (or non-HDL) cholesterol concentrations.Number needed to treat to prevent one event revealed exclusion from the treatment of some people with higher cholesterol levels, who may benefit more than others needlessly exposed to statins with no realistic prospect of benefit. Furthermore, abandonment of cholesterol therapeutic goals disadvantaged people with higher levels. ### Long_Answer: These problems can be overcome by basing the decision to treat on the NNT calculated both from absolute CVD risk and also on the LDL (or non-HDL) cholesterol reduction achievable with statin treatment. This need not adds an additional layer of complexity for the clinician, because computer programmes already used to estimate CVD risk could be easily amended, thus permitting more effective deployment of statins in the population. ### Final_Prediction: yes

### Question: Do racial and ethnic colorectal cancer patterns affect the cost-effectiveness of colorectal cancer screening in the United States? ### Context: Colorectal cancer screening beginning at age 50 is recommended for all Americans considered at "average" risk for the development of colorectal cancer.We used 1988-1995 California Cancer Registry data to compare the cost-effectiveness of two 35-year colorectal cancer screening interventions among Asians, blacks, Latinos, and Whites.Average annual age-specific colorectal cancer incidence rates were highest in blacks and lowest in Latinos. Screening beginning at age 50 was most cost-effective in blacks and least cost-effective in Latinos (measured as dollars spent per year of life saved), using annual fecal occult blood testing (FOBT) combined with flexible sigmoidoscopy every 5 years and using colonoscopy every 10 years. A 35-year screening program beginning in blacks at age 42, whites at age 44, or Asians at age 46 was more cost-effective than screening Latinos beginning at age 50. ### Long_Answer: Colorectal cancer screening programs beginning at age 50, using either FOBT and flexible sigmoidoscopy or colonoscopy in each racial or ethnic group, are within the $40,000-$60,000 per year of life saved upper cost limit considered acceptable for preventive strategies. Screening is most cost-effective in blacks because of high age-specific colorectal cancer incidence rates. ### Final_Prediction: yes

### Question: Does [ Routine written intervention asserting the advantages of multiple blood cultures increase their order rate among doctors ]? ### Context: Obtaining two or more blood culture sets is important for achieving good sensitivity and for detecting contamination. However, many doctors still only order one set for their laboratory testing. We wished to determine if routine written intervention to these doctors could increase the number of multiple blood cultures they ordered.On November 11, 2011 at Tokyo Teishin Hospital, we began sending letters asserting the advantages of using multiple blood culture sets to doctors who only ordered solitary blood cultures. The effect of the intervention was determined by measuring the order rate of multiple blood culture sets at the hospital. We compared the order rate one year before intervention with that of one year after. We used a chi-square test (without Yates correction) to analyze the data, and p values less than 0.05 were considered to be statistically significant; all tests were two-tailed.Before written intervention, the order rate of multiple blood cultures was 41%. This increased significantly to 68% after intervention (p < 0.001). The latter figure was 1.7 times greater than the former (relative risk, 1.7; 95% confidence interval, 1.5-1.8). ### Long_Answer: Routine written educational intervention asserting the advantage of multiple blood cultures led to an increase in their order rate by doctors. While this is a significant increase, it is still insufficient. Therefore, we propose the need for internal policies requiring at least two blood culture sets to ensure better sensitivity and detection of contamination. To enforce these policies, hospital personnel should be allowed to routinely intervene by either sending warning letters to the doctors or displaying this information on the patient's electronic chart. ### Final_Prediction: yes

### Question: Is chronic gastritis with expression of inducible nitric oxide synthase associated with high expression of interleukin-6 and hypergastrinaemia? ### Context: High levels of inducible nitric oxide synthase and nitrotyrosine in Helicobacter pylori-infected gastric mucosa may contribute to development of gastric cancer. We investigated the relation between expression of inducible nitric oxide synthase and proinflammatory cytokines in gastric mucosa and serum markers of gastritis.The study included 103 patients with H. pylori infection. We examined levels of interleukin-1beta, interleukin-6 and interleukin-8 by enzyme-linked immunosorbent assay and evaluated expression of inducible nitric oxide synthase and nitrotyrosine by immunohistochemical staining. Furthermore, we assessed serum levels of pepsinogens, gastrin, anti-parietal cell antibody, nitrite and nitrate, as markers of gastritis.Thirty-seven of 103 (35.6%) gastric mucosa specimens showed simultaneous expression of inducible nitric oxide synthase and nitrotyrosine. In these patients (inducible nitric oxide synthase-positive group), the serum level of gastrin was significantly higher than that of the inducible nitric oxide synthase-negative group (509.5 +/- 141.5 pg/mL vs. 210.0 +/- 227.2 pg/mL; P < 0.01), whereas there were no significant differences in serum levels of pepsinogen, anti-parietal cell antibody, and nitrate and nitrite or in scores of histological gastritis. Interleukin-6 levels were significantly higher in the inducible nitric oxide synthase-positive group than in the inducible nitric oxide synthase-negative group (25.9 +/- 7.0 pg/mg protein vs. 10.6 +/- 4.9 pg/mg protein; P < 0.05). ### Long_Answer: Inducible nitric oxide synthase-producing gastritis was correlated with high levels of interleukin-6. Patients with hypergastrinaemia should be carefully followed on a long-term basis to ensure that the development of any malignancy is detected early. ### Final_Prediction: yes

### Question: Does anodization increase early integration of Osstem implants in sheep femurs? ### Context: Spark discharge anodic oxidation forms a porous TiO2 film on the surface of titanium oral implants, increasing surface roughness and concentrations of calcium and phosphate ions. In this study, anodic-treated oral implants were placed in an animal model and analysed using clinical, micro-computerized tomographic (micro-CT) and histometric techniques.Pairs of 3.5 mm x 8.5 mm long titanium implants (Osstem Implant Co., Ltd. Seoul, Korea), with blasted (control) or blasted and oxidized surfaces (test), were placed into the right femoral condyles of 10 sheep. Animals were sacrificed after 1 month unloaded healing. Resonant frequency analysis (RFA) was measured in implant stability quotient (ISQ) using the Mentor II device. Specimens were scanned using medium resolution micro-CT (Skyscan 1172). Mean percent bone-to-implant contact (%BIC) was calculated from two images per implant by three different operators, using Image J software. Inter- and intra-examiner differences were calculated. Specimens were then embedded in methacrylate and undemineralized ground sections were digitized. Mean %BIC was measured using Image J at x 20 magnification for the best-three consecutive threads from the most central section.Mean micro-CT %BIC was similar for control and test (57.2 +/- 0.05% versus 56.4 +/- 0.03%, p = 0.5). There was considerable inter-examiner variability (interclass correlation coefficient = 0.44). RFA showed no clinically-detectable difference between the two groups (control ISQ: 75.2 +/- 4.2; test ISQ: 76.3 +/- 1.7; p = 0.48). However, histometric analysis found a marked and highly statistically-significant difference (%BIC Test 72.5 +/- 8.6%, Control 46.2 +/- 12.1%, p = 0.01). ### Long_Answer: The novel anodic oxidation technique increased early ossointegration of rough-surfaced implants by 157%. Neither clinical testing with resonant frequency analysis nor radiographic analysis using micro-CT had sufficient resolution to detect this improvement. Whether this gain in early bone-implant contact is clinically significant in the context of early occlusal loading is the subject of subsequent experiments. ### Final_Prediction: yes

### Question: Does seromuscular colocystoplasty lined with urothelium protect dogs from acidosis during ammonium chloride loading? ### Context: We compared the metabolism of intravesical ammonium chloride in dogs in which the bladder had been enlarged by seromuscular colocystoplasty lined with urothelium, dogs that had undergone conventional colocystoplasty and control dogs.Eight adult female mongrel dogs were divided into control (2), colocystoplasty (3) and seromuscular colocystoplasty (3) groups. Serum creatinine, bicarbonate, sodium, chloride, and potassium levels were measured every 2 weeks during the 6-week recovery period. Six weeks after augmentation the dogs were placed under general anesthesia, the bladder was instilled with a hyperosmolar solution of 400 mmol/l. ammonium chloride, the femoral artery and portal vein were cannulated to obtain blood samples and the ureters were divided with the proximal ends diverted to allow serial urine measurements. Blood and urine electrolyte analysis was performed at 0, 60, 120, 180 and 240 minutes after the intravesical instillation of ammonium chloride.During acid loading dogs that had undergone conventional colocystoplasty had a progressive decrease in serum carbon dioxide and arterial pH as well as increased levels of serum chloride and a significant increase in plasma ammonia concentration in the portal vein compared to controls and dogs that had undergone seromuscular colocystoplasty. In contrast, there were no differences in seromuscular colocystoplasty compared to control animals. ### Long_Answer: Increased ammonia in the portal vein and hyperchloremic acidosis in dogs that underwent conventional colocystoplasty suggest intravesical absorption of ammonium chloride. Dogs that underwent augmentation with seromuscular colocystoplasty lined with urothelium seemed to respond to acute intravesical ammonium in a way similar to that of control dogs and they are protected from these metabolic anomalies. ### Final_Prediction: yes

### Question: Does hemoperfusion with an immobilized polymyxin B column reduce the blood level of neutrophil elastase? ### Context: We investigated whether direct hemoperfusion with an immobilized polymyxin B column (DHP with PMX) could reduce the blood level of neutrophil elastase.20 sepsis patients were enrolled in the study. DHP with PMX was performed twice within a 24-hour period. Neutrophil elastase was measured 7 times.Neutrophil elastase was 468 +/- 75.1 microg/l, while it was 1,531 +/- 201.7 microg/l immediately after the first session, declined to 351 +/- 73.9 microg/l before the second session of DHP with PMX, and increased again to 599.3 +/- 112.7 microg/l immediately after the second session, 328 +/- 73.7 microg/l at 24 h, 264 +/- 39.3 microg/l at 48 h, and 230 +/- 36.1 microg/l at 72 h after DHP with PMX. The levels from 48 h onwards were significantly lower compared with that before treatment. ### Long_Answer: DHP with PMX has an overall effect that reduces circulating neutrophil elastase levels. ### Final_Prediction: yes

### Question: Does p53 dependent centrosome clustering prevent multipolar mitosis in tetraploid cells? ### Context: p53 abnormality and aneuploidy often coexist in human tumors, and tetraploidy is considered as an intermediate between normal diploidy and aneuploidy. The purpose of this study was to investigate whether and how p53 influences the transformation from tetraploidy to aneuploidy.Live cell imaging was performed to determine the fates and mitotic behaviors of several human and mouse tetraploid cells with different p53 status, and centrosome and spindle immunostaining was used to investigate centrosome behaviors. We found that p53 dominant-negative mutation, point mutation, or knockout led to a 2∼ 33-fold increase of multipolar mitosis in N/TERT1, 3T3 and mouse embryonic fibroblasts (MEFs), while mitotic entry and cell death were not significantly affected. In p53-/- tetraploid MEFs, the ability of centrosome clustering was compromised, while centrosome inactivation was not affected. Suppression of RhoA/ROCK activity by specific inhibitors in p53-/- tetraploid MEFs enhanced centrosome clustering, decreased multipolar mitosis from 38% to 20% and 16% for RhoA and ROCK, respectively, while expression of constitutively active RhoA in p53+/+ tetraploid 3T3 cells increased the frequency of multipolar mitosis from 15% to 35%. ### Long_Answer: p53 could not prevent tetraploid cells entering mitosis or induce tetraploid cell death. However, p53 abnormality impaired centrosome clustering and lead to multipolar mitosis in tetraploid cells by modulating the RhoA/ROCK signaling pathway. ### Final_Prediction: yes

### Question: Does cholesterol-enriched diet cause age-related macular degeneration-like pathology in rabbit retina? ### Context: Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several pathological hallmarks including β-amyloid (Aβ) accumulation, oxidative stress, and apoptotic cell death. The causes of AD and AMD are likely multi-factorial with several factors such as diet, environment, and genetic susceptibility participating in the pathogenesis of these diseases. Epidemiological studies correlated high plasma cholesterol levels with high incidence of AD, and feeding rabbits with a diet rich in cholesterol has been shown to induce AD-like pathology in rabbit brain. High intake of cholesterol and saturated fat were also long been suspected to increase the risk for AMD. However, the extent to which cholesterol-enriched diet may also cause AMD-like features in rabbit retinas is not well known.Male New Zealand white rabbits were fed normal chow or a 2% cholesterol-enriched diet for 12 weeks. At necropsy, animals were perfused with Dulbecco's phosphate-buffered saline and the eyes were promptly removed. One eye of each animal was used for immunohistochemistry and retina dissected from the other eye was used for Western blot, ELISA assays, spectrophotometry and mass spectrometry analyses.Increased levels of Aβ, decreased levels of the anti-apoptotic protein Bcl-2, increased levels of the pro-apoptotic Bax and gadd153 proteins, emergence of TUNEL-positive cells, and increased generation of reactive oxygen species were found in retinas from cholesterol-fed compared to normal chow-fed rabbits. Additionally, astrogliosis, drusen-like debris and cholesterol accumulations in retinas from cholesterol-fed rabbits were observed. As several lines of evidence suggest that oxidized cholesterol metabolites (oxysterols) may be the link by which cholesterol contributes to the pathogenesis of AMD, we determined levels of oxysterols and found a dramatic increase in levels of oxysterols in retinas from cholesterol-fed rabbits. ### Long_Answer: Our results suggest that cholesterol-enriched diets cause retinal degeneration that is relevant to AMD. Furthermore, our data suggests high cholesterol levels and subsequent increase in the cholesterol metabolites as potential culprits to AMD. ### Final_Prediction: yes

### Question: Endonasal measurement of mucociliary clearance at various locations in the nose: a new diagnostic tool for nasal function? ### Context: Mucociliary clearance is one of the major functions of the nasal epithelium. Limited information on the physiology or malfunction could up to now only be obtained by experimental investigations in vitro with cytological measurements of ciliary beat frequency or with extensive, time-consuming in-vivo-tests.We developed a new technique, which measures the transport capacity at various locations at the mucosa in the nose of a sitting patient with a short (30 sec) video-endoscopic examination. The velocity of a 500 microm TiO2-microsphere as inert marker, which is placed on the mucosa region of interest, is measured by a vector-analytic calculation in mm/min.: We validated this technique in 20 subjects with measurements on the floor of the nose. The inter-individual variance and variable transport speed at different locations as known from the literature could be confirmed. ### Long_Answer: This technique allows for the first time to measure the mucociliary clearance at various locations inside the nose of a patient in a short and easy to perform procedure, which up to now necessitated extensive or experimental set-ups. Besides the establishment of a register of mucociliary clearance at various anatomical localisations inside the nose (olfactory epithelium, conchae, surrounding of the ostiae etc.), we intend to verify if this technique can be used as a new diagnostic tool to obtain a deeper insight into some pathologic alterations or uncharacteristic symptoms ("post-nasal-drip") or drug-effects in the nose and in the tracheo-bronchial system. ### Final_Prediction: nan

### Question: Is sirolimus-based regimen associated with decreased expression of glomerular vascular endothelial growth factor? ### Context: Sirolimus (SRL) is a potent immunosuppressant used in organ transplantation. It is known to decrease vascular endothelial growth factor (VEGF) synthesis, making it an interesting treatment option for transplant patients who develop Kaposi sarcoma or other malignant diseases. Because VEGF plays a key role in glomerular function and vascular remodelling, we determined the effect of SRL on renal VEGF expression.Using immunohistochemistry and quantitative image analysis, we examined renal VEGF expression in routine kidney biopsies performed at 1 year post-transplant in the CONCEPT study, a prospective randomized study comparing a cyclosporine (CsA)-based regimen to a SRL-based regimen in association with mycophenolate mofetil (MMF).A total of 74 patients were included in this substudy; 35 were randomized to the CsA group and 39 to the SRL group. Using continuous variables, the mean percentage of glomerular VEGF expression at Week 52 was significantly lower in the SRL group (14.7 ± 13%) compared to CsA group (21.2 ± 14%: P = 0.02). The percentage of glomerular VEGF expression at Week 52 was not influenced by recipient or donor age, gender, renal function, CsA dose, CsA blood level, SRL dose or SRL blood level. It was significantly lower in patients with a proteinuria over versus below 0.5 g/day (11.58 ± 7.9 versus 19.45 ± 15.53; P = 0.036). ### Long_Answer: There is emerging evidence that the VEGF system can play either a beneficial or a detrimental role depending on the specific pathologic situations. Therefore, modulating the renal VEGF axis by using an SRL-based regimen may influence the evolution of kidney injury associated with renal transplantation. ### Final_Prediction: yes

