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### Question: Is hippocampal and prefrontal atrophy in patients with early non-demented Parkinson 's disease related to cognitive impairment? ### Context: Early stage patients with Parkinson's disease (PD) show cognitive impairment in frontal lobe functions and memory tests. Hippocampal atrophy is seen in medicated patients with advanced PD.To examine whether prefrontal or hippocampal atrophy are already present in early stage PD, and whether such atrophy is associated with cognitive impairment.Twenty non-medicated, non-demented patients with early stage PD and 22 neurologically healthy age matched controls were studied. All subjects underwent magnetic resonance imaging to study hippocampal and prefrontal atrophy. Atrophy was evaluated by a neuroradiologist using a five point scale. In addition, the patients underwent a neuropsychological test battery sensitive to frontal lobe functions and memory.Patients with PD had atrophy in the right and the left prefrontal cortex. In the right hippocampus, the mean atrophy score was 1.15 in PD and 0.45 in controls. Corresponding figures for the left hippocampus were 1.05 for PD and 0.64 for controls. In PD, the left hippocampus atrophy correlated with verbal memory and prefrontal atrophy correlated with impaired performance in a test measuring vigilance. ### Long_Answer: Non-medicated, non-demented patients with early stage PD show hippocampal and prefrontal atrophy. Impaired memory is related to hippocampal atrophy, whereas sustained attention is related to prefrontal atrophy. ### Final_Prediction: yes

### Question: Does oxygen removal during pathogen inactivation with riboflavin and UV light preserve protein function in plasma for transfusion? ### Context: Photochemical pathogen inactivation technologies (PCT) for individual transfusion products act by inhibition of replication through irreversibly damaging nucleic acids. Concern on the collateral impact of PCT on the blood component's integrity has caused reluctance to introduce this technology in routine practice. This work aims to uncover the mechanism of damage to plasma constituents by riboflavin pathogen reduction technology (RF-PRT).Activity and antigen of plasma components were determined following RF-PRT in the presence or absence of dissolved molecular oxygen.Employing ADAMTS13 as a sentinel molecule in plasma, our data show that its activity and antigen are reduced by 23 ± 8% and 29 ± 9% (n = 24), respectively, which corroborates with a mean decrease of 25% observed for other coagulation factors. Western blotting of ADAMTS13 shows decreased molecular integrity, with no obvious indication of additional proteolysis nor is riboflavin able to directly inhibit the enzyme. However, physical removal of dissolved oxygen prior to RF-PRT protects ADAMTS13 as well as FVIII and fibrinogen from damage, indicating a direct role for reactive oxygen species. Redox dye measurements indicate that superoxide anions are specifically generated during RF-PRT. Protein carbonyl content as a marker of disseminated irreversible biomolecular damage was significantly increased (3·1 ± 0·8 vs. 1·6 ± 0·5 nmol/mg protein) following RF-PRT, but not in the absence of dissolved molecular oxygen (1·8 ± 0·4 nmol/mg). ### Long_Answer: RF-PRT of single plasma units generates reactive oxygen species that adversely affect biomolecular integrity of relevant plasma constituents, a side-effect, which can be bypassed by applying hypoxic conditions during the pathogen inactivation process. ### Final_Prediction: yes

### Question: Does tIM-4 expressed by mucosal dendritic cells play a critical role in food antigen-specific Th2 differentiation and intestinal allergy? ### Context: Food allergy accounts for significant morbidity. The etiology and immune mechanisms of food allergy, however, have remained poorly understood. In this study, we aimed to determine the role of T-cell immunoglobulin-domain and mucin-domain (TIM)-4, a recently identified member of cell surface molecules, in the pathogenesis of intestinal allergy in a murine model.We report that TIM-4 as well as costimulatory molecules were up-regulated in intestinal mucosal dendritic cells by in vitro or in vivo exposure to Staphylococcus enterotoxin B (SEB). SEB-conditioned intestinal dendritic cells loaded with a food macromolecule ovalbumin (OVA) induced potent OVA-specific T-helper (Th)2 lymphocyte responses in vitro and such Th2 responses were inhibited completely by TIM-4 blockade.In vivo exposure to both SEB and OVA resulted in OVA-specific Th2 differentiation and intestinal allergic responses including increased serum immunoglobulin E and Th2 cytokine levels, activation of OVA-specific Th2 cells detected both ex vivo and in situ, and mast cell degranulation. Of importance, in vivo abrogation of TIM-4 or its cognate ligand TIM-1 by using a polyclonal antibody remarkably dampened Th2 differentiation and intestinal allergy. ### Long_Answer: Our study thus identifies TIM-4 as a novel molecule critically required for the development of intestinal allergy. ### Final_Prediction: yes