### Question: Are malnutrition and inflammation associated with impaired pulmonary function in patients with chronic kidney disease? ### Context: Inflammation and malnutrition are common findings in patients with chronic kidney disease (CKD). We hypothesized that in inflamed and malnourished patients, respiratory and peripheral muscle dysfunction may have significant consequences on pulmonary function. The aim of this study was to investigate possible associations between pulmonary function and inflammation and malnutrition in patients with CKD.We studied 109 patients (63% males; 53+/-12 years) at the initiation of dialysis treatment (GFR 7.5+/-2.5 ml/min). Pulmonary function tests [forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and peak expiratory flow (PEF)] were performed and the percentages of predicted values were calculated (%FEV(1), %FVC and %PEF). Systemic inflammation, assessed by high-sensitivity C-reactive protein (hsCRP) and nutritional status assessed by subjective global assessment (SGA), lean body mass (LBM) (estimated with dual energy X-ray absorptiometry) and hand-grip strength (HGS), were evaluated at the same time.Significant negative correlations were found between hsCRP and the percent predicted values for all pulmonary function tests [%FEV(1) (Rho = -0.45), %FVC (Rho = -0.43) and %PEF (Rho = -0.38)], respectively. Malnourished patients defined as SGA >or=2 had lower %FEV(1) (64+/-19 vs 82+/-23%; P<0.001) and %FVC (67+/-18 vs 83+/-21%; P<0.001) than well nourished patients. Significant correlations were observed between HGS and %FVC (Rho = 0.38; P <0.001), %FEV(1) (Rho = 0.37; P<0.001) and %PEF (Rho = 0.22; P<0.05) and between LBM and %PEF (Rho = 0.20; P<0.05). Multivariate Cox analysis showed that cardiovascular disease and low %FVC were associated with poor survival. ### Long_Answer: Impaired pulmonary function is associated with malnutrition and inflammation, and predicts mortality in CKD patients. This may reflect an impact of malnutrition and inflammation on respiratory muscle performance, leading to pulmonary dysfunction, which could influence the clinical outcome. ### Final_Prediction: yes

### Question: Does riproximin modulate multiple signaling cascades leading to cytostatic and apoptotic effects in human breast cancer cells? ### Context: Riproximin, a type II ribosome-inactivating protein (RIP), has shown significant cytotoxic effects in diverse types of cancer cells. To better understand its therapeutic potential, elaborated investigations on the mechanistic aspects of riproximin deem crucial. In this study, we focused on riproximin-mediated changes in cellular properties and corresponding molecular pathways in breast cancer cells.Cytotoxicity of riproximin was determined by MTT assay, while the clonogenic and migratory effects were determined by colony formation, migration, and scratch assays. Cytostatic and apoptotic effects were studied by flow cytometry and nuclear staining procedures. Alterations at molecular levels were scrutinized by means of microarray and qRT-PCR methodologies.Riproximin induced significant cytotoxic effects in the selected human breast cancer cells MDA-MB-231 and MCF-7. Profound inhibition of migration and colony formation were observed in both cell lines in response to riproximin exposure. Concomitantly, a significant arrest in S phase and nuclear fragmentation were observed as causes for its cytostatic and apoptotic effects, respectively. Genetic profiling revealed pronounced induction of the anticancer cytokine IL24/MDA-7 and ER-stress-related GADD genes. In addition, prominent inhibition of the genes relevant to migration (RHO GTPases), anti-apoptotic activities (BCL family), and cell cycle (cyclins) was also noticed. ### Long_Answer: Riproximin, with its significant antineoplastic effects, modulates multiple cytostatic and apoptotic pathways in breast cancer cells. Results from these investigations highlight the future therapeutic potential of this naturally occurring compound for breast cancer. ### Final_Prediction: yes

### Question: Are high-end normal adrenocorticotropic hormone and cortisol levels associated with specific cardiovascular risk factors in pediatric obesity : a cross-sectional study? ### Context: The hypothalamic-pituitary-adrenal (HPA) axis, and in particular cortisol, has been reported to be involved in obesity-associated metabolic disturbances in adults and in selected populations of adolescents. The aim of this study was to investigate the association between morning adrenocorticotropic hormone (ACTH) and cortisol levels and cardiovascular risk factors in overweight or obese Caucasian children and adolescents.This cross-sectional study of 450 obese children and adolescents (aged 4 to 18 years) was performed in a tertiary referral center. ACTH, cortisol, cardiovascular risk factors (fasting and post-challenge glucose, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, and hypertension) and insulin resistance were evaluated. All analyses were corrected for confounding factors (sex, age, puberty, body mass index), and odds ratios were determined.ACTH and cortisol levels were positively associated with systolic and diastolic blood pressure, triglycerides, fasting glucose and insulin resistance. Cortisol, but not ACTH, was also positively associated with LDL-cholesterol. When adjusted for confounding factors, an association between ACTH and 2 h post-oral glucose tolerance test glucose was revealed. After stratification according to cardiovascular risk factors and adjustment for possible confounding factors, ACTH levels were significantly higher in subjects with triglycerides ≥90th percentile (P <0.02) and impaired fasting glucose or glucose tolerance (P <0.001). Higher cortisol levels were found in subjects with blood pressure ≥95th percentile and LDL-cholesterol ≥90th percentile. Overall, the highest tertiles of ACTH (>5.92 pmol/l) and cortisol (>383.5 nmol/l) although within the normal range were associated with increases in cardiovascular risk factors in this population. ### Long_Answer: In obese children and adolescents, high morning ACTH and cortisol levels are associated with cardiovascular risk factors. High ACTH levels are associated with high triglyceride levels and hyperglycemia, while high cortisol is associated with hypertension and high LDL-cholesterol. These specific relationships suggest complex mechanisms through which the HPA axis may contribute to metabolic impairments in obesity, and merit further investigations. ### Final_Prediction: yes

### Question: Do Asian breast cancer patients have poorer survival than their western counterparts? ### Context: The difference in breast cancer incidence and prognosis between ethnic groups seeks an explanation. We have recently shown that Swedish women are two to three times more likely to be diagnosed with breast cancer compared with Singaporean women. In the present paper, we compare breast cancer survival in the two countries.We compared the survival of 10,287 Singaporean women and 17,090 Swedish women with breast cancer. Relative survival ratios were used to describe the prognosis in the two populations. A Poisson regression model was used to calculate relative risks for different follow-up periods, age groups, time of diagnosis and disease stages.The majority of the Swedish women had local cancer (80%) compared with Singaporean women (51%). The overall 5-year relative survival of the Swedish women appeared better (80%) than that of the Singaporean women (70%). A similar survival pattern was observed, however, between the two countries in a stage-by-stage comparison. Survival improved for all women in Singapore over the two decades, but only in the premenopausal women in Stockholm. In 1980 to 1989, premenopausal Singaporean women had 27% increased risk of death compared with Swedish women, adjusted for stage and year of follow-up, while the postmenopausal women had 48% increased risk. In 1990 to 1999, this risk decreased by 19% and 22% for the premenopausal and postmenopausal Singaporean women compared with the Swedish women. ### Long_Answer: The stage-dependent prognosis was similar for Singaporean women and for Swedish women. Singaporean women, both premenopausal and postmenopausal, had pronounced improvement in prognosis over the calendar periods, probably contributed by marked economic improvement, leading to better medical facilities and management with increased awareness of patients to diagnosis and treatment, as well as improved treatment options. Improvement seen only in the premenopausal women in Stockholm was probably due to improved treatment options. ### Final_Prediction: nan

### Question: Does butein suppress breast cancer growth by reducing a production of intracellular reactive oxygen species? ### Context: Butein has various functions in human diseases including cancer. While anti-cancer effects of butein have been revealed, it is urgent to understand a unique role of butein against cancer. In this study, we demonstrate that butein inhibition of reactive oxygen species (ROS) production results in suppression of breast cancer growth.Different breast cancer cell lines were treated with butein and then subjected to cell viability and apoptosis assays. Butein-sensitive or -resistant breast cancer cells were injected into mammary fat pads of immunocompromised mice and then butein was injected. Breast cancer cells were categorized on the basis of butein sensitivity.Butein reduced viabilities of different breast cancer cells, while not affecting those of HER2-positive (HER2+) HCC-1419, SKBR-3 and HCC-2218 breast cancer cells. Butein reduction of ROS levels was correlated with apoptotic cell death. Furthermore, butein reduction of ROS level led to inhibitions of AKT phosphorylation. N-acetyl-L-cysteine (NAC), a free radical scavenger, also reduced ROS production and AKT phosphorylation, resulting in apoptotic cell death. In contrast, inhibitory effects of both butein and NAC on ROS production and AKT phosphorylation were not detected in butein-resistant HER2+ HCC-1419, SKBR-3 and HCC-2218 cells. In the in vivo tumor growth assays, butein inhibited tumor growth of butein-sensitive HER2+ BT-474 cells, while not affecting that of butein-resistant HER2+ HCC-1419 cells. Moreover, butein inhibition of ROS production and AKT phosphorylation was confirmed by in vivo tumor growth assays. ### Long_Answer: Our study first reveals that butein causes breast cancer cell death by the reduction of ROS production. Therefore, our finding provides better knowledge for butein effect on breast cancer and also suggests its treatment option. ### Final_Prediction: yes

### Question: Do microtubules contribute to the birefringence of the retinal nerve fiber layer? ### Context: The retinal nerve fiber layer (RNFL) exhibits birefringence that is due to the oriented cylindrical structure of the ganglion cell axons. Possible birefringent structures include axonal membranes, microtubules (MTs), and neurofilaments. MTs are generally assumed to be a major contributor, but this has not been demonstrated. In this study, the MT depolymerizing agent colchicine was used to evaluate the contribution of MTs to RNFL birefringence.Retinal nerve fiber bundles of isolated rat retina were observed through an imaging polarimeter set near extinction. Images were taken over an extended period. During baseline, the tissue was perfused with a physiological solution. During a treatment period, the solution was switched either to a control solution identical with the baseline solution or to a similar solution containing colchicine. The contrast of nerve fiber bundles was used to follow change of RNFL birefringence over time.When imaged by the polarimeter, birefringent retinal nerve fiber bundles appeared as either bright or dark stripes. Bundles displayed as bright stripes were used to follow changes in retardance. The contrast of nerve fiber bundles was stable in control experiments. However, in treatment experiments, bundles were bright during the baseline period, but the contrast of bundles decreased rapidly when the colchicine solution was applied; bundles were barely visible after 30 minutes of treatment. After 70 minutes, the bundle contrast was close to zero at all wavelengths studied (440-780 nm). ### Long_Answer: MTs make a significant contribution to RNFL birefringence. The decrease of RNFL birefringence in glaucoma may indicate a loss of MTs. ### Final_Prediction: yes

### Question: Are serine proteases HTRA1 and HTRA3 down-regulated with increasing grades of human endometrial cancer? ### Context: The high temperature requirement factor A (HTRA) family consists of serine proteases with domains homologous to those of bacterial HTRA. Four human HTRA members have been described: HTRA1-4. HTRA1 and HTRA3 share a high degree of domain homologies and may therefore share a functional similarity. HTRA1 mRNA and protein is reported to be down-regulated in SV40-transformed cells, a malignant melanoma cell line, ovarian tumors, and ovarian cancer cell lines, suggesting a progressive loss of HTRA1 and the protein in cancer. This raises the possibility that HTRA3 may likewise be involved in cancer. This study examined the expression of mRNA and protein levels of HTRA1 and HTRA3 in human endometrial cancer (EC).Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was performed in normal endometrium (n = 4) and in three grades of EC (n = 5 for each EC grade). Immunohistochemistry was used to determine the protein expression and the cellular localization of HTRA1 and HTRA3 in normal endometrium tissue (n = 6) and in three grades of EC (n = 8-10 for each EC grade).RT-PCR analysis showed a significant reduction of HTRA1 and HTRA3 mRNA in endometrial cancer compared to normal endometrium. HTRA1 and HTRA3 protein showed a similar pattern of expression in EC tissue. Positive immunostaining, scored semiquantitatively, revealed a significant decrease of HTRA1 and 3 protein expression with increasing grades of EC. ### Long_Answer: These data suggest that HTRA1 and HTRA3 mRNA and protein levels decrease with increasing grades of EC. ### Final_Prediction: yes

### Question: Do novel hydroxyapatite nanorods improve anti-caries efficacy of enamel infiltrants? ### Context: Enamel resin infiltrants are biomaterials able to treat enamel caries at early stages. Nevertheless, they cannot prevent further demineralization of mineral-depleted enamel. Therefore, the aim of this work was to synthesize and incorporate specific hydroxyapatite nanoparticles (HAps) into the resin infiltrant to overcome this issue.HAps were prepared using a hydrothermal method (0h, 2h and 5h). The crystallinity, crystallite size and morphology of the nanoparticles were characterized through XRD, FT-IR and TEM. HAps were then incorporated (10wt%) into a light-curing co-monomer resin blend (control) to create different resin-based enamel infiltrants (HAp-0h, HAp-2h and HAp-5h), whose degree of conversion (DC) was assessed by FT-IR. Enamel caries lesions were first artificially created in extracted human molars and infiltrated using the tested resin infiltrants. Specimens were submitted to pH-cycling to simulate recurrent caries. Knoop microhardness of resin-infiltrated underlying and surrounding enamel was analyzed before and after pH challenge.Whilst HAp-0h resulted amorphous, HAp-2h and HAp-5h presented nanorod morphology and higher crystallinity. Resin infiltration doped with HAp-2h and HAp-5h caused higher enamel resistance against demineralization compared to control HAp-free and HAp-0h infiltration. The inclusion of more crystalline HAp nanorods (HAp-2h and HAp-5h) increased significantly (p<0.05) the DC. ### Long_Answer: Incorporation of more crystalline HAp nanorods into enamel resin infiltrants may be a feasible method to improve the overall performance in the prevention of recurrent demineralization (e.g. caries lesion) in resin-infiltrated enamel. ### Final_Prediction: yes

### Question: Do superior and basal segment lung cancers in the lower lobe have different lymph node metastatic pathways and prognosis? ### Context: Although the lower lobe is a large entity that occupies half of the hemithorax, all tumors located within the lower lobe have been treated uniformly regardless of tumor location. The aim of this study was to reveal differences in the metastatic pathway to the mediastinum and in prognosis of N2 disease between lung cancers originating from superior and basal segment of the lower lobe.Data on 139 patients who underwent pulmonary resection with systematic nodal dissection for pN2 non-small cell lung cancer (NSCLC) originating from the lower lobe between 1980 and 2001 were retrospectively reviewed. Those lower lobe N2 tumors were divided into two groups by origin: 51 were superior segment, and 88 were basal segment.The superior segment group showed a significantly higher incidence of superior mediastinal metastasis than the basal segment group (64% vs 36%, p = 0.0012). When superior mediastinal metastasis existed, the basal segment group showed a significantly higher incidence of synchronous subcarinal metastasis than the superior segment group (81% vs 39%, p = 0.0006). Pneumonectomy was required significantly more often in the superior segment group than in the basal segment group (45% vs 17%, p = 0.0003). The basal segment origin tumors with only subcarinal metastasis showed significantly better prognosis than other lower lobe N2 tumors (5-year survival, 43% vs 18%; p = 0.0155). ### Long_Answer: Basal segment tumor metastasizes to the superior mediastinum mostly through the subcarinal node, whereas superior segment tumors often metastasize directly to the superior mediastinum without concomitant metastasis to the subcarinal node. Superior mediastinal dissection will be mandatory for accurate staging of superior segment tumors even when the subcarinal node is negative on frozen section. As for the prognosis among lower lobe N2 tumors, only in cases with basal segment tumor without superior mediastinal metastasis may long-term survival be expected. ### Final_Prediction: yes

### Question: Do patients undergoing physical testing report pain intensity reliably? ### Context: To determine the reliability of patient reports of pain intensity during the application of physical tests.A single examiner required participants to use the numeric pain rating scale (NPRS) to report the intensity of pain provoked during physical testing of the hip. Standardized versions of 14 physical tests were used on 18 people with hip pain. Tests were repeated at 1 hour and 2-7 days later. Within- and between-session reliability of reports of pain intensity was calculated using intraclass correlation coefficients (ICCs) and Lin's concordance correlation coefficients (CCCs). Standard errors of measurement (SEMs) were calculated.ICC/CCC values for within-session reports of pain intensity ranged from 0.34 (95% confidence interval [95% CI] -0.08, 0.66) to 0.88 (95% CI 0.73, 0.95). Patients demonstrated "substantial" or "almost perfect" reliability in reporting pain intensity with 9 of 14 tests and "moderate" reliability with 3 tests. Two tests were unreliable (ICC 0.35 and 0.34). ICC/CCC values for between-session reports of pain intensity ranged from -0.05 (95% CI -0.42, 0.34) to 0.84 (95% CI 0.44, 0.95). Patients demonstrated substantial or almost perfect reliability in reporting pain intensity with 11 of 14 tests. Two tests were unreliable (ICC 0.26 and -0.05). The average SEM value of 0.9 points on the NPRS was the same for both within- and between-session testing (range 0.6-1.6). ### Long_Answer: Patient reports of the intensity of pain provoked by physical tests are sufficiently reliable to be clinically useful. However, the SEM of 0.9 points should be considered when precise calculations of changes in pain intensity are important. ### Final_Prediction: nan

### Question: Are vKORC1 and CYP2C9 genotypes predictors of warfarin-related outcomes in children? ### Context: Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children.Clinical and genetic data for 93 children (age ≤ 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay.With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. ### Long_Answer: This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children. ### Final_Prediction: yes

### Question: Does aKAP150 contribute to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus? ### Context: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca(2+)-activated K(+) (BKCa) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes mellitus is unknown.To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus.We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. d-glucose-dependent suppression of BKCa channel β1 subunits required Ca(2+) influx via voltage-gated L-type Ca(2+) channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits and attenuated high-fat diet-induced elevation in arterial blood pressure. ### Long_Answer: Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes mellitus. ### Final_Prediction: yes

### Question: Does volume of lymphatic metastases independently influence prognosis in colorectal cancer? ### Context: To evaluate the prognostic relevance of the volume of nodal metastatic disease in colorectal cancer patients.One hundred node-positive patients with T2 or T3 carcinoma of the colon or rectum after routine histologic examination of the regional nodes were studied. The metastatic tumor was measured with an ocular micrometer, and the tumor volume was determined.The mean lymph node metastatic tumor volume was 5.1 +/- 4.99 mm(3) (range, 0.05 to 83,434 mm(3)). There was only a weak positive correlation with number of nodes involved with metastatic disease and tumor volume in nodes (r =.45). Median follow-up was 39 months (range, 1 to 87 months). The number of nodes was highly predictive of outcome. Individuals with one to three positive nodes had a substantially better survival than individuals with four or more positive nodes (P <.001). The volume of nodal metastatic disease correlated with outcome (P =.019). Patients dying as a result of disease had substantially greater mean metastatic nodal volume than those who were alive (3,705 v 1,783 mm(3); P =.036). However, the total metastatic nodal volume did not, independent of positive nodes or number of positive nodes, predict outcome. Individuals with micrometastatic nodal volume did not have improved survival when compared with individuals with macrometastatic nodal volume (P =.79). ### Long_Answer: The number of nodes involved with metastatic tumor, rather the volume of metastatic involvement of the regional lymph nodes, predicts outcome. These results suggest that micrometastatic disease may have a similar prognosis as macrometastatic disease when the same number of lymph nodes are involved with metastatic tumor. ### Final_Prediction: no

### Question: Is admission hyperglycemia a reliable outcome predictor in children with severe traumatic brain injury? ### Context: To identify the relationship between admission hyperglycemia and outcome in children with severe brain injury at hospital discharge and 6 months later.A retrospective analysis of blood glucose levels was conducted in 61 children with severe brain injury admitted to the Pediatric Intensive Care Unit between November 1, 2005 and October 30, 2009. Hyperglycemia was considered for a cut off value of > 150 mg/dL, based on literature. Outcome was measured with the Glasgow Outcome Scale at hospital discharge and 6 months after discharge. Death was also analyzed as an outcome measure.Mean admission blood glucose of the patients was 251 mg/dL (68-791). Hyperglycemia was noted on admission in 51 (83.6%) patients. A moderately significant positive correlation was found between admission blood glucose and severity of head trauma according to Abbreviated Injury Score (r = 0.46). Mean admission glucose level of non-survivors was significantly higher (207 mg/dL vs. 455 mg/dL, p < 0.001). Mean blood glucose level of the patients in bad outcome group was found significantly higher compared to that of the patients in good outcome group at hospital discharge and 6 months after discharge (185 mg/dL vs. 262 mg/dL, p < 0.15 and 184 mg/dL vs. 346 mg/dL, p < 0.04, respectively). ### Long_Answer: Hyperglycemia could be considered as a marker of brain injury and, when present upon admission, could reflect extensive brain damage, frequently associated with mortality and bad outcome. Further studies are needed to investigate the effect of strict glycemic control on mortality and outcomes. ### Final_Prediction: yes

### Question: Is current evidence insufficient to define an optimal threshold for intervention in isolated type II endoleak after endovascular aneurysm repair? ### Context: To report a systematic review and meta-regression of the association between the threshold for intervention in patients with isolated type II endoleak after endovascular aneurysm repair (EVAR) and the fate of the aneurysm sac.Medline, trial registries, conference proceedings, and article reference lists were searched to identify case series reporting sac outcomes following a specific treatment threshold for isolated type II endoleak. Articles were classified by the threshold for intervention as conservative, selective (intervention for >5-mm sac expansion or persistent type II endoleak >6 months), or aggressive (any type II endoleak or persistent for >3 months) and sac outcomes were extracted for review. Standard meta-regression to estimate the pooled odds ratios (OR), presented with the 95% confidence interval (CI), was performed to identify whether an aggressive, selective, or conservative threshold for intervention was associated with sac expansion or sac regression.Ten series were analyzed that reported the outcomes of isolated type II endoleak in 231 patients; of these, 56 patients were treated at an aggressive threshold, 104 at a selective threshold, and 71 at a conservative threshold. The majority (194/231, 84.0%) demonstrated either stable or shrinking sacs during follow-up. No ruptures occurred. Meta-regression demonstrated no evidence that any strategy, compared to using a conservative approach, reduced sac expansion (aggressive estimated OR 0.70, 95% CI 0.15 to 3.31, p = 0.60; selective estimated OR 1.72, 95% CI 0.49 to 6.00, p = 0.34) or improved sac regression (aggressive estimated OR 0.55, 95% CI 0.02 to 16.94, p = 0.69; selective estimated OR 5.54, 95% CI 0.39 to 79.21, p = 0.17). ### Long_Answer: There is inadequate information to support any one threshold for intervention. The rarity of rupture and sac expansion confirms the predominantly benign nature of isolated type II endoleak. In the absence of statistical support for a uniform approach to this problem, patient and physician preference remain key. Prospective data are still needed to investigate whether an optimum management algorithm can be devised. ### Final_Prediction: yes

### Question: Does enhancement of canonical Wnt/β-catenin signaling activity by HCV core protein promote cell growth of hepatocellular carcinoma cells? ### Context: The Hepatitis C virus (HCV) core protein has been implicated as a potential oncogene or a cofactor in HCV-related hepatocellular carcinoma (HCC), but the underlying mechanisms are unknown. Overactivation of the Wnt/β-catenin signaling is a major factor in oncogenesis of HCC. However, the pathogenesis of HCV core-associated Wnt/β-catenin activation remains to be further characterized. Therefore, we attempted to determine whether HCV core protein plays an important role in regulating Wnt/β-catenin signaling in HCC cells.Wnt/β-catenin signaling activity was investigated in core-expressing hepatoma cells. Protein and gene expression were examined by Western blot, immunofluorescence staining, RT-qPCR, and reporter assay.HCV core protein significantly enhances Tcf-dependent transcriptional activity induced by Wnt3A in HCC cell lines. Additionally, core protein increases and stabilizes β-catenin levels in hepatoma cell line Huh7 through inactivation of GSK-3β, which contributes to the up-regulation of downstream target genes, such as c-Myc, cyclin D1, WISP2 and CTGF. Also, core protein increases cell proliferation rate and promotes Wnt3A-induced tumor growth in the xenograft tumor model of human HCC. ### Long_Answer: HCV core protein enhances Wnt/β-catenin signaling activity, hence playing an important role in HCV-associated carcinogenesis. ### Final_Prediction: yes

### Question: Does stem cell therapy improve the outcome of liver resection in cirrhotics? ### Context: Significant proportions of liver cirrhotic patients develop hepatocellular carcinoma and have to undergo hepatic resection. The compromised cirrhotic liver cannot withstand further removal of hepatic tissue, thus, leading to postoperative complication and death.In this study, we enrolled 20 patients having liver cirrhosis with hepatocellular carcinoma and randomly assigned them into two groups to receive autologous stem cells or placebo.After 3 weeks, all participants underwent liver resection and were followed for 12 weeks postoperative. We observed that the group receiving preoperative stem cell therapy had shown a significant improvement in all parameters of liver function and had no postoperative complications compared to the group treated with placebo, which showed no improvement in liver parameters and had postoperative complications. ### Long_Answer: In conclusion, autologous stem cell therapy can improve the surgical outcome in cirrhotic livers and should be considered as an adjuvant treatment in such patients undergoing hepatic resection. ### Final_Prediction: yes

### Question: Are increased circulating cell signalling phosphoproteins in sera useful for the detection of pancreatic cancer? ### Context: Intracellular phosphoprotein activation significantly regulates cancer progression. However, the significance of circulating phosphoproteins in the blood remains unknown. We investigated the serum phosphoprotein profile involved in pancreatic cancer (PaCa) by a novel approach that comprehensively measured serum phosphoproteins levels, and clinically applied this method to the detection of PaCa.We analysed the serum phosphoproteins that comprised cancer cellular signal pathways by comparing sera from PaCa patients and benign controls including healthy volunteers (HVs) and pancreatitis patients.Hierarchical clustering analysis between PaCa patients and HVs revealed differential pathway-specific profiles. In particular, the components of the extracellular signal-regulated kinase (ERK) signalling pathway were significantly increased in the sera of PaCa patients compared with HVs. The positive rate of p-ERK1/2 (82%) was found to be superior to that of CA19-9 (53%) for early stage PaCa. For the combination of these serum levels, the area under the receiver-operator characteristics curves was showing significant ability to distinguish between the two populations in independent validation set, and between cancer and non-cancer populations in another validation set. ### Long_Answer: The comprehensive measurement of serum cell signal phosphoproteins is useful for the detection of PaCa. Further investigations will lead to the implementation of tailor-made molecular-targeted therapeutics. ### Final_Prediction: yes

### Question: Do malarial pigment haemozoin , IFN-gamma , TNF-alpha , IL-1beta and LPS stimulate expression of inducible nitric oxide synthase and production of nitric oxide in immuno-purified human monocytes? ### Context: Enhanced production of nitric oxide (NO) following upmodulation of the inducible isoform of NO synthase (iNOS) by haemozoin (HZ), inflammatory cytokines and LPS may provide protection against Plasmodium falciparum malaria by killing hepatic and blood forms of parasites and inhibiting the cytoadherence of parasitized erythrocytes (RBC) to endothelial cells. Monocytes and macrophages are considered to contribute importantly to protective upregulation of iNOS and production of NO. Data obtained with murine phagocytes fed with human HZ and synthetic HZ (sHZ) indicate that supplemental treatment of those cells with IFN-gamma elicited significant increases in protein and mRNA expression of iNOS and NO production, providing a potential mechanism linking HZ phagocytosis and increased production of NO. Purpose of this study was to analyse the effect of P. falciparum HZ and sHZ supplemental to treatment with IFN-gamma and/or a stimulatory cytokine-LPS mix on iNOS protein and mRNA expression in immuno-purified human monocytes.Adherent immunopurified human monocytes (purity >85%), and murine phagocytic cell lines RAW 264.7, N11 and ANA1 were fed or not with P. falciparum HZ or sHZ and treated or not with IFN-gamma or a stimulatory cytokine-LPS mix. Production of NO was quantified in supernatants, iNOS protein and mRNA expression were measured after immunoprecipitation and Western blotting and quantitative RT-PCT, respectively.Phagocytosis of HZ/sHZ by human monocytes did not increase iNOS protein and mRNA expression and NO production either after stimulation by IFN-gamma or the cytokine-LPS mix. By contrast, in HZ/sHZ-laden murine macrophages, identical treatment with IFN-gamma and the cytokine-LPS mix elicited significant increases in protein and mRNA expression of iNOS and NOS metabolites production, in agreement with literature data. ### Long_Answer: Results indicate that human monocytes fed or not with HZ/sHZ were constantly unable to express iNOS and generate NOS metabolites even after stimulation with IFN-gamma or a cytokine-LSP mix that were very active on HZ-fed murine phagocytic lines. Present data do not support the hypothesis that monocytes are mediators of anti-parasitic defence in clinical malaria via activation of iNOS and production of NO, and suggest caution in extrapolating data obtained with murine or hybrid systems to human malaria. ### Final_Prediction: no

### Question: Immigrant general practitioners in Norway: a special resource? ### Context: To explore whether and how immigrant general practitioners (GPs) in two major cities in Norway think that their own ethnic background affects their practices and their work.Qualitative focus group and individual interviews with seven immigrant GPs, five men and two women, age 36-65 years. Their clinical experience in Norwegian primary health care ranged from four to 30 years. Analysis was conducted by systematic text condensation.First, immigrant GPs described a gradual process of becoming bicultural: the GPs communicate with immigrant patients on their own terms and draw upon their special knowledge from abroad to help selected patients, while also adapting to Norwegian cultural expectations of the GP's role. Second, the GPs described being aware of cultural issues in consultations with immigrant and Norwegian patients, but rarely making these issues explicit. The GPs ventured that cultural awareness, together with their personal experience in their own countries and as immigrants in Norway, made them able to sometimes help immigrant patients better than Norwegian GPs. Third, immigrant GPs experienced a big workload related to immigrant patients, but they accepted this as a natural part of their work. Fourth, immigrant GPs felt that they had to work harder and be more careful than their Norwegian colleagues in order to avoid complaints from patients, and to be accepted by colleagues. ### Long_Answer: Immigrant GPs express broad cultural competence and keen cultural awareness in their consultations. The immigrant background of these GPs could be considered as a special resource for clinical practice. ### Final_Prediction: nan

### Question: Does the addition of Serenoa repens to tamsulosin improve its therapeutical efficacy in benign prostatic hyperplasia? ### Context: In this prospective study patients had to have prostate volume (PV)<50 mL, International Prostate Symptom Score (IPSS) of 7-18, Quality of Life score (QoLs)>3, a maximal flow rate (Qmax) of 5-15 mL/s, with post voiding residual volume (PVR)<150 mL and serum prostatic antigen (PSA)<4 ng/mL. TAM (0.4 mg) was administered once a day, SR (320 mg) daily or SR (320 mg) + TAM (0.4 mg) daily for a median period of 6 months.A total of 297 patients were recruited, whereas 265 patients were fully available: 87 into the group TAM, 97 into the group SR and 81 into the group TAM + SR. There was no statistically significant difference between the treatment groups in the sense of demographic and other baseline parameters. No difference was found among the 3 treatment groups, neither in the major endpoint of the study in the sense of a change between baseline and final evaluation in total IPSS, obstructive and irritative subscores, improvement of QoLs, increase in Qmax, nor for the second endpoint including diminution of PV, PSA and PVR. During the treatment period 20 (23%) of the patients managed with TAM and 17 (21%) with TAM + SR had drug- treated with related adverse reactions. No adverse effect was detected in the group SR. ### Long_Answer: Treatment of BPH by both SR and TAM seems to be efficacious alone. None of them had superiority over another and, additionally, a combined therapy (TAM + SR) does not provide extra benefits. Furthermore, SR is a well-tolerated agent that can be used alternatively in the treatment of LUTS/BPH. ### Final_Prediction: nan

### Question: Does the ubiquitin proteasome system function as an inhibitory constraint on synaptic strengthening? ### Context: Long-lasting forms of synaptic plasticity have been shown to depend on changes in gene expression. Although many studies have focused on the regulation of transcription and translation during learning-related synaptic plasticity, regulated protein degradation provides another common means of altering the macromolecular composition of cells.We have investigated the role of the ubiquitin proteasome system in long-lasting forms of learning-related plasticity in Aplysia sensory-motor synapses. We find that inhibition of the proteasome produces a long-lasting (24 hr) increase in synaptic strength between sensory and motor neurons and that it dramatically enhances serotonin-induced long-term facilitation. The increase in synaptic strength produced by proteasome inhibitors is dependent on translation but not transcription. In addition to the increase in synaptic strength, proteasome inhibition leads to an increase in the number of synaptic contacts formed between the sensory and motor neurons. Blockade of the proteasome in isolated postsynaptic motor neurons produces an increase in the glutamate-evoked postsynaptic potential, and blockade of the proteasome in the isolated presynaptic sensory cells produces increases in neurite length and branching. ### Long_Answer: We conclude that both pre- and postsynaptic substrates of the ubiquitin proteasome function constitutively to regulate synaptic strength and growth and that the ubiquitin proteasome pathway functions in mature neurons as an inhibitory constraint on synaptic strengthening. ### Final_Prediction: yes

### Question: Do discriminative stimuli that control instrumental tobacco-seeking by human smokers also command selective attention? ### Context: Incentive salience theory states that acquired bias in selective attention for stimuli associated with tobacco-smoke reinforcement controls the selective performance of tobacco-seeking and tobacco-taking behaviour.To support this theory, we assessed whether a stimulus that had acquired control of a tobacco-seeking response in a discrimination procedure would command the focus of visual attention in a subsequent test phase.Smokers received discrimination training in which an instrumental key-press response was followed by tobacco-smoke reinforcement when one visual discriminative stimulus (S+) was present, but not when another stimulus (S-) was present. The skin conductance response to the S+ and S- assessed whether Pavlovian conditioning to the S+ had taken place. In a subsequent test phase, the S+ and S- were presented in the dot-probe task and the allocation of the focus of visual attention to these stimuli was measured.Participants learned to perform the instrumental tobacco-seeking response selectively in the presence of the S+ relative to the S-, and showed a greater skin conductance response to the S+ than the S-. In the subsequent test phase, participants allocated the focus of visual attention to the S+ in preference to the S-. Correlation analysis revealed that the visual attentional bias for the S+ was positively associated with the number of times the S+ had been paired with tobacco-smoke in training, the skin conductance response to the S+ and with subjective craving to smoke. Furthermore, increased exposure to tobacco-smoke in the natural environment was associated with reduced discrimination learning. ### Long_Answer: These data demonstrate that discriminative stimuli that signal that tobacco-smoke reinforcement is available acquire the capacity to command selective attentional and elicit instrumental tobacco-seeking behaviour. ### Final_Prediction: yes