### Question: Does molecular hydrogen suppress reactive astrogliosis related to oxidative injury during spinal cord injury in rats? ### Context: Spinal cord injury (SCI) can induce excessive astrocyte activation. Hydrogen has been deemed as a novel antioxidant. We investigated whether molecular hydrogen could act as an antiastrogliosis agent during SCI and oxidative injury in experimental rats and cultured astrocytes.Hydrogen-rich saline (HS, 8 mL/kg, i.p.) was injected every 12 h after SCI in rats. The expression of STAT3, p-STAT3, and glial fibrillary acidic protein (GFAP); the release of IL-1β, IL-6, and TNF-α; and astrogliosis, along with the BBB score, were evaluated. Culturing astrocytes with hydrogen-rich medium, the intracellular reactive oxygen species (ROS), astrogliosis, and the release of proinflammatory cytokines were assessed after H2O2-induced injury.In the HS group, the expression of STAT3, p-STAT3, and GFAP and the proinflammatory cytokines were decreased in local spinal cord on postoperation day (POD) 3; on PODs 7 and 14, reactive astrogliosis was suppressed, and the locomotor function was also improved. Furthermore, hydrogen-rich medium attenuated the intracellular production of ROS (especially HO•), astrogliosis, and the secretion of proinflammatory cytokines in astrocytes 12 h after H2O2-induced injury. ### Long_Answer: Molecular hydrogen could suppress reactive astrogliosis after contusive SCI and reduce the release of proinflammatory cytokines produced by active astrocytes related to oxidative injury. Thus, molecular hydrogen is potential to be a neuroprotective agent. ### Final_Prediction: yes

### Question: Thermoplastic mask in radiotherapy: a source of anxiety for the patient? ### Context: The thermoplastic mask often used to immobilize patients in radiotherapy can cause varying levels of stress and anxiety. This study aimed at evaluating the anxiety related to the use of radiotherapy masks and the coping strategies adopted by patients.Nineteen patients treated with radiotherapy mask for head and neck cancer, a brain tumour or a lymphoma, were met twice by a psychologist, either after the making of the mask and the first course of radiotherapy, or in the middle and at the end of treatment. Thirty-four semi-structured interviews were treated using a thematic content analysis and 13 patients answered to anxiety (STAI-YB) and coping (WCC) scales.The STAI-YB anxiety scores related to wearing the masks were low during the radiotherapy treatment period, and were confirmed by the remarks of patients recorded during the semi-structured interviews. Most patients had a positive perception of the mask, and considered it as a friend or protection. Twelve out of the 13 patients admitting to anxiety benefited from problem focused coping strategies. ### Long_Answer: Thermoplastic mask-related anxiety is low and possibly lies in the positive representation patients have about the mask. The explanations provided by health professionals on the radiotherapy mask possibly have a very positive effect on this perception. ### Final_Prediction: nan

### Question: Health promotion in megachurches: an untapped resource with megareach? ### Context: INTRODUCTION. In the United States, megachurches (churches with 2,000+ attendance) represent a community institution with extensive reach within the population. Despite this potential for reach, the current health promotion practices of megachurches are unknown. This study aimed to document current health promotion activities and resources for health promotion in megachurches.Staff at megachurches were recruited to take an online survey of health promotion programs, health promotion-related beliefs, barriers, and existing resources.Respondents (n = 110 churches) indicated that churches were primarily Baptist (23.6%) or nondenominational (21.1%), had 2,500 to 4,999 congregation members (44.5%), primarily White congregation members (83.5%), and 31 to 60 employees (45.4%). Churches reported 4.73 ± 2.54 activities/year, most commonly reporting clubs or teams related to physical activity (74.5%), hands-on classes (65.5%), and educational activities (59.1%). Most churches (39.1%) reported their primary faith leader was minimally involved in health-related activities. The most common barrier was competition for time/space with other church activities (46.2%). Churches reported several employee health-related policies. Respondents reported a budget of $0 to $499/year for health-related programs (44.4%). ### Long_Answer: These findings provide insight regarding the current status of health promotion in megachurches. These large churches are a potential health promotion partner for researchers and practitioners for developing culturally tailored interventions. ### Final_Prediction: nan