### Question: Are metacarpal geometry changes during Thoroughbred race training compatible with sagittal-plane cantilever bending? ### Context: Bending of the equine metacarpal bones during locomotion is poorly understood. Cantilever bending, in particular, may influence the loading of the metacarpal bones and surrounding structures in unique ways.We hypothesised that increased amounts of sagittal-plane cantilever bending may govern changes to the shape of the metacarpal bones of Thoroughbred racehorses during training. We hypothesised that this type of bending would require a linear change to occur in the combined second moment of area of the bones for sagittal-plane bending (I) during race training.Six Thoroughbred racehorses were used, who had all completed at least 4 years of race training at a commercial stable. The approximate change in I that had occurred during race training was computed from radiographic measurements at the start and end of training using a simple model of bone shape.A significant (P < 0.001), approximately linear pattern of change in I was observed in each horse, with the maximum change occurring proximally and the minimum change occurring distally. ### Long_Answer: The pattern of change in I was compatible with the hypothesis that sagittal-plane cantilever bending governed changes to the shape of the metacarpal bones during race training. ### Final_Prediction: yes

### Question: Is interference of creatinine measurement in CAPD fluid dependent on glucose and creatinine concentrations? ### Context: High glucose concentration in CAPD fluid is known to interfere with creatinine measurement, which is required for assessment of peritoneal membrane permeability and adequacy of dialysis. Correction formulae have been proposed but they may be method/analyser-dependent. We studied such interference in detail.CAPD fluid was diluted to prepare six specimens with glucose concentrations ranging from 9.1 to 154.4 mmol/l. To each specimen, creatinine standard was added to give five different concentrations from 50 to 800 mumol/l. The 30 specimens were assayed for creatinine with six routine clinical chemistry analysers (Hitachi 911 and 747, Technicon RAXT and SMAC3, Beckman CX7, and Kodak Ektachem 700). Creatinine interference was calculated by subtracting the apparent creatinine concentration with corresponding baseline creatinine concentration (measured at glucose = 9.1 mmol/l) in the same series.At constant creatinine concentration, interference increased with increasing glucose concentration to varying extents (up to 200%) amongst the six analysers. At constant glucose concentration, interference decreased with increasing creatinine concentration in analysers using the alkaline picrate reaction but increased in the Kodak analyser using enzymatic assay. ### Long_Answer: Interference of creatinine measurement in CAPD fluid is dependent on glucose and creatinine concentrations, and each centre should derive specific correction formulae for its analytical system. ### Final_Prediction: yes

### Question: Does case report to suggest an algorithm for management of total fertilisation failure prior to use of donor gametes? ### Context: Total fertilisation failure (TFF), even with intracytoplasmic sperm injection (ICSI), occurs in approximately 3 % of cycles, can be recurrent and the exact cause is difficult to elucidate. Differentiation between oocyte and sperm-related cause of TFF is possible using mouse oocyte-activation techniques, but is not an option within most clinical settings. Therefore, the management of these couples is clinically driven, and the endpoint, if recurrent, is often the use of donor gametes. However, with the invariable lack of a definitive cause of TFF, any decision between the use of donor sperm or oocytes remains an emotive one. We present two case reports demonstrating the importance of appropriate investigation, activation techniques (mechanical and chemical) and clinical management options to develop a clinical algorithm prior to the use of donor gametes.This study is composed of two case reports of assisted reproduction investigation and treatment within an assisted conception unit for couples with recurrent total fertilisation failure.Using appropriate investigation (endocrine, urological and embryological) and treatments (ICSI, IMSI, oocyte-activation techniques), a fertilisation rate of 48 % was achieved in two cycles in couples following a total of nine previous cycles (and 200 previously collected eggs) with TFF. ### Long_Answer: Oocyte activation requires the triggering of intracellular calcium oscillations by the release of a sperm-specific factor (phospholipase C zeta (PLCζ)) into the oocyte cytoplasm. Although, PLCζ deficiencies have been demonstrated as putative causes of failed activation, impaired oocyte responsiveness may also be a factor. The use of donor gametes is often recommended and is often the required endpoint of treatment. However, these reports outline a clinical algorithm that potentially offers success without donation, and also offers a systematic approach to help decide whether donor oocytes or sperm should be recommended. ### Final_Prediction: yes

### Question: Is fractalkine shedding mediated by p38 and the ADAM10 protease under pro-inflammatory conditions in human astrocytes? ### Context: The fractalkine (CX3CR1) ligand is expressed in astrocytes and reported to be neuroprotective. When cleaved from the membrane, soluble fractalkine (sCX3CL1) activates the receptor CX3CR1. Although somewhat controversial, CX3CR1 is reported to be expressed in neurons and microglia. The membrane-bound form of CX3CL1 additionally acts as an adhesion molecule for microglia and infiltrating white blood cells. Much research has been done on the role of fractalkine in neuronal cells; however, little is known about the regulation of the CX3CL1 ligand in astrocytes.The mechanisms involved in the up-regulation and cleavage of CX3CL1 from human astrocytes were investigated using immunocytochemistry, Q-PCR and ELISA. All statistical analysis was performed using GraphPad Prism 5.A combination of ADAM17 (TACE) and ADAM10 protease inhibitors was found to attenuate IL-1β-, TNF-α- and IFN-γ-induced sCX3CL1 levels in astrocytes. A specific ADAM10 (but not ADAM17) inhibitor also attenuated these effects, suggesting ADAM10 proteases induce release of sCX3CL1 from stimulated human astrocytes. A p38 MAPK inhibitor also attenuated the levels of sCX3CL1 upon treatment with IL-1β, TNF-α or IFN-γ. In addition, an IKKβ inhibitor significantly reduced the levels of sCX3CL1 induced by IL-1β or TNF-α in a concentration-dependent manner, suggesting a role for the NF-kB pathway. ### Long_Answer: In conclusion, this study shows that the release of soluble astrocytic fractalkine is regulated by ADAM10 proteases with p38 MAPK also playing a role in the fractalkine shedding event. These findings are important for understanding the role of CX3CL1 in healthy and stimulated astrocytes and may benefit our understanding of this pathway in neuro-inflammatory and neurodegenerative diseases. ### Final_Prediction: yes

### Question: Does scorecard implementation improve identification of postpartum patients at risk for venous thromboembolism? ### Context: To evaluate if an intensive educational intervention in the use of a standardized venous thromboembolism (VTE) risk assessment tool (scorecard) improves physicians' identification and chemoprophylaxis of postpartum patients at risk for VTE.After implementation of a VTE scorecard and prior to an intensive educational intervention, postpartum patients (n = 140) were evaluated to assess scorecard completion, risk factors, and chemoprophylaxis. A performance improvement campaign focusing on patient safety, VTE prevention, and scorecard utilization was then conducted. Evaluation of the same parameters was subsequently performed for a similar group of patients (n = 133). Differences in scorecard utilization and risk assessment were tested for statistical significance.Population-at-risk rates were similar in both assessment periods (31.4% vs 28.6%; p = NS). The greatest risk factors included cesarean delivery, body mass index (BMI) >30 and age >35. Scorecard completion rates for all patients increased in the postintervention period (15.7% vs 67.7%; p < .001). Postintervention scorecard completion rates for the at-risk population also improved (20% vs 79%; p < .001). In the postintervention group, those at risk with completed scorecards had higher prophylaxis rates than those at risk without scorecards (73% vs 25%; p = .03). At-risk patients with completed scorecards had 2.6 times more orders for chemoprophylaxis than at-risk patients without scorecards in both time periods (odds ratio [OR] = 8.4; 95% confidence interval [CI] 3.1-22.8). ### Long_Answer: Utilization of a VTE scorecard coupled with an educational intervention for health care providers increases detection and chemoprophylaxis orders for at-risk patients. Encouraging universal scorecard assessment standardizes identification and chemoprophylaxis of at-risk patients who were otherwise not perceived to be at risk. ### Final_Prediction: yes

### Question: Does [ Postprandial lipemia induce endothelial dysfunction and higher insulin resistance in healthy subjects ]? ### Context: To assess the effect of postprandial lipemia on endothelial function, insulin resistance, and lipid profile in healthy subjects.A prospective', interventional study in 14 healthy young men aged 18-25 years who were given a high-fat meal. Endothelial function was measured using flow-mediated dilation (FMD) in the brachial artery, flow velocity, mean arterial pressure and serum nitrite/nitrate levels (NO(2)/NO(3)). Glucose, insulin, total cholesterol, and triglyceride levels were also tested. Insulin resistance was determined by calculating the HOMA-IR index (Homeostatic Model Assessment-Insulin Resistance).Baseline FMD was 5.9 ± 1.1%. Postprandial lipemia reduced endothelial function by approximately 50% in the first (3.3 ± 0.5%, p=0.03) and second (3.3 ± 0.4%, p=0.04) moment respectively. This finding was associated to an increased flow rate in the brachial artery and lower NO(2)/NO(3) levels (p<0.05). Higher cholesterol and triglyceride levels were found 1h and 2h postprandial (p<0.05). HOMA-IR was significantly increased 1h and 2h postprandial (p<0.05). ### Long_Answer: Postprandial lipemia causes changes in circulating lipid profile and induces endothelial dysfunction and higher insulin resistance. ### Final_Prediction: yes

### Question: Does active substance use at housing entry impair outcomes in supported housing for chronically homeless persons? ### Context: Recent clinical and policy trends have favored low-demand housing (provision of housing not contingent on alcohol and drug abstinence) in assisting chronically homeless people. This study compared housing, clinical, and service use outcomes of participants with high levels of substance use at time of housing entry and those who reported no substance use.Participants in the outcome evaluation of the 11-site Collaborative Initiative on Chronic Homelessness (N=756), who were housed within 12 months of program entry and received an assessment at time of housing and at least one follow-up (N=694, 92%), were classified as either high-frequency substance users (>15 days of using alcohol or>15 days of using marijuana or any other illicit drugs in the past 30 days; N=120, 16%) or abstainers (no days of use; N=290, 38%) on entry into supported community housing. An intermediate group reporting from one to 15 days of use (N=284, 38%) was excluded from the analysis. Mixed-model multivariate regression adjusted outcome findings for baseline group differences.During a 24-month follow-up, the number of days housed increased dramatically for both groups, with no significant differences. High-frequency substance users maintained higher, though declining, rates of substance use throughout follow-up compared with abstainers. High-frequency users continued to have more frequent or more severe psychiatric symptoms than the abstainers. Total health costs declined for both groups over time. ### Long_Answer: Active-use substance users were successfully housed on the basis of a low-demand model. Compared with abstainers, users maintained the higher rates of substance use and poorer mental health outcomes that were observed at housing entry but without relative worsening. ### Final_Prediction: nan

### Question: Do myofibroblasts from salivary gland adenoid cystic carcinomas promote cancer invasion by expressing MMP2 and CXCL12? ### Context: Salivary gland adenoid cystic carcinoma (ACC) is one of the most common malignant tumours in the oral and maxillofacial region, and has high aggressive potential. Tumour and stroma interactions are critical in determining the biological characteristics of malignancy. The aim of this study was to investigate the presence of myofibroblasts and their roles in the invasive characteristics of ACC.Immunohistochemistry was used to detect the expression of vimentin (VIM), α-smooth muscle actin (α-SMA), matrix metalloproteinase 2 (MMP2) and CD34 in ACCs and normal salivary gland controls. A significant difference in α-SMA expression was found between normal controls and ACCs, suggesting the presence of myofibroblasts in ACCs. Immunohistochemical staining also demonstrated higher MMP2 expression in the stroma of ACCs than in the controls (P < 0.001). Primary culture of myofibroblasts from one ACC showed great invasive activity, with high expression of MMP2 and C-X-C motif chemokine 12 (CXCL12) by reverse transcription polymerase chain reaction (RT-PCR) analysis. ### Long_Answer: This study demonstrated the presence of myofibroblasts in ACC. Myofibroblasts might be related to the aggressive growth behaviour of ACC, owing to their high levels of expression of MMP2 and CXCL12. ### Final_Prediction: yes

### Question: Is severity of obstructive sleep apnea related to aldosterone status in subjects with resistant hypertension? ### Context: We previously described a significant correlation between plasma aldosterone concentration (PAC) and severity of obstructive sleep apnea (OSA) in patients with resistant hypertension. This investigation examines the relationship between aldosterone status and OSA in patients with resistant hypertensive-with and without hyperaldosteronism.One hundred and nine consecutive patients with resistant hypertension were prospectively evaluated with plasma renin activity (PRA), PAC, 24-hour urinary aldosterone excretion (UAldo), and polysomnography. Hyperaldosteronism (PRA < 1 ng x mL(-1) x h(-1) and UAldo > or = 12 microg/24-h) prevalence was 28% and OSA prevalence was 77%. In patients with hyperaldosteronism, OSA prevalence was 84%, compared with 74% in hypertensive patients with normal aldosterone levels. There were no significant differences in body mass index or neck circumference between aldosterone groups. PAC and UAldo were both significantly correlated with apnea-hypopnea index (AHI) in the high-aldosterone group (p = 0.568, p = 0.0009; p = 0.533, p = 0.002, respectively). UAldo correlated weakly with apnea-hypopnea index in the normal-aldosterone group, but there was no significant correlation between PAC and AHI in the normal-aldosterone group (p = 0.224, p = 0.049; p = 0.015, p = 0.898, respectively). ### Long_Answer: Our analysis of patients with resistant hypertension confirms a markedly high prevalence of OSA in this group. Furthermore, severity of OSA was greater in those patients with hyperaldosteronism and related to the degree of aldosterone excess. The correlation between OSA severity and aldosterone supports the hypothesis that aldosterone excess contributes to greater severity of OSA. ### Final_Prediction: yes

### Question: Are glandular mast cells with distinct phenotype highly elevated in chronic rhinosinusitis with nasal polyps? ### Context: Although chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is characterized by T(H)2 inflammation, the role of mast cells is poorly understood.The objective of this study was to investigate the presence, localization, and phenotype of mast cells in patients with CRS.We collected nasal tissue and nasal lavage fluid from patients with CRS and control subjects. We analyzed mRNA for the mast cell proteases tryptase, chymase, and carboxypeptidase A3 by using real-time PCR and measured mast cell protease proteins by using ELISA, immunohistochemistry, and immunofluorescence.Tryptase mRNA was significantly increased in nasal polyps (NPs) from patients with CRSwNP (P< .001) compared with uncinate tissue from patients with CRS or control subjects. Tryptase protein was also elevated in NPs and in nasal lavage fluids from patients with CRSwNP. Immnohistochemistry showed increased numbers of mast cells in epithelium and glands but not within the lamina propria in NPs. The mast cells detected in the epithelium in NPs were characterized by the expression of tryptase and carboxypeptidase A3 but not chymase. Mast cells expressing all the 3 proteases were abundant within the glandular epithelium of NPs but were not found in normal glandular structures. ### Long_Answer: Herein we demonstrated a unique localization of mast cells within the glandular epithelium of NPs and showed that mast cells in NPs have distinct phenotypes that vary by tissue location. Glandular mast cells and the diverse subsets of mast cells detected may contribute to the pathogenesis of CRSwNP. ### Final_Prediction: yes

### Question: Is atypical squamous cells that cannot exclude high-grade squamous intraepithelial lesion clinically significant? ### Context: To determine the cumulative risk of cervical intraepithelial neoplasia (CIN) 2 or 3 in patients with atypical squamous cells, cannot exclude HSIL (ASC-H).A retrospective analysis was performed to identify patients referred to the dysplasia clinic with ASC-H. Initial evaluation included colposcopy, endocervical curettage, and an ectocervical biopsy, when indicated, in all the patients. A follow-up evaluation was performed at 6 and 12 months. Cumulative histological diagnosis of CIN 2 or 3 at 12 months served as the clinical end point.Two hundred twenty-nine patients with ASC-H and with a mean age of 32.8 years were evaluated. At the time of initial colposcopy, only 10.0% (23/229; 95% CI = 6.5%-15%) of the patients had histological evidence of CIN 2 or 3. The cumulative risk of CIN 2 or 3 was 12.2% (95% CI = 8%-17%). ### Long_Answer: Evaluation of patients with ASC-H with colposcopy does lead to the detection of CIN 2 or 3 but perhaps at a rate lower than previously reported. ### Final_Prediction: nan

### Question: Is transoral gastroplasty safe , feasible , and induces significant weight loss in morbidly obese patients : results of the second human pilot study? ### Context: Bariatric surgical treatments have been proven to induce long-term weight loss in morbidly obese patients, but complications are relatively frequent. We recently reported a first human multicenter trial assessing the safety, feasibility, and weight loss results of the Transoral Gastroplasty (TOGA) system (Satiety Inc., Palo Alto, CA) at 6 months. Here we report the 6-month results of the second phase of the pilot trial with the TOGA system, with technical improvements to the device.Patients met established criteria for bariatric surgery. The TOGA system, a set of transoral endoscopically guided staplers, was used to create a stapled restrictive pouch along the lesser curvature of the stomach. Follow-up was at 1 week and at 1, 3, and 6 months. At 3 months, re-treatment consisting in additional distal restrictions was allowed if necessary.Data were available for 11 patients in our center (7 female, mean age 44.2 years, mean body mass index 41.6). The procedure was completed safely in all patients. There were no serious adverse events. Mean excess weight loss was 19.2 %, 33.7 %, and 46.0 % at 1, 3, and 6 months, respectively. Average body mass index decreased from 41.6 before treatment to 33.1 at 6 months. Absolute mean weight loss was 9.9 kg, 17.5 kg, and 24.0 kg at 1, 3, and 6 months, respectively. A dramatic improvement in quality-of-life measures was observed in all patients. ### Long_Answer: This second pilot trial confirmed the feasibility and safety of transoral gastroplasty. The early results and technical improvements reported in the present study are encouraging in terms of safety, early weight loss, and quality of life, and clearly allowed multicenter trials, which are planned to start soon. ### Final_Prediction: yes