### Question: Are infection reduction strategies including antibiotic stewardship protocols in surgical and trauma intensive care units associated with reduced resistant gram-negative healthcare-associated infections? ### Context: Resistance to broad-spectrum antibiotics by gram-negative organisms is increasing. Resistance demands more resource utilization and is associated with patient morbidity and death. We describe the implementation of infection reduction protocols, including antibiotic stewardship, and assess their impact on multi-drug-resistant (MDR) healthcare-acquired gram-negative infections.Combined infection reduction and antibiotic stewardship protocols were implemented in the surgical and trauma intensive care units at Vanderbilt University Hospital beginning in 2002. The components of the program were: (1) Protocol-specific empiric and therapeutic antibiotics for healthcare-acquired infections; (2) surgical antibiotic prophylaxis protocols; and (3) quarterly rotation/limitation of dual antibiotic classes. Continuous healthcare-acquired infection surveillance was conducted by independent practitioners using National Heath Safety Network criteria. Linear regression analysis was used to estimate trends in MDR gram-negative healthcare-acquired infections.A total of 1,794 gram-negative pathogens were isolated from healthcare-acquired infections during the eight-year observation period. The proportion of healthcare-acquired infections caused by MDR gram-negative pathogens decreased from 37.4% (2001) to 8.5% (2008), whereas the proportion of healthcare-acquired infections caused by pan-sensitive pathogens increased from 34.1% to 53.2%. The rate of total healthcare-associated infections per 1,000 patient-days that were caused by MDR gram-negative pathogens declined by -0.78 per year (95% confidence interval [CI] -1.28, -0.27). The observed rate of healthcare-acquired infections per 1,000 patient days attributable to specific MDR gram-negative pathogens decreased over time: Pseudomonas -0.14 per year (95% CI -0.20, -0.08), Acinetobacter-0.49 per year (95% CI -0.77, -0.22), and Enterobacteriaceae -0.14 per year (95% CI -0.26, -0.03). ### Long_Answer: Implementation of an antibiotic stewardship protocol as a component of an infection reduction campaign was associated with a decrease in resistant gram-negative healthcare-acquired infections in intensive care units. These results further support widespread implementation of such initiatives. ### Final_Prediction: yes

### Question: Do prostate-specific antigen ( PSA ) velocity and benign prostate hypertrophy predict for PSA spikes following prostate brachytherapy? ### Context: To evaluate if variants of serum PSA or benign prostatic hypertrophy correlate with the development of a PSA spike following permanent prostate brachytherapy.Two-hundred-eighteen hormone-naïve patients with clinical T1b-T3a (1997 AJCC) prostate cancer who were treated with brachytherapy between August 1995 and November 1999, with or without supplemental external beam radiation therapy, and who remained free of biochemical failure were analyzed. The median follow-up was 46 months. A PSA spike was defined as a rise > or =0.2 ng/mL followed by a durable decline. Biochemical disease-free survival was defined by the ASTRO Consensus Definition with the additional constraint that the most recent PSA be < or =1.0 ng/mL. In addition, none of the patients possessed equivocal biochemical results (1 or 2 consecutive PSA rises or a declining PSA >1.0 ng/mL). In addition to previously reported clinical, treatment, and dosimetric parameters evaluated for spike, PSA density, transition zone (TZ) PSA density, percent free PSA, PSA velocity, PSA doubling time, TZ volume, and transition zone index (TZI) were included. The PSA kinetics of 18 hormone naïve patients who were implanted during the same time period and subsequently failed were also evaluated.Fifty-two (23.9%) developed a PSA spike. Of the demographic and preimplant clinical parameters, patient age, TZ volume, TZI, TZ PSA density, and 125I were statistically significant predictors for a PSA spike. Of the postimplant parameters, V200, follow-up, first postimplant PSA, and most recent PSA predicted for a PSA spike. In multivariate Cox regression analysis, PSA nadir, TZI, follow-up, age, months to PSA nadir and preimplant PSA velocity were significant predictors for spike. However, when variables only determinable after a PSA spike were included in the multivariate analysis, TZI, age, PSA velocity, and first postimplant PSA were predictors for a spike. Using categorical cutpoints of TZI >0.25, age at implant <62 years, and first postimplant PSA >1.0 ng/mL in the regression analysis, a positive likelihood ratio for a PSA spike of >1.8 was noted for each variable. Patients with PSA progression displayed significantly different PSA kinetics than those with a spike. ### Long_Answer: In multivariate analysis, PSA nadir, TZI, patient age, months to PSA nadir, follow-up, and preimplant PSA velocity were predictive of a PSA spike. However, when only variables identifiable prior to a spike were evaluated, TZI, patient age, preimplant PSA velocity, and first postimplant PSA were the strongest predictors for a PSA spike. ### Final_Prediction: yes