### Question: Does genetic variation of γ-tocopherol methyltransferase gene contribute to elevated α-tocopherol content in soybean seeds? ### Context: Improvement of α-tocopherol content is an important breeding aim to increase the nutritional value of crops. Several efforts have been conducted to improve the α-tocopherol content in soybean [Glycine max (L.) Merr.] through transgenic technology by overexpressing genes related to α-tocopherol biosynthesis or through changes to crop management practices. Varieties with high α-tocopherol content have been identified in soybean germplasms. The heritability of this trait has been characterized in a cross between high α-tocopherol variety Keszthelyi Aproszemu Sarga (KAS) and low α-tocopherol variety Ichihime. In this study, the genetic mechanism of the high α-tocopherol content trait of KAS was elucidated.Through QTL analysis and fine mapping in populations from a cross between KAS and a Japanese variety Ichihime, we identified γ-TMT3, which encodes γ-tocopherol methyltransferase, as a candidate gene responsible for high α-tocopherol concentration in KAS. Several nucleotide polymorphisms including two nonsynonymous mutations were found in the coding region of γ-TMT3 between Ichihime and KAS, but none of which was responsible for the difference in α-tocopherol concentration. Therefore, we focused on transcriptional regulation of γ-TMT3 in developing seeds and leaves. An F5 line that was heterozygous for the region containing γ-TMT3 was self-pollinated. From among the progeny, plants that were homozygous at the γ-TMT3 locus were chosen for further evaluation. The expression level of γ-TMT3 was higher both in developing seeds and leaves of plants homozygous for the γ-TMT3 allele from KAS. The higher expression level was closely correlated with high α-tocopherol content in developing seeds. We generated transgenic Arabidopsis plants harboring GUS gene under the control of γ-TMT3 promoter from KAS or Ichihime. The GUS activity assay showed that the activity of γ-TMT3 promoter from KAS was higher than that of Ichihime. ### Long_Answer: The genetic variation in γ-TMT3, which plays a major role in determining α-tocopherol concentration, provides significant information about the regulation of tocopherol biosynthesis in soybean seeds. This knowledge will help breeding programs to develop new soybean varieties with high α-tocopherol content. ### Final_Prediction: yes

### Question: Are morphohistological features of pancreatic stump the main determinant of pancreatic fistula after pancreatoduodenectomy? ### Context: Pancreatic surgery is challenging and associated with high morbidity, mainly represented by postoperative pancreatic fistula (POPF) and its further consequences. Identification of risk factors for POPF is essential for proper postoperative management.Evaluation of the role of morphological and histological features of pancreatic stump, other than main pancreatic duct diameter and glandular texture, in POPF occurrence after pancreaticoduodenectomy.Between March 2011 and April 2013, we performed 145 consecutive pancreaticoduodenectomies. We intraoperatively recorded morphological features of pancreatic stump and collected data about postoperative morbidity. Our dedicated pathologist designed a score to quantify fibrosis and inflammation of pancreatic tissue.Overall morbidity was 59,3%. Mortality was 4,1%. POPF rate was 28,3%, while clinically significant POPF were 15,8%. Male sex (P = 0.009), BMI ≥ 25 (P = 0.002), prolonged surgery (P = 0.001), soft pancreatic texture (P < 0.001), small pancreatic duct (P < 0.001), pancreatic duct decentralization on stump anteroposterior axis, especially if close to the posterior margin (P = 0.031), large stump area (P = 0.001), and extended stump mobilization (P = 0.001) were related to higher POPF rate. Our fibrosis-and-inflammation score is strongly associated with POPF (P = 0.001). ### Long_Answer: Pancreatic stump features evaluation, including histology, can help the surgeon in fitting postoperative management to patient individual risk after pancreaticoduodenectomy. ### Final_Prediction: yes

### Question: Does the Sirt1 activator SRT3025 provide atheroprotection in Apoe-/- mice by reducing hepatic Pcsk9 secretion and enhancing Ldlr expression? ### Context: The deacetylase sirtuin 1 (Sirt1) exerts beneficial effects on lipid metabolism, but its roles in plasma LDL-cholesterol regulation and atherosclerosis are controversial. Thus, we applied the pharmacological Sirt1 activator SRT3025 in a mouse model of atherosclerosis and in hepatocyte culture.Apolipoprotein E-deficient (Apoe(-/-)) mice were fed a high-cholesterol diet (1.25% w/w) supplemented with SRT3025 (3.18 g kg(-1) diet) for 12 weeks. In vitro, the drug activated wild-type Sirt1 protein, but not the activation-resistant Sirt1 mutant; in vivo, it increased deacetylation of hepatic p65 and skeletal muscle Foxo1. SRT3025 treatment decreased plasma levels of LDL-cholesterol and total cholesterol and reduced atherosclerosis. Drug treatment did not change mRNA expression of hepatic LDL receptor (Ldlr) and proprotein convertase subtilisin/kexin type 9 (Pcsk9), but increased their protein expression indicating post-translational effects. Consistent with hepatocyte Ldlr and Pcsk9 accumulation, we found reduced plasma levels of Pcsk9 after pharmacological Sirt1 activation. In vitro administration of SRT3025 to cultured AML12 hepatocytes attenuated Pcsk9 secretion and its binding to Ldlr, thereby reducing Pcsk9-mediated Ldlr degradation and increasing Ldlr expression and LDL uptake. Co-administration of exogenous Pcsk9 with SRT3025 blunted these effects. Sirt1 activation with SRT3025 in Ldlr(-/-) mice reduced neither plasma Pcsk9, nor LDL-cholesterol levels, nor atherosclerosis. ### Long_Answer: We identify reduction in Pcsk9 secretion as a novel effect of Sirt1 activity and uncover Ldlr as a prerequisite for Sirt1-mediated atheroprotection in mice. Pharmacological activation of Sirt1 appears promising to be tested in patients for its effects on plasma Pcsk9, LDL-cholesterol, and atherosclerosis. ### Final_Prediction: yes

### Question: Are advanced glycation end-product-modified proteins of pathogenetic importance in fibromyalgia? ### Context: To quantify the serum levels of the advanced glycation end-product (AGE) pentosidine in 41 patients with fibromyalgia (FM) and 46 healthy controls. The formation of pentosidine is closely related to oxidative stress.Pentosidine was measured by reverse-phased high-performance liquid chromatography with gradient separation on a RP-18 column.Patients with FM have significantly higher pentosidine serum levels than healthy subjects. ### Long_Answer: AGE modification of proteins leads to reduced solubility and high resistance to proteolytic digestion of such altered proteins (e.g. AGE-modified collagens). AGEs are also able to stimulate different kinds of cells via activation of the NFkappaB, mediated by specific receptors of AGEs (e.g. RAGE) on the cell surface. Both mechanisms may contribute to the development, perpetuation and spreading of pain phenomena in FM patients. ### Final_Prediction: nan

### Question: Is trace lithium inversely associated with male suicide after adjustment of climatic factors? ### Context: Previously, we showed the inverse association between lithium in drinking water and male suicide in Kyushu Island. The narrow variation in meteorological factors of Kyushu Island and a considerable amount of evidence regarding the role of the factors on suicide provoked the necessities of adjusting the association by the wide variation in sunshine, temperature, rain fall, and snow fall.To keep the wide variation in meteorological factors, we combined the data of Kyushu (the southernmost city is Itoman, 26°) and Hokkaido (the northernmost city is Wakkanai, 45°). Multiple regression analyses were used to predict suicide SMRs (total, male and female) by lithium levels in drinking water and meteorological factors.After adjustment of meteorological factors, lithium levels were significantly and inversely associated with male suicide SMRs, but not with total or female suicide SMRs, across the 153 cities of Hokkaido and Kyushu Islands. Moreover, annual total sunshine and annual mean temperature were significantly and inversely associated with male suicide SMRs whereas annual total rainfall was significantly and directly associated with male suicide SMRs. ### Long_Answer: The limitations of the present study include the lack of data relevant to lithium levels in food and the proportion of the population who drank tap water and their consumption habits. ### Final_Prediction: yes

### Question: Do mucosal T-cell phenotypes in persistent atopic and nonatopic rhinitis show an association with mast cells? ### Context: Allergic rhinitis is characterized by selective expansion of T cell subsets with a CD4+ phenotype. Recently, we identified a subpopulation of nonallergic rhinitis subjects with increased epithelial mast cell and eosinophil populations, suggestive of local mucosal allergy. Previously, T cell subsets have not been characterized in this subselection of nonallergic subjects and furthermore, their relationship to mast cell and basophil effector cells remain unidentified.To determine if a subpopulation of nonallergic subjects with idiopathic rhinitis (IR) have localized allergy confined to their nasal mucosa by comparing the T cell subsets and major histocompatibility complex (MHC) II expressing cells to persistent allergic rhinitis (PAR). Furthermore, the relationship between T cell subsets and mast cells/basophils was investigated.None of the symptomatic patients in this study were clinically allergen-challenged. Nasal turbinate mucosa was removed from patients with PAR, IR and normal controls. Morphometry was performed on immunostained sections for T cell subset populations including CD3+, CD4+, CD8+, CD25+, CD45RA+, CD45RO+, human leucocyte antigen (HLA)-DRalpha (MHC class II), mast cell tryptase and for basophils.Subjects with persistent allergic rhinitis differed to normal controls in showing significantly increased numbers of total (CD3+), activated (CD25+) and allergen-naïve (CD45RA+) T lymphocytes in their nasal mucosa (P < 0.025). The naïve CD45RA+ memory T cells correlated to mucosal mast cells in PAR (P = 0.03). IR patients differ to allergic subjects in showing significantly reduced numbers of epithelial HLA-DRalpha+ cells (P = 0.007), but increased numbers of CD8+ lymphocytes (P = 0.02). The CD8+ T cells correlated with mucosal mast cell numbers (P = 0.02). In both rhinitis groups, basophils were present in very low numbers obviating the need for statistical analysis. ### Long_Answer: PAR is characterized by increased numbers of CD3+, CD25+ and CD45RA+ T lymphocytes compared with normal mucosa. Allergic and nonallergic rhinitis groups can be separated by significant differences in the number of epithelial antigen presenting cells (APCs) (HLA-DRalpha+) and sub-epithelial activated (CD25+) T cells. Moreover, IR patients do not significantly differ to their allergic counterparts with respect to total (CD3+) and naïve (CD45RA+) T cell numbers, or numbers of epithelial activated (CD25+) lymphocytes. IR subjects show significantly increased numbers of CD8+ lymphocytes compared with control mucosa and although our findings suggest that the initiating inflammatory events may differ, both rhinitis groups show a similarity in pathology involving mucosal mast cells with an association to infiltrating T cells. ### Final_Prediction: yes

### Question: Does olopatadine inhibit anti-immunoglobulin E-stimulated conjunctival mast cell upregulation of ICAM-1 expression on conjunctival epithelial cells? ### Context: Olopatadine is a clinically effective dual-action (antihistamine/mast cell stabilizer) ophthalmic antiallergic agent. We have previously demonstrated that olopatadine inhibits tumor necrosis factor alpha (TNF-alpha) release from purified human conjunctival mast cells and that supernates from stimulated mast cells upregulate intercellular adhesion molecule 1 (ICAM-1) expression on epithelial cells via TNF-alpha.To investigate the effect of olopatadine on the TNF-alpha-mediated mast cell upregulation of ICAM-1 expression on conjunctival epithelial cells.Human conjunctival mast cells and epithelial cells were purified (>95%) from cadaveric tissue. Conjunctival mast cells were preincubated with three doses (30, 300, or 3,000 microM) of olopatadine or buffer alone for 30 minutes followed by 90-minute challenge with anti-immunoglobulin E (10 microg/mL). The resulting supernates were incubated with conjunctival epithelial cell monolayers for 24 hours along with the following treatments: rTNF-alpha, mast cell supernate + anti-TNF-alpha, recombinant (r)TNF-alpha + anti-TNF-alpha, the three doses of olopatadine, olopatadine supernates, olopatadine supernates + rTNF-alpha. ICAM-1 expression was measured using flow cytometry.Anti-IgE-stimulated human conjunctival mast cell supernates upregulated human conjunctival epithelial cell ICAM-1 expression to the same extent as rTNF-alpha. ICAM-1 upregulation could be completely blocked with anti-TNF-alpha. Preincubation of conjunctival mast cells with olopatadine significantly blocked the ability of supernates to upregulate ICAM-1 on conjunctival epithelial cells. ICAM-1 expression could be restored by adding rTNF-alpha to the olopatadine-preincubated mast cell supernates. ### Long_Answer: Olopatadine is able to significantly decrease the anti-immunoglobulin E mast cell supernate-mediated upregulation of ICAM-1 on human conjunctival epithelial cells in vitro. This seems to be mediated through an effect on a TNF-alpha-specific mechanism. ### Final_Prediction: yes

### Question: Do modest doses of beta-glucan reduce concentrations of potentially atherogenic lipoproteins? ### Context: In 1997, the US Food and Drug Administration passed a unique ruling that allowed oat bran to be registered as the first cholesterol-reducing food at a dosage of 3 g beta-glucan/d.The effects of a low dose of oat bran in the background diet only were investigated in volunteers with mild-to-moderate hyperlipidemia.The study was a double-blind, placebo-controlled, randomized, parallel study. Sixty-two healthy men (n = 31) and women (n = 31) were randomly allocated to consume either 20 g oat bran concentrate (OBC; containing 3 g beta-glucan) or 20 g wheat bran (control) daily for 8 wk. Fasting blood samples were collected at weeks -1, 0, 4, 8, and 12. A subgroup (n = 17) was studied postprandially after consumption of 2 meals (containing no OBC or wheat bran) at baseline and after supplementation. Fasting plasma samples were analyzed for total cholesterol, HDL cholesterol, triacylglycerol, glucose, and insulin. LDL cholesterol was measured by using the Friedewald formula. The postprandial samples were anlayzed for triacylglycerol, glucose, and insulin.No significant difference was observed in fasting plasma cholesterol, LDL cholesterol, glucose, or insulin between the OBC and wheat-bran groups. HDL-cholesterol concentrations fell significantly from weeks 0 to 8 in the OBC group (P = 0.05). There was a significant increase in fasting glucose concentrations after both OBC (P = 0.03) and wheat-bran (P = 0.02) consumption. No significant difference was found between the OBC and wheat-bran groups in any of the postprandial variables measured. ### Long_Answer: A low dosage of beta-glucan (3 g/d) did not significantly reduce total cholesterol or LDL cholesterol in volunteers with plasma cholesterol concentrations representative of a middle-aged UK population. ### Final_Prediction: no

### Question: Do evidence suggesting that the keratinized portions of the upper and lower lid margins make complete contact during deliberate blinking? ### Context: To investigate whether the keratinized portions of the upper and lower eyelid margins make complete contact during deliberate blinking.Ten asymptomatic subjects (21.7 ± 1.5 years) with healthy eyelids were enrolled. A 0.1-μL drop of unpreserved 2% fluorescein placed in the temporal (T) third of the keratinized lower lid margin was observed for 10 deliberate blinks, under 16× magnification. If 10 complete blinks did not alter the drop, the subject squeezed their lids shut. The number of lid squeezes to alter the drop appearance was recorded and repeated for the central (C) and nasal (N) sections. Meibomian gland (MG) functionality was assessed with standardized diagnostic expression. Liquid fluorescein was used to assess the proximity of the line of Marx (LOM) to the lower lid MG orifices.In all cases, 10 complete deliberate blinks did not alter the drop. The mean numbers of lid squeezes to alter the drop was: T = 1.5 ± 1.3, C = 1.9 ± 1.8, and N = 1.2 ± 0.8. The mean number of functional MGs per lid section was as follows: T = 0.8 ± 2.2, C = 4.3 ± 2.3, and N = 4.4 ± 0.8. The LOM relative to the MG orifices was as follows-T: LOM in 30% of eyes was posterior to the MG orifices and in 70% of eyes was mixed (a combination of the LOM posterior, touching, bisecting, or anterior to the MG orifices); C: 70% posterior, 30% mixed; and N: 90% posterior, 10% mixed. ### Long_Answer: Counterintuitively, the keratinized portions of the upper and lower eyelid margins frequently do not make full contact during what appears to be complete blinking. ### Final_Prediction: no

### Question: Are many community hospitals undertreating breast cancer? ### Context: To compare treatment patterns and long-term outcomes between teaching and community hospitals treating patients with infiltrating ductal carcinoma (IDC).All IDCs from the Florida Cancer Data System from 1994 to 2000 were examined.Overall, 24,834 operative cases of IDC were identified. Teaching hospitals treated 11.3% of patients with a larger proportion of stage III and IV disease (39.8% vs. 33.0%). Five- and 10-year overall survival rates at teaching hospitals were 84% and 72%, compared with 81% and 69% at high-volume community hospitals and 77% and 63% at low-volume hospitals (P<0.001). The greatest differences on survival were observed in patients with advanced IDC. Examination of practice patterns demonstrated that multimodality therapy was most frequently administered in teaching hospitals. Breast-conserving surgery was more frequently performed at teaching hospitals (41.5% vs. 38.9% P = 0.008). On multivariate analysis, it was found that treatment at a teaching hospital was a significant independent predictor of improved survival (hazard ratio = 0.763, P<0.001). This survival benefit was greater and independent of high-volume center status (hazard ratio = 0.903, P<0.02). ### Long_Answer: Patients with IDC treated at teaching hospitals have significantly better survival than those treated at high-volume centers or community hospitals, particularly in the setting of advanced disease. Poorer long-term outcomes for IDC at community hospitals seem to be, at least in part, because of decreased use of proven life-extending adjuvant therapies. These results should encourage community hospitals to institute changes in treatment approaches to invasive breast cancer to optimize patient outcomes. ### Final_Prediction: nan

### Question: Is small bowel obstruction in pregnancy a complex surgical problem with a high risk of fetal loss? ### Context: Small bowel obstruction (SBO) in pregnancy is rare and is most commonly caused by adhesions from previous abdominal surgery. Previous literature reviews have emphasised the need for prompt laparotomy in all cases of SBO because of the significant risks of fetal loss and maternal mortality. We undertook a review of the contemporary literature to determine the optimum management strategy for SBO in pregnancy.The MEDLINE® and PubMed databases were searched for cases of SBO in pregnancy between 1992 and 2014. Two cases from our own institution were also reviewed.Forty-six cases of SBO in pregnancy were identified, with adhesions being the most common aetiology (50%). The overall risk of fetal loss was 17% and the maternal mortality rate was 2%. In cases of adhesional SBO, 91% of cases were managed surgically, with 14% fetal loss. Two cases (9%) were managed conservatively with no complications. Magnetic resonance imaging (MRI) was used to diagnose SBO in 11% of cases. ### Long_Answer: Based on our experience and the contemporary literature, we recommend that urgent MRI of the abdomen should be undertaken to diagnose the aetiology of SBO in pregnancy. In cases of adhesional SBO, conservative treatment may be safely commenced, with a low threshold for laparotomy. In other causes, such as volvulus or internal hernia, laparotomy remains the treatment of choice. ### Final_Prediction: yes

### Question: Does intensity of surveillance affect survival after surgery for sarcomas? ### Context: Whether current postoperative surveillance regimes result in improved overall survival (OS) of patients with extremity sarcomas is unknown.QUESTIONS/We hypothesized that a less intensive followup protocol would not be inferior to the conventional followup protocol in terms of OS. We (1) assessed OS of patients to determine if less intensive followup regimens led to worsened survival and asked (2) whether chest radiograph followup group was inferior to CT scan followup group in detecting pulmonary metastasis; and (3) whether less frequent (6-monthly) followup interval was inferior to more frequent (3-monthly) followup in detecting pulmonary metastasis and local recurrence.A prospective randomized single-center noninferiority trial was conducted between January 2006 and June 2010. On the basis of 3-year survival of 60% with intensive, more frequent followup, 500 nonmetastatic patients were randomized to demonstrate noninferiority by a margin (delta) of 10% (hazard ratio [HR], 1.36). The primary end point was OS at 3 years. The secondary objective was to compare disease-free survival (DFS) (time to recurrence) at 3 years. At minimum followup of 30 months (median, 42 months; range, 30-81 months), 178 deaths were documented.Three-year OS and DFS for all patients was 67% and 52%, respectively. Three-year OS was 67% and 66% in chest radiography and CT groups, respectively (HR, 0.9; upper 90% confidence interval [CI], 1.13). DFS rate was 54% and 49% in chest radiography and CT groups, respectively (HR, 0.82; upper 90% CI, 0.97). Three-year OS was 64% and 69% in 6-monthly and 3-monthly groups, respectively (HR, 1.2; upper 90% CI, 1.47). DFS was 51% and 52% in 6-monthly and 3-monthly groups, respectively (HR, 1.01; upper 90% CI, 1.2). Almost 90% of local recurrences were identified by patients themselves. ### Long_Answer: Inexpensive imaging detects the vast majority of recurrent disease in patients with sarcoma without deleterious effects on eventual outcomes. Patient education regarding self-examination will detect most instances of local recurrence although this was not directly assessed in this study. Although less frequent visits adequately detected metastasis and local recurrence, this trial could not conclusively demonstrate noninferiority in OS for a 6-monthly interval of followup visits against 3-monthly visits. ### Final_Prediction: nan

### Question: Does Anastomotic Leak Contribute to High Failure-to-rescue Rates? ### Context: Our aim was to evaluate failure-to-rescue (FTR) after anastomotic leak (AL) in colectomy patients.In the era of pay for performance, it is imperative that we understand the quality measures under which we are scrutinized. FTR has been proposed as a marker of surgical quality. We investigated the role of complications in FTR rates in colectomy patients.Patients who underwent nonemergent colectomy from 2012 to 2013 were identified from the The American College of Surgeons National Quality Improvement Program (ACS NSQIP database). Mortality after AL was assessed and stratified in relation to mortality after other postoperative complications. χ and logistic regression analysis were used to assess the effect of AL on mortality.We identified 30,101 patients who met inclusion criteria, 1127 suffered an AL (3.7%). FTR was increased in patients with AL compared with those without AL (6% vs 1%, P < 0.001). The mortality rate after leak was similar to mortality after other major complications. Independent risk factors for death after AL included older age (odds ratio [OR] 3.140; 95% confidence interval [CI], 1.744-5.651), cancer diagnosis (OR 2.032; 95% CI, 1.177-3.507), and open approach (OR 2.124; 95% CI, 1.194-3.776) while preoperative bowel preparation was protective (OR 0.563; 95% CI, 0.328-0.969). ### Long_Answer: AL is a common complication after colectomy with a relatively high FTR rate. As hospitals are penalized for not reaching specific rates of FTR, we must better understand these complex relationships to improve quality and safety of patient care. ### Final_Prediction: nan

### Question: Is tumor size the primary prognosticator for pancreatic cancer after regional pancreatectomy? ### Context: The purpose of this study was to evaluate the regional pancreatectomy as surgical therapy for ductal adenocarcinoma of the pancreas and to evaluate potential prognostic factors.Regional pancreatectomy was developed as a more adequate surgical procedure for pancreatic cancer in an attempt to improve the cure rate for this highly lethal disease. Few studies have evaluated large numbers of patients treated with this technique, and in recent years the emphasis has been on more limited surgery for pancreatic cancer.Fifty-six patients with ductal adenocarcinoma of the pancreatic head were treated by regional subtotal or total pancreatectomy. Clinical and pathologic parameters were reviewed and potential prognostic factors were compared statistically. The three patients who died within 30 days of the operation were excluded from the survival analysis.Primary tumor size was the strongest determinant of prognosis. The mean tumor size was 3.9 cm (range, 1-7 cm). Eighty-five percent of patients had peripancreatic soft tissue invasion microscopically, and 58% had regional lymph node metastasis. Kaplan-Meier survival curves indicated a 33% 5-year survival for patients with tumor 2.5 cm or less in diameter (n=12) and 12% for patients with larger tumors (n=39). No patient with a tumor larger than 5 cm survived more than 5 years. Mean tumor size was not significantly associated with lymph node metastases, but 5 of 12 patients (42%) with primary tumor < or =2.5 cm had lymph node metastases. Twenty-four percent of patients with negative lymph nodes and 14% with positive lymph nodes survived 5 years. The difference was not statistically significant (p=0.3), but this is likely related to sample size. The 30- day operative mortality was 5.3%. The most common complications were infection, gastrointestinal bleeding, and gastric stasis. ### Long_Answer: After regional pancreatectomy, tumor size is the strongest predictor of prognosis. A multi- institutional randomized prospective trial of regional pancreatectomy versus pancreaticoduodenectomy is warranted in previously untreated, noninfected cases. ### Final_Prediction: yes

### Question: Do insulin analogues differently activate insulin receptor isoforms and post-receptor signalling? ### Context: Five insulin analogues, with modified insulin-like molecular structures, are currently approved for treating diabetic patients. They activate cell signalling and biological responses via insulin receptor isoforms (IR-A and IR-B), each having specific characteristics for eliciting cell responses. The molecular and biological effects of these analogues on receptor isoforms in comparison to native insulin are not well defined, and their effects on the IGF1 receptor (IGF1R) are controversial. The characterisation of these effects was the aim of the present study.Short-acting (insulin lispro [B28Lys,B29Pro human insulin], insulin aspart [B28Asp human insulin], insulin glulisine [B3Lys,B29Glu human insulin]) and long-acting (insulin glargine [A21Gly,B31Arg,B32Arg human insulin], insulin detemir [B29Lys(epsilon-tetradecanoyl),desB30 human insulin]) insulin analogues were studied in three engineered cell models (R(-), IGF1R-deprived mouse fibroblasts transfected with either only human IR-A or IR-B or IGF1R). Receptor binding and phosphorylation, AKT and extracellular signal-regulated kinase (ERK) activation, cell proliferation and colony formation were evaluated after exposing the cells to each analogue and were compared with insulin, IGF1 and the carcinogenic analogue B10Asp.All short-acting insulin analogues produced molecular and biological effects similar but not identical to those of insulin. Relative to insulin, long-acting analogues more strongly activated the ERK pathway via both IR-A and IGF1R as well as increased cell proliferation. At the concentration tested, no analogue (except B10Asp via IR-A) had increased transforming activity. ### Long_Answer: Cell models that permit comparisons of the activity of insulin to that of insulin analogues via each receptor individually indicate that only minor differences exist between insulin and short-acting analogues. By contrast, long-acting analogues activate the mitogenic signalling pathway more effectively than insulin and cause increased cell proliferation. ### Final_Prediction: yes

### Question: Decline in human fertility rates with male age: a consequence of a decrease in male fecundity with aging? ### Context: The objective of this study is to investigate the influence of male age on human fertility, defined as the birth rate for a given population.Data from the Spanish National Statistics Institute (INE) for the year 2004 from a total of 454,753 newborn infants and sorted by male and female age groups were evaluated. In order to correct the influence of female age-related fertility, a different analysis was performed considering only women under 30 years of age.From a demographic point of view, male fertility started to decline at 35-39 years of age. This decline is constant and follows an exponential pattern (slope -0.11 to -0.12). The trend persisted when the data were adjusted for every 1,000 men in the age group, as well as when only women under the age of 30 were considered. Male fertility showed a 21-23% annual decrease starting at the age of 39. ### Long_Answer: An exponential decrease in human fertility which is independent of the woman's age was observed with male aging. This decay is probably due to a downfall in male fecundity, closely related to a decline in sperm quality. However, social or behavioral causes for this trend cannot be excluded. ### Final_Prediction: nan

### Question: Is there equity in long-term healthcare utilization after traumatic brain injury? ### Context: To quantify the long-term use of various types of healthcare services in patients with traumatic brain injury and to estimate the relative contribution of predisposing characteristics, enabling factors and health-related needs to determine whether there is equity in healthcare utilization.Cross-sectional study.Seventy-nine non-institutionalized moderate to severe patients with traumatic brain injury (age range 16-67 years).Healthcare use was measured at 3-5 years post-injury. The relative contribution of predisposing characteristics, enabling factors, and health-related needs to the utilization of various types of care was analysed using logistic regression to determine whether there was equity in healthcare utilization.At least one healthcare service was used by 68% of the patients. Health-related needs explained most of the utilization. However, predisposing characteristics were also related to the use of other medical care and supportive care. Patients with a high internal locus of control were more likely to be users of supportive care, and patients with a high locus of control with the physician were more likely to visit medical specialists. ### Long_Answer: The results suggest that most of our patients who needed care, received care. However, inequity could not be ruled out completely as predisposing characteristics also contributed to some types of healthcare utilization. ### Final_Prediction: nan

### Question: Does vagal sparing surgical technique but not stoma size affect body weight loss in rodent model of gastric bypass? ### Context: The aim of this study was to evaluate whether gastric bypass with or without vagal preservation resulted in a different outcome.Body weight, food intake and postprandial peptide YY (PYY) and glucagon-like peptide (GLP-1) levels were compared between gastric bypass (n = 55) and sham-operated rats (n = 27) in three groups. In group 1 (n = 17), the vagal nerve was not preserved, while in group 2 the vagal nerve was preserved during gastric bypass (n = 10). In group 3, gastric bypass rats (n = 28) were randomised for either one of the two techniques.Rats in which the vagal nerve was preserved during gastric bypass showed a lower body weight (p < 0.001) and reduced food intake (p < 0.001) compared to rats in which the vagal nerve was not preserved during the gastric bypass operation. Levels of PYY and GLP-1 were significantly increased after gastric bypass compared to sham-operated controls (p < 0.05), but there was no difference between gastric bypass rats with and without vagal preservation. Differences in food intake and body weight were not related to the size of the gastro-jejunostomy in gastric bypass rats. There were no signs of malabsorption or inflammation after gastric bypass. ### Long_Answer: We propose that the vagal nerve should be preserved during the gastric bypass operation as this might play an important role for the mechanisms that induce weight loss and reduce food intake in rats. In contrast, the gastro-jejunal stoma size was found to be of minor relevance. ### Final_Prediction: yes

### Question: Do lower cuff pressures improve the seal of pediatric laryngeal mask airways? ### Context: Hyperinflation of laryngeal mask airway (LMA) cuffs may be harmful because of the exertion of high pressures on pharyngeal and laryngeal structures. Although cuff manometers may be used to monitor cuff pressure, their use is not routine in many institutions and clinical endpoints are used instead. Furthermore, it is common clinical practice to add air to the cuff in the presence of an air leak to obtain a better seal.In a prospective audit, the authors assessed air leakage around pediatric sized LMAs (n = 200) following inflation guided by common clinical endpoints (slight outward movement of the LMA) and then following adjustment of the cuff pressure to the recommended pressure range (<60 cmH(2)O) according to institutional guidelines with the use of a calibrated cuff manometer, directly after induction of anesthesia. Following induction, all children were gently ventilated with pressure control ventilation with 10 cmH(2)O and a positive end-expiratory pressure of 5 cmH(2)O.Following inflation of the cuff guided by clinical endpoints, the median initial cuff pressure (LMA size 1-3) was 92 (size 3) to >120 cmH(2)O (size 1) and the median leakage around the cuff ranged from 0.66 to 1.07 ml x kg(-1). Following cuff pressure adjustment according to the recommended pressure range (<60 cmH(2)O), the leakage decreased significantly to 0.51-0.79 ml x kg(-1) (P = 0.002 for size 1, P < 0.001 for size 1.5-3). ### Long_Answer: The use of clinical endpoints to inflate LMA cuffs is not only associated with significant hyperinflation in the majority of patients but also with an increased leakage around the LMA cuff when compared with adjusted LMA cuff pressures. Therefore, cuff manometers should routinely be used not only to avoid unnecessary hyperinflation but also to improve cuff sealing of LMA in children. ### Final_Prediction: yes

### Question: Does interventional therapy prolong the patency of hemodialysis fistulas and grafts? ### Context: To retrospectively evaluate procedural success and patency after endovascular treatment of acute dysfunctional hemodialysis fistulas and grafts in a non-preselected patient cohort.185 angiographies of hemodialysis fistulas and grafts on the upper extremities were analyzed for 120 patients (53 male, 67 female; mean-age 63.1 +/- 11.4, range 24 - 91). 70 % (n = 130) were native arteriovenous fistulas, 17 % (n = 31) were prosthetic grafts, and 13 % (n = 24) were non-specific. In total, 278 lesions requiring endovascular treatment were detected. 13 % (n = 35) of the lesions were located in the arterial inflow, 18 % (n = 49) in native arteriovenous anastomoses, 7 % (n = 19) in prosthetic grafts and 62 % (n = 171) in the venous outflow. The primary, secondary and cumulative patency after endovascular treatment was calculated.In 51 % (n = 94) of the cases endovascular treatment could be performed, in 8 % (n = 14) no lesion requiring treatment was detected, and in 42 % (n = 77) intervention was not considered possible. In 45 % (n = 124) of the detected lesions endovascular treatment was successful, in 18 % (n = 51) the intervention failed, and in 37 % (n = 103) intervention was not considered possible. The complication rate was 5 % (n = 10). The primary, secondary, and cumulative patency rates for 50 % of the hemodialysis fistulas and grafts after endovascular treatment were 65, 191, and 370 days, respectively. The results differed significantly from each other with p<0.05 in the log rank test and log rank trend test. ### Long_Answer: Endovascular treatment of acute dysfunctional hemodialysis fistulas and grafts is effective in restoring the patency for hemodialysis. ### Final_Prediction: nan

### Question: Isolation gowns: a false sense of security? ### Context: Isolation gowns have traditionally been used in health care situations to protect against microbial contamination. There is now concern over protection of the health care worker from contamination by patients' blood and body fluids. We quantitatively determined the effectiveness of commercially available isolation gowns against human blood leakage or strike through.More than 1200 samples of 11 types of disposable gown and one type of reusable gown (new and washed 40 and 80 times) were tested at five different pressures (0.25 to 2 psi) and six durations (1 second to 2 minutes) by means of an apparatus designed to simulate pressures generated during gown usage.In all studied conditions, testing showed significant differences (p less than 0.0001) in the amount of strike through allowed by the gowns and demonstrated important differences in the gowns' protective capabilities. ### Long_Answer: Although traditional thought assumes that isolation gowns protect the wearer from contamination, our data show this belief may provide a false sense of security. ### Final_Prediction: nan