### Question: Are hER1-4 protein concentrations in normal breast tissue from breast cancer patients expressed by the same profile as in the malignant tissue? ### Context: The epidermal growth factor receptor HER2 is overexpressed or amplified in 25%-30% of patients with breast cancer. The mechanism behind HER2 amplification is unknown, but may be a patho-physiological phenomenon caused by continuous stimulation and activation of the HER1-4 system. We have mapped the protein concentrations of HER1-4 in breast cancer tissue, autologous reference tissue, normal breast tissue and serum samples, to see whether non-cancer cells from these patients express a protein profile indicating general activation.Tissue samples from malignant and adjacent normal breast tissue (autologous reference tissue) were collected from 118 women consecutively admitted for surgical treatment of breast cancer. In addition, 26 samples of normal breast tissue were collected from healthy women having breast reduction surgery. The tissue samples were homogenized and the proteins extracted. The tissue and serum concentrations of HER1-4 were determined quantitatively using a commercially available enzyme linked immunosorbent assay (ELISA) method.HER1 was down regulated in cancer tissue when compared to autologous reference tissue (p=8 x 10(-6)), while HER2 (p<10(-7)) and HER3 (p=3 x 10(-5)) were up regulated. Comparing autologous reference tissue with normal tissue showed down regulation of HER1 (p=0.122) and up regulation of HER2 (p=10(-6)), HER3 (p<10(-7)) and HER4 (p<10(-7)). Furthermore, we observed that correlations between the receptor combinations HER1-2, HER1-3 and HER1-4 were maintained from normal breast tissue to autologous reference breast tissue, but were lost in cancer tissue. ### Long_Answer: We suggest that these findings indicate that breast cancer is a systemic disease where the HER1-4 system in autologous reference tissue is continuously activated, thus favoring the subsequent development of cancer. ### Final_Prediction: yes

### Question: Does adenovirus-mediated gene transfer of human inducible nitric oxide synthase in porcine vein grafts inhibit intimal hyperplasia? ### Context: The aim of this study is to determine whether adenoviral inducible nitric oxide synthase (iNOS) gene transfer could inhibit intimal hyperplasia (IH) in porcine internal jugular veins interposed into the carotid artery circulation.Porcine internal jugular veins were transduced passively with 1 x 10(11) particles of an adenoviral vector carrying either the human iNOS (AdiNOS) or beta-galactosidase (AdlacZ) cDNA for 30 minutes and then interposed into the carotid artery circulation. Segments of each vein graft were maintained in an ex vivo organ culture to measure nitrite accumulation, a marker of nitric oxide synthesis. The grafts were analyzed immunohistochemically for the presence of neutrophils, macrophages, and leukocytes by staining for myeloperoxidase, ED1, and CD45, respectively, at 3 (n = 4) and 7 (n = 4) days. Morphometric analyses and cellular proliferation (Ki67 staining) were assessed at 3 (n = 4), 7 (n = 4), and 21 days (n = 8).AdlacZ-treated vein grafts demonstrated high levels of beta-galactosidase expression at 3 days with a gradual decline thereafter. Nitrite production from AdiNOS-treated vein grafts was approximately fivefold greater than AdlacZ-treated grafts (P =.00001). AdiNOS or AdlacZ treatment was associated with minimal graft inflammation. Cellular proliferation rates were significantly reduced in AdiNOS-treated grafts as compared with controls at both 3 (41%, P =.000004) and 7 days (32%, P =.0001) after bypass. This early antiproliferative effect was most pronounced at the distal anastomosis (65%, P =.0005). The iNOS gene transfer reduced the intimal/medial area ratio in vein grafts at 7 (36%, P =.009) and 21 days (30%, P =.007) versus controls. This inhibition of IH was again more prominent in the distal segments of the grafts (P =.01). ### Long_Answer: Adenovirus-mediated iNOS gene transfer to porcine internal jugular vein grafts effectively reduced cellular proliferation and IH. Although iNOS gene transfer reduced IH throughout the entire vein graft, the most pronounced effect was measured at the distal anastomosis. These results suggest potential for iNOS-based genetic modification of vein grafts to prolong graft patency. ### Final_Prediction: yes