### Question: Is incisional hernia rate after laparoscopic colorectal resection reduced with standardisation of specimen extraction? ### Context: Incisional hernia is a common complication of laparoscopic colorectal surgery. Extraction site may influence the rate of incisional hernias. Major risk factors for the development of incisional hernias include age, diabetes, obesity and smoking status. In this study, we investigated the effect of specimen extraction site on incisional hernia rate.Two cohorts of patients who underwent laparoscopic colorectal resections in a single centre in 2005 (n=85) and 2009 (n=139) were studied retrospectively. In 2005 all specimens were extracted through transverse muscle cutting incisions. In 2009 all specimens were extracted through midline incisions. Demographic variables, rate of incisional hernias and risk factors for hernia development were compared between the year groups. All patients had been followed up clinically for two years.A total of 224 patients (mean age: 67.5 years, standard deviation: 16.35 years) were included in this study. Of these, 85 patients were in the 2005 transverse group and 139 were in the 2009 midline group. The total incisional hernia rate for the series was 8.0% at the two-year follow-up visit. For the 2005 group, the incisional hernia rate was 15.3% (n=13) and for the 2009 group, it was 3.6% (n=5) (p<0.01). The body mass index was higher in patients who developed incisional hernias than in those who did not (p=0.02). ### Long_Answer: The 2005 group had a significantly higher incisional hernia rate than the 2009 group. This is due to the differences in the incision technique and extraction site between the two groups. ### Final_Prediction: yes

### Question: Does cognitive behavioral therapy in combination with systemic family therapy improve mild to moderate postpartum depression? ### Context: To explore the effect of cognitive behavioral therapy (CBT) in combination with systemic family therapy (SFT) on mild to moderate postpartum depression and sleep quality.249 primiparous women with mild to moderate postpartum depression were recruited and randomly assigned to a control group (n=128), which received conventional postpartum care, or to a psychological intervention group (n=121), which received conventional postpartum care combined with psychological intervention. The Edinburgh Postnatal Depression Scale (EPDS) and Pittsburgh Sleep Quality Index (PSQI) were employed to evaluate depression and sleep quality, respectively.104 patients in the intervention group and 109 in the control group completed the study. After intervention, the EPDS score, PSQI score, sleep quality score, sleep latency score, sleep duration score, habitual sleep efficiency score, sleep disturbance score, and daytime dysfunction score were significantly lower in the intervention group than in the control group. The EPDS and PSQI scores of each group at different time points after intervention were markedly decreased compared with those before intervention, and the reduction in the intervention group was more evident than that in the control group. ### Long_Answer: CBT in combination with SFT can improve depression and sleep quality in patients with mild to moderate postpartum depression. ### Final_Prediction: yes

### Question: Does suppression of atrogin-1 and MuRF1 prevent dexamethasone-induced atrophy of cultured myotubes? ### Context: The mechanistic role of the ubiquitin ligases atrogin-1 and MuRF1 in glucocorticoid-induced muscle wasting is not fully understood. Here, we tested the hypothesis that glucocorticoid-induced muscle atrophy is at least in part linked to atrogin-1 and MuRF1 expression and that the ubiquitin ligases are regulated by compensatory mechanisms.The expression of atrogin-1 and MuRF1 was suppressed individually or in combination in cultured L6 myotubes by using siRNA technique. Myotubes were treated with dexamethasone followed by determination of mRNA and protein levels for atrogin-1 and MuRF1, protein synthesis and degradation rates, and myotube morphology.Suppression of atrogin-1 resulted in increased expression of MuRF1 and vice versa, suggesting that the ubiquitin ligases are regulated by compensatory mechanisms. Simultaneous suppression of atrogin-1 and MuRF1 resulted in myotube hypertrophy, mainly reflecting stimulated protein synthesis, and prevented dexamethasone-induced myotube atrophy, mainly reflecting inhibited protein degradation. ### Long_Answer: The results provide evidence for a link between upregulated atrogin-1 and MuRF1 expression and glucocorticoid-induced muscle atrophy. The study also suggests that atrogin-1 and MuRF1 levels are regulated by compensatory mechanisms and that inhibition of both ubiquitin ligases may be needed to prevent glucocorticoid-induced muscle proteolysis and atrophy. ### Final_Prediction: yes

### Question: Is endothelial cell proliferation suppressed by plasma but not serum from women with preeclampsia? ### Context: Evidence has been sought for a circulating factor derived from the placenta that suppresses endothelial cell proliferation and hence contributes to the maternal endothelial cell disturbances of preeclampsia.The effects of sera and plasmas from women with proteinuric preeclampsia and from matched normal pregnant control women on endothelial cell proliferation were compared. The recovery of endothelial cell inhibitory activity from syncytiotrophoblast microvesicles added to male blood and prepared as plasma or serum was determined to investigate the possible placental origin of the inhibitory factor.Sera from women with preeclampsia did not inhibit endothelial cell proliferation. In contrast, plasma from preeclamptic women significantly suppressed endothelial cell growth at 20% dilution compared with controls, and suppression was more pronounced in severe preeclampsia. The inhibitory activity of syncytiotrophoblast microvesicles added to blood could not be recovered from serum, only from plasma, which may explain why there was no suppression with sera from preeclamptic women. ### Long_Answer: These results confirm that there is a blood-borne endothelial cell suppressive factor in preeclampsia that may be derived from the placenta. ### Final_Prediction: yes

### Question: Does tissue plasminogen activator attenuate ventilator-induced lung injury in rats? ### Context: To test the hypothesis that the tissue plasminogen activator (tPA) may counteract the inhibitory effect of plasminogen activator inhibitors (PAI) and attenuate lung injury in a rat model of ventilator-induced lung injury (VILI).Adult male Sprague-Dawley rats were ventilated with a HVZP (high-volume zero PEEP) protocol for 2 h at a tidal volume of 30 mL/kg, a respiratory rate of 25 breaths/min, and an inspired oxygen fraction of 21%. The rats were divided into 3 groups (n=7 for each): HVZP+tPA group receiving tPA (1.25 mg/kg, iv) 15 min before ventilation, HVZP group receiving HVZP+vehicle injection, and a control group receiving no ventilation. After 2 h of ventilation, the rats were killed; blood and lungs were collected for biochemical and histological analyses.HVZP ventilation significantly increased total protein content and the concentration of macrophage inflammatory protein-2 (MIP-2) in the bronchoalveolar lavage fluid (BALF) as well as the lung injury score. Rats that received HVZP ventilation had significantly higher lung PAI-1 mRNA expression, plasma PAI-1 and plasma D-dimer levels than the control animals. tPA treatment significantly reduced the BALF total protein and the lung injury score as compared to the HVZP group. tPA treatment also significantly decreased the plasma D-dimer levels and the HVZP ventilation-induced lung vascular fibrin thrombi. tPA treatment showed no effect on MIP-2 level in BALF. ### Long_Answer: These results demonstrate that VILI increases lung PAI-1 mRNA expression, plasma levels of PAI-1 and D-dimers, lung injury score and vascular fibrin deposition. tPA can attenuate VILI by decreasing capillary-alveolar protein leakage as well as local and systemic coagulation as shown by decreased lung vascular fibrin deposition and plasma D-dimers. ### Final_Prediction: yes

### Question: Lack of effect of norfloxacin on hyperdynamic circulation in bile duct-ligated rats despite reduction of endothelial nitric oxide synthase function: result of unchanged vascular Rho-kinase? ### Context: In cirrhosis, portal hypertension is maintained by splanchnic vasodilation owing to overproduction of the vasodilator nitric oxide (NO) and defective contractile signalling by Rho-kinase. NO overproduction is partially caused by bacterial translocation from the gut to mesenteric lymph nodes. However, the effects of intestinal bacterial decontamination on hyperdynamic circulation or vascular contractility are unknown. We investigated the haemodynamic and vascular effects of norfloxacin in rats with secondary biliary cirrhosis.Cirrhosis was induced by bile duct ligation (BDL). One group was treated with norfloxacin (20 mg/kg/day, 5 days, orally). Bacterial growth in the lymph nodes was determined on blood agar plates. Invasive haemodynamic measurements were combined with coloured microspheres. Aortic contractility was assessed myographically. Protein expression/phosphorylation was examined by Western blot analysis.Norfloxacin treatment of BDL rats abolished bacterial translocation to mesenteric lymph nodes. BDL rats had hyperdynamic circulation, including portal hypertension and splanchnic vasodilation. None of these parameters was changed by norfloxacin, although norfloxacin reduced endothelial NO synthase expression and phosphorylation. The latter was associated with a diminished activity of protein kinase G (PKG), which mediates NO-induced vasodilation. However, norfloxacin had no effect on aortic contractility to methoxamine or Ca2+, or the aortic expression of RhoA, Rho-kinase and beta-arrestin 2, or the phosphorylation of the Rho-kinase substrate moesin. ### Long_Answer: Short-term treatment of BDL rats with norfloxacin does not change hyperdynamic circulation or vascular contractility, despite reduction of PKG activity. ### Final_Prediction: nan

### Question: Could acupuncture be an adequate alternative to dexamethasone in pediatric tonsillectomy? ### Context: Usage of nonpharmacological treatment contributes to an overall patient well-being, assisting in physical and emotional healing. Acupuncture has been reported to be useful in reducing early postoperative vomiting (POV) and attenuating postoperative pain.AIM: The aim of this study was to compare the effect of dexamethasone vs acupuncture at P6 bilaterally and CV13 on the incidence and severity of POV in children undergoing tonsillectomy with or without adenoidectomy.One hundred and twenty children, ASA I-III aged 2-8 years undergoing elective tonsillectomy were included in this prospective randomized double-blind study. Children were randomly divided into two equal groups (60 each). At induction of anesthesia, the dexamethasone group received 0.15 mg·kg(-1) dexamethasone IV plus sham acupuncture, and the acupuncture group received acupuncture at P6 bilaterally and CV13 plus 2 ml of normal saline IV. Vomiting was recorded at 0-6, 6-24, and 0-24 h postoperatively.There was no difference in the incidence of vomiting between the acupuncture and dexamethasone groups. The mean difference in time to first oral intake (95% CI) was 4.3 (0.5-8.6) min between dexamethasone group and acupuncture group; P = 0.426. The mean difference in time until first vomit (95% CI) was 12 (9.5-13.8) min between both groups. No significant differences between Kaplan-Meier curves for time until first vomit (log-rank test) were obtained (P = 0.697). ### Long_Answer: Acupuncture at P6 bilaterally and CV13 provided similar antiemetic effect to dexamethasone in children undergoing tonsillectomy. ### Final_Prediction: nan

### Question: Is non-visualization of the cavum septi pellucidi synonymous with agenesis of the corpus callosum? ### Context: To describe a cohort of fetuses with non-visualization of the cavum septi pellucidi (CSP) without callosal agenesis and to assess the significance of this finding with respect to postnatal development.We reviewed the files of all patients referred because of suspected fetal supratentorial midline anomalies, and identified those fetuses with a diagnosis of non-visualization or obliteration of the CSP.From an initial cohort of 114 patients we identified 23 cases. Mean ( ± SD) gestational age at referral was 24.5 ± 1.3 weeks; referral diagnoses (with more than one in some cases) included: non-visualization or an echogenic CSP (n = 18), suspected callosal anomaly (n = 5), other findings (n = 5). The fetuses were examined for the first time at the Fetal Neurology Clinic at a mean gestational age of 26.6 ± 3.1 weeks (range, 22-34 weeks; median, 27 weeks). In all of the fetuses the zone where fluid should have been observed was echogenic. In 17 fetuses this was an apparently isolated finding and in six it was associated with other findings, but only one fetus had associated malformations. Follow-up was available for 16 children at a mean age of 17.4 months (range, 4-36 months; median, 19.5 months). Normal development was reported in 14 children. One child had infantile hypotonia but normal developmental milestones and another had mild motor delay and language delay. These two children did not have associated anomalies at the prenatal scan. ### Long_Answer: Non-visualization of the CSP is not always associated with agenesis of the corpus callosum. When isolated it may be considered a variation of normal development. ### Final_Prediction: no

### Question: Telemedicine: a solution to the followup of rural trauma patients? ### Context: Outpatient followup of rural trauma patients is problematic for physicians and patients. Our hypothesis was that telemedicine-based followup of trauma patients discharged to remote areas is feasible and is associated with high patient and physician satisfaction.We chose 11 counties in Kentucky surrounding a remote telemedicine site as our region of interest. Any adult trauma patient who was discharged from our Level I trauma center to this geographic region was eligible to have routine followup appointment(s) at the TeleTrauma Clinic. Patients were examined and interviewed with the assistance of a nurse, an electronic stethoscope, and a close-up imaging instrument. Radiographs performed at the telemedicine site were viewed. Patients and physicians completed a survey after the appointment.To date, we have conducted 22 telemedicine-based followup assessments of trauma patients. The average age and Injury Severity Score were 42 years and 18, respectively. Plain radiographs were reviewed in 13 cases. Our patient surveys indicated a high degree of satisfaction with the teleappointment. In 15 of 22 patients, no further clinical followup was arranged. The differences in travel distances and times for an appointment at the TeleTrauma Clinic versus an appointment at our Level I trauma center were significant. The average and median duration of the appointments was 14 minutes. All telemedicine encounters were done by two physicians, who recorded a high level of satisfaction. ### Long_Answer: Our early experience with the outpatient followup of remote trauma victims by telemedicine is encouraging. Patient surveys indicate a high degree of satisfaction. As a result of our favorable experience, telemedicine-based followup may be expanded to other regions of Kentucky. ### Final_Prediction: nan

### Question: Do proinflammatory cytokines inhibit secretion in rat bile duct epithelium? ### Context: Cholestatic disorders often are associated with portal inflammation, but whether or how inflammation contributes to cholestasis is unknown. Thus we studied the effects of proinflammatory cytokines on bile duct epithelia secretory mechanisms.Isolated bile duct units (IBDUs) were cultured with interleukin (IL)-6, interferon gamma, tumor necrosis factor (TNF)-alpha, and IL-1 alone or in combination. Ductular secretion was measured using video-optical planimetry. Bicarbonate and Cl(-) transport were assessed microfluorimetric measuring pH(i) (BCECF) and [Cl(-)](i) transients (MEQ). Expression of Cl(-)/HCO(3)(-) exchanger (AE-2), cystic fibrosis transmembrane conductance regulator (CFTR), and the secretin receptor (SR) were assessed by ribonuclease protection assay. Cellular cyclic adenosine monophosphate (cAMP) levels were studied by enzymatic immunoassay. Paracellular permeability was assessed using fluorescein-labeled dextrans (FD) in cholangiocyte monolayers (NRC-1).Although not effective when given alone, each combination of IL-6, interferon gamma, IL-1, and TNF-alpha inhibited secretion in IBDU. Cytokines inhibited cAMP formation, AE-2 activity, and cyclic AMP-dependent Cl(-) efflux, but not that induced by purinergic agonists. AE-2 gene expression was unaffected by proinflammatory cytokines, whereas CFTR and SR expression was increased. In addition, paracellular transit of FD across NRC-1 monolayers was increased. ### Long_Answer: Inflammatory cytokines inhibit cAMP-dependent fluid secretion in cholangiocytes and impair the barrier functions of biliary epithelia. These changes may represent the molecular mechanisms by which inflammation leads to ductular cholestasis in vivo. ### Final_Prediction: yes

### Question: Does thyroid function influence fracture risk? ### Context: To prospectively study the relation between TSH and risk of hip and forearm fractures.A population-based cohort study.In a substudy of the second survey of the Nord Trøndelag Health Study, Norway (HUNT2, 1995-97), linked with a hospital-based fracture registry, we investigated the relation between baseline TSH and risk of hip and/or forearm fractures.A total of 16 610 women and 8595 men aged 40 years or more, without previous self-reported thyroid disease and hip or forearm fractures.During 12.5 years follow-up, a total of 1870 women and 342 men experienced hip or forearm fractures. Overall, there was no relation between baseline TSH and fracture risk. However, there was weak evidence that women with TSH<0.5 and>3.5 mU/l had a slightly increased risk of hip fractures (hazard ratio (HR) 1.30, 95% CI 0.97-1.94 and HR 1.19, 95% CI 0.93-1.52) compared with the reference group with TSH of 1.5-2.4 mU/l. Supplementary analyses showed higher hip fracture risk in women with TSH>4.0 mU/l and negative thyroid peroxidase antibodies (TPOAb) compared with the reference group (HR 1.75, 95% CI 1.24-2.46). ### Long_Answer: We found no statistically significant relation between baseline TSH and subsequent fracture risk, but the data suggest a weak positive association with hip fracture risk among women with both low and high TSH. The latter association was confined to women with negative TPOAb status. ### Final_Prediction: nan

### Question: Is recurrence of radiation enterocolitis within 1 year predictive of 5-year mortality in surgical cases of radiation enterocolitis : our 18-year experience in a single center? ### Context: Pelvic irradiation is commonly used in the treatment of pelvic malignancies. Chronic radiation enterocolitis is the most serious complication resulting from such treatment, and it frequently requires surgery. The prognosis for patients after surgery remains ill-defined. We conducted a retrospective study to identify risk factors associated with mortality for patients who received surgery for chronic radiation enterocolitis.From 1985 to 2009, a total of 89 patients were diagnosed as having chronic radiation enterocolitis in Taichung Veterans General Hospital. The chart records of 35 surgical and 54 nonsurgical patients were reviewed. A total of 21 candidate risk factors were selected from (1) those related to rapid disease progression (recurrence within 1 year, reoperation within 1 year, short latency), (2) those mentioned in published series (diabetes mellitus, history of smoking, history of abdominopelvic surgery), and (3) other risk factors that might adversely affect outcomes (older age, higher radiation dosage, longer latency period). Factors with p < 0.1 in univariate analysis were subjected to multivariate analysis to identify those that were independent risk factors.Surgical patients were significantly older (65.09 vs. 61.61 years, p = 0.011), had a longer latency period (17.08 vs. 8.09 months, p = 0.037), and were associated with a higher percentage of radiation uropathy (54.28 vs. 12.96%, p < 0.0001) than nonsurgical patients. There was no difference in radiation dosage between surgical and nonsurgical cases (p = 0.152). Recurrence of radiation enterocolitis within 1 year following surgery (p = 0.022), older age (p = 0.002), and uncured cancer (p = 0.001) were identified as independent risk factors for poor overall survival after surgery. All patients (100%) who had recurrent radiation enterocolitis within 1 year of surgery died within 5 years of recurrence. ### Long_Answer: The surgical cases were older, had a longer latency period, and had a higher percentage of radiation uropathy .Recurrence of radiation enterocolitis within 1 year after surgery, older age, and uncured cancer were independent risk factors associated with mortality for patients who received surgery for chronic radiation enterocolitis. ### Final_Prediction: yes

### Question: Do 3-year prospective multicenter study on one-stage implant surgery and early loading in the edentulous mandible? ### Context: The long-term success rates achieved in dental implantology suggest that flexibility might well exist within the various implant systems to a degree that an altered protocol (ie, one-stage surgery and immediate or early loading) can be performed under controlled conditions. However, before variations of the protocol can be considered for general use, they must be subjected to critical analysis, particularly with respect to the predictability of osseointegration, alteration of soft tissue barrier, and relative change in bone height around the implants.The aim of this prospective multicenter study was to evaluate implant survival and periimplant conditions around endosseous implants placed in a one-stage surgical procedure and early loading.A total of 170 implants were placed in 40 patients with mandibular edentulism and were functionally loaded within 6 weeks with overdentures (n = 30) or fixed prostheses (n = 10). All patients and prosthetic constructions were evaluated according to a standardized protocol during 3 years of follow-up. Cumulative implant survival rates were calculated, and implant loss in relation to implant size and bone quality and quantity were evaluated. Furthermore, the protocol included assessment of clinical (plaque and bleeding scores, prosthesis stability) and radiographic parameters.Over a period of 3 years, the implant survival rate was 93% for both implants and prostheses (fixed or removable). No implants were lost after the first year of loading. The periimplant tissues were in a healthy condition. Mean marginal bone resorption from the time of loading to the 3-year follow-up was 0.41 mm (SD 0.52). ### Long_Answer: From this study it may be concluded that early loading results in good implant survival and proper periimplant health in edentulous mandibles. ### Final_Prediction: yes

### Question: Do two waves of anisotropic growth generate enlarged follicles in the spiny mouse? ### Context: Mammals exhibit a remarkable variety of phenotypes and comparative studies using novel model species are needed to uncover the evolutionary developmental mechanisms generating this diversity. Here, we undertake a developmental biology and numerical modeling approach to investigate the development of skin appendages in the spiny mouse, Acomys dimidiatus.We demonstrate that Acomys spines, possibly involved in display and protection, are enlarged awl hairs with a concave morphology. The Acomys spines originate from enlarged placodes that are characterized by a rapid downwards growth which results in voluminous follicles. The dermal condensation (dermal papilla) at the core of the follicle is very large and exhibits a curved geometry. Given its off-centered position, the dermal papilla generates two waves of anisotropic proliferation, first of the posterior matrix, then of the anterior inner root sheath (IRS). Higher in the follicle, the posterior and anterior cortex cross-section areas substantially decrease due to cortex cell elongation and accumulation of keratin intermediate filaments. Milder keratinization in the medulla gives rise to a foamy material that eventually collapses under the combined compression of the anterior IRS and elongation of the cortex cells. Simulations, using linear elasticity theory and the finite-element method, indicate that these processes are sufficient to replicate the time evolution of the Acomys spine layers and the final shape of the emerging spine shaft. ### Long_Answer: Our analyses reveal how hair follicle morphogenesis has been altered during the evolution of the Acomys lineage, resulting in a shift from ancestral awl follicles to enlarged asymmetrical spines. This study contributes to a better understanding of the evolutionary developmental mechanisms that generated the great diversity of skin appendage phenotypes observed in mammals. ### Final_Prediction: yes

### Question: Are multiple regimes of constrained chromosome motion regulated in the interphase Drosophila nucleus? ### Context: Increasing evidence indicates specific changes in the three-dimensional organization of chromosomes in the cell nucleus during the cell cycle and development. These changes may be linked to changes in both the coordinated regulation of gene transcription and the timing of chromosome replication. While there is cytological evidence for short-range diffusive motion of chromosomes during interphase, the mechanisms for large-scale chromosome remodeling inside the nucleus remain unknown.Chromosome motion was tracked in Drosophila spermatocyte nuclei by 3D fluorescence microscopy. The Lac repressor/lac operator system was used to label specific chromosomal sites in live tissues, allowing extended observation of chromatin motion in different cell cycle stages. Our results reveal a highly dynamic chromosome organization governed by two types of motion: a fast, short-range component over a 1-2 s time scale and a slower component related to long-range chromosome motion within the nucleus. The motion patterns are consistent with a random walk. In early G2, short-range motion occurs within a small, approximately 0.5 microm radius domain, while long-range motion is confined to a much larger, chromosome-sized domain. Progression through G2 as cells approach meiotic prophase is accompanied by a complete arrest of long-range chromosome motion. ### Long_Answer: Our analysis provides direct evidence for cell cycle-regulated changes in interphase chromatin motion. These changes are consistent with changes in local and long-range constraints on chromosome motility. We propose that dynamic interactions between chromosomes and internal nuclear structures modulate the range and rate of interphase chromatin diffusion and thereby regulate large-scale nuclear chromosome organization. ### Final_Prediction: yes

### Question: Do older men with higher self-rated socioeconomic status have shorter telomeres? ### Context: previous studies examining the relationship between socioeconomic status and telomere length showed conflicting results, one study finding shorter telomere length in subjects with lower socioeconomic status and one showing no relationship.cross-sectional study.community-living elderly Chinese in Hong Kong.this study examines the relationship between self-rated social economic status and telomere length in Hong Kong Chinese men and women aged 65 years and over living in the community.information was collected from 958 men and 978 women regarding possible confounding factors such as the presence of chronic diseases, smoking, physical activity level, dietary intake and body mass index. Telomere length was measured by quantitative PCR.in men only, after adjustment for age and other confounding factors, a higher ranking in community standing was associated with shorter telomere length. ### Long_Answer: men with higher self-rated socioeconomic status have shorter telomeres, possibly mediated through psychosocial rather than lifestyle factors or the presence of chronic disease. There may be cultural ethnic and age-related differences in social determinants of health. ### Final_Prediction: yes

### Question: Are hand abnormalities strongly associated with the duration of diabetes mellitus? ### Context: To study the prevalence of hand abnormalities in diabetic patients and to evaluate associations between the hand abnormalities and diabetic variables, ergonomic factors and smoking habits.Cross-sectional study of 100 patients selected at random. Setting. Out-patient clinic, Department of Internal Medicine, Orebro Medical Centre Hospital in Sweden.Presence and extent of carpal tunnel syndrome (CTS), Dupuytren's contracture (DC), flexor tenosynovitis (FTS), and limited joint mobility (LJM). Duration of diabetes, metabolic control, chronic diabetic complications, blood pressure, ergonomic factors and smoking habits.Carpal tunnel syndrome, DC, FTS and LJM were each present in about 20% of the patients. Hand abnormalities were observed in 50 patients and more than one abnormality was found in 26 of the patients. The hand abnormalities were associated with the duration of diabetes but not with the metabolic control or with other diabetic complications. However, the diabetic complications were associated with bad metabolic control and with the duration of diabetes. Hand abnormalities correlated with heavy manual work but not with smoking habits. Twenty-five of the 50 patients with hand syndromes were disabled to such an extent that surgery was recommended. ### Long_Answer: The prevalence of hand abnormalities in diabetic patients is high and increases with the duration of diabetes. In many cases patients with hand abnormalities can be helped by surgery. ### Final_Prediction: yes

### Question: Does swietenia macrophylla King induce mitochondrial-mediated apoptosis through p53 upregulation in HCT116 colorectal carcinoma cells? ### Context: Swietenia macrophylla King is a traditional herb used to treat various diseases including hypertension, diabetes and cancer. Previous study demonstrated its anti-tumor effect but the potential mechanisms have not been clearly defined. The current study was to further investigate the underlying mechanism of ethyl acetate fraction of Swietenia macrophylla (SMEAF)-induced anti-proliferative effect and apoptosis in HCT116 colorectal carcinoma cell.Cell viability was evaluated in HCT116 cells by trypan blue exclusion assay. Apoptotic cell death was detected by Hoechst 33342/propidium iodide (PI) staining and intracellular reactive oxygen species (ROS) was analyzed by flow cytometry. The apoptotic gene and protein expression were determined by Real-time quantitative PCR (q-PCR) and immunofluorescence staining using flow cytometry, respectively.SMEAF significantly inhibited HCT116 cell viability and induced apoptosis in a dose-dependent manner. SMEAF-induced apoptosis was triggered by the activation of p53 and intracellular reactive oxygen species (ROS) production. Moreover, the significant increase in p53 was accompanied by a decrease murine double minute 2 (MDM2) expression. SMEAF significantly increased the expression of the Bax protein resulting in a markedly elevated Bax/Bcl-2 ratio which may have triggered the mitochondrial apoptotic pathway, resulting in caspase-3/7 and caspase-9 activation. ### Long_Answer: These results suggested that SMEAF exerts its antitumor activity in HCT116 cells by activating proapoptotic signaling pathway through intracellular ROS formation triggering the mitochondrial-mediated pathway via p53 activation. ### Final_Prediction: yes

### Question: Are micromegakaryocytes specific for refractory cytopenia of childhood (RCC)? ### Context: Micromegakaryocytes (microMKs) are considered the most reliable dysplastic feature for myelodysplastic syndrome (MDS), particularly refractory cytopenia of childhood (RCC); there is no minimal threshold for the diagnosis of RCC. Since most RCC patients present with thrombocytopenia, the presence of microMKs should raise concern for MDS/RCC. This study attempted to investigate the prevalence of microMKs and associated marrow fibrosis in patients with thrombocytopenia unrelated to MDS/RCC and the need for establishing a threshold for microMKs for the diagnosis of MDS/RCC.Bone marrow biopsies of pediatric patients with thrombocytopenia unrelated to RCC were examined for microMKs and fibrosis by CD61 immunohistochemical and reticulin stains respectively.Thirty eight patients (1-18 years old) were included: 33 immune thrombocytopenia (ITP), 3 chronic thrombocytopenia, and 2 inherited macrothrombocytopenia. Fourteen cases (37%) had microMKs; four cases showed increased marrow fibrosis associated with microMKs (two had ITP and two had macrothrombocytopenia). All patients are alive and none developed MDS (follow up: 3months to 4 years). ### Long_Answer: MicroMKs can be seen in pediatric patients with thrombocytopenia unrelated to RCC. Hence the mere presence of microMKs is insufficient for the diagnosis of RCC in the pediatric population, and a quantitative threshold needs to be established. ### Final_Prediction: nan

### Question: Do cysteinyl-leukotriene levels in sputum differentiate asthma from rhinitis patients with or without bronchial hyperresponsiveness? ### Context: We have previously reported that asthma differs from rhinitis with or without bronchial hyperresponsiveness in the perception and degree of lower airway inflammation.The aim of the present study was to investigate whether sputum levels of inflammatory markers could further distinguish these patient groups.Patients with seasonal allergic rhinitis with or without asthma or bronchial hyperresponsiveness to methacholine were investigated. Induced sputum was performed during as well as off season, and analysed for cysteinyl-leukotrienes, hyaluronan, eosinophilic cationic protein (ECP) and other inflammatory markers.Asthmatic patients differentiated from those with rhinitis with or without bronchial hyperresponsiveness in levels of cysteinyl-leukotrienes [geometric mean: 3.3 (lower 95%-upper 95% confidence interval (CI) of geometric mean: 1.9-5.1) vs. 1.4 (0.9-2.2) and 0.7 (0.3-1.6) pg/microg total protein] and hyaluronan [0.30 (0.22-0.43) vs. 0.15 (0.10-0.20) and 0.20 (0.12-0.35) ng/microg total protein] in sputum. The levels of cysteinyl-leukotrienes decreased in sputum from the asthmatic patients, while the levels of hyaluronan remained elevated off-season. Furthermore, elevated levels of ECP were noticed among both the asthmatic and rhinitis patients with hyperresponsiveness compared with controls [0.022 (0.014-0.033) and 0.015 (0.011-0.021) compared with 0.010 (0.007-0.014) ng/microg total protein]. The level of ECP remained elevated off season. ### Long_Answer: Cysteinyl-leukotrienes are possibly more related to mast cell-mediated inflammation and remodelling, also indicated by increased levels of hyaluronan during and off season. This inflammation may be partly different from the eosinophil-driven inflammation. ### Final_Prediction: yes

### Question: Do serum sRANKL/OPG predict recurrence after radiofrequency catheter ablation of lone atrial fibrillation? ### Context: Radiofrequency catheter ablation (RFCA) is a widely accepted strategy for eliminating atrial fibrillation (AF). A considerable recurrence rate has partly been ascribed to atrial remodeling. Osteoprotegerin (OPG)/receptor activator of nuclear factor-κB (RANK)/RANK ligand (RANKL) axis may contribute to the development and progression of AF by regulating atrial structural remodeling. This study aimed to determine the relationship between serum soluble RANKL (sRANKL)/OPG and the risk of recurrent arrhythmia after ablation of lone AF.We enrolled 527 lone AF patients undergoing first-time RFCA with complete follow-up data. Pre-ablation venous blood samples were obtained for measurement of serum sRANKL and OPG.During the follow-up period of 15 (3-64)months, AF recurred in 187 patients (35.5%). Recurrence was associated with an elevation of serum sRANKL level and sRANKL/OPG ratio. In multivariate survival regression, persistent AF, AF duration, left atrial diameter, amiodarone after ablation, particularly serum sRANKL level and sRANKL/OPG ratio independently predicted AF recurrence. According to ROC curve analysis, the best diagnostic values of serum sRANKL level and sRANKL/OPG ratio for predicting recurrence were 4.89 pmol/l and 0.76, respectively. ### Long_Answer: Baseline serum high sRANKL level and sRANKL/OPG ratio are associated with AF recurrence after primary ablation procedure in lone AF patients, and may be used in the prediction of AF recurrence in these patients. ### Final_Prediction: yes

### Question: Is gemtuzumab ozogamicin ( MylotargTM ) infrequently associated with sinusoidal obstructive syndrome/veno-occlusive disease? ### Context: Gemtuzumab ozogamicin (GO) is approved for the treatment of older adults with acute myeloid leukemia in first relapse. Several reports have suggested an association between GO administration and hepatic veno-occlusive disease (VOD), which has recently been termed sinusoidal obstructive syndrome (SOS). However, the majority of these studies were done in patients who had undergone high-dose therapy with stem cell transplantation or when GO was administered in combination with other cytotoxic chemotherapy.We performed a retrospective review of all patients treated at our institution with single-agent GO, either as initial therapy or in the relapsed and refractory setting. All patients were planned to receive GO 9 mg/m2 in two doses, 14 days apart. We reviewed liver function tests before and after administration and analyzed hepatic injuries in the context of patients' other comorbid conditions. Patients were classified as experiencing liver toxicity if their liver function(s) abnormality lasted for > 7 days, as documented by repeated serum studies.Forty-seven patients were analyzed. Response rate (27.2%) and median duration of response (6 months) were comparable to other reports. All patients were assessable for liver toxicity, of which 23 (48%) had elevation of at least one of their liver function tests (alanine aminotransferase, aspartate aminotransferase, total bilirubin or alkaline phosphatase). Elevations in liver function test(s) were noted at a median of 14 days (range 7-175 days). Eight patients had other comorbid conditions that could explain their liver abnormality, making the incidence of direct GO-induced liver injury 31%. However, only one patient had radiographic and clinical evidence suggesting SOSVOD. ### Long_Answer: When administered using the recommended dose and schedule, GO has little association with VODSOS if given as a single agent. In this retrospective review, the incidence of GO-related SOSVOD is as low as 2%. ### Final_Prediction: yes