### Question: Do South African universities provide the required training platforms for otolaryngology specialist training? ### Context: Concern exists about the quality of specialist training platforms at South African universities and teaching hospitals.We conducted an audit of the quality of training at South African otolaryngology (ENT) training institutions from the perspective of the registrars.Some institutions were deficient in terms of supervision, theatre time, access to teaching aids and research tools, and range of surgery, and do not provide the required training platforms for ENT specialist training. Five out of 8 institutions have produced<2 publications in peer-reviewed journals over the past 5 years. ### Long_Answer: The HPCSA fails to adequately police the quality of training in South Africa. Training programme shortcomings must urgently be addressed to ensure proper education and training of otolaryngologists. ### Final_Prediction: nan

### Question: Is radiographic progression associated with increased cardiovascular risk in patients with axial spondyloarthritis? ### Context: To compare the cardiovascular disease (CVD) risk between axial spondyloarthritis (axSpA) patients and matched controls, and to identify factors associated with increased CVD risk in axSpA patients.This cross-sectional study enrolled 185 axSpA patients who fulfilled the Assessment for Spondyloarthritis (ASAS) criteria and 925 age- and sex-matched controls. None of the subjects had a previous history of CVD or diabetes mellitus. Traditional CVD risk factors were assessed and the 10-year CVD risk was calculated using the Framingham risk score (FRS). Estimated 10-year CVD risk was compared between axSpA patients and matched controls. Disease activity and radiographic progression in the sacroiliac joint and spine of axSpA patients were evaluated at the time of CVD risk assessment.High-density lipoprotein (HDL) cholesterol levels were lower in axSpA patients than in the matched controls (p = 0.004); however, systolic blood pressure was higher (p < 0.001). The FRS was 5.0 ± 6.6% for controls and 6.3 ± 8.7% for axSpA patients (p = 0.046). Both the grade of sacroiliitis on X-ray and the number of syndesmophytes correlated with the FRS (p = 0.009 and p = 0.001, respectively), but disease activity variables did not. The FRS was significantly higher in axSpA patients with a greater number of syndesmophytes (p = 0.035). Multivariate analysis identified the number of syndesmophytes as being independently associated with the FRS (p < 0.001). ### Long_Answer: The FRS was higher in axSpA patients than in a matched general population. Radiographic progression in the spine was associated with a high estimated 10-year CVD risk. ### Final_Prediction: yes

### Question: Is primary melanoma of the CNS in children driven by congenital expression of oncogenic NRAS in melanocytes? ### Context: NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRAS(G12D)) in mouse melanocytes. When NRAS(G12D) was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma. Unexpectedly, however, it did induce early-onset primary melanoma of the central nervous system (CNS). The tumors were rapidly proliferating and caused neurologic symptoms, rapid health deterioration, and death. NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS. We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor for primary melanoma of the CNS in children, and we present a mouse model of this disease. ### Long_Answer: We show that the acquisition of NRAS mutations in melanocytes during embryogenesis is a risk factor for early-onset melanoma of the CNS. We have developed a powerful mouse model to study this rare but devastating childhood disease, and to develop therapeutic approaches for its treatment. ### Final_Prediction: yes

### Question: Do novel acylated steroidal glycosides from Caralluma tuberculata induce caspase-dependent apoptosis in cancer cells? ### Context: Pregnane glycosides are potent cytotoxic agents which may represent new leads in the development of anti-tumour drugs, particularly in the treatment of breast cancer, because of the structural similarity to estrogenic agonists. Caralluma species are natural sources of a wide variety of pregnane glycosides. The aim of the study was to isolate, using an activity-guided fractionation approach, novel pregnane glycosides for testing on breast cancer and other tumour lines.The effect of crude extracts, specific organic fractions and isolated compounds from Caralluma tuberculata was tested on the growth and viability of MCF-7 estrogen-dependent, and MDA-MB-468 estrogen-independent breast cancer cells, Caco-2 human colonic cells, HUVECs and U937 cells. Neutral red uptake and MTT assays were used. Apoptosis was detected by Western blot of poly-(ADP ribose) polymerase (PARP) as were other markers of nuclear fragmentation (DNA ladder assay, staining of cells with nuclear dye DAPI). The involvement of caspases was investigated using the pan-caspase inhibitor Z-VAD-FMK.The ethyl acetate fraction of Caralluma tuberculata was found to be the most potent anti-proliferative fraction against all three cancer cell lines. Two novel steroidal glycosides were isolated from the active fraction after a series of chromatographic experiments. The structure of the isolated compounds was elucidated solely based on 2D-NMR (HMBC, HETCOR, DQF-COSY) and MS spectral analysis as compound 1: 12-O-benzoyl-20-O-acetyl-3β,12β,14β,20β-tetrahydroxy-pregnan-3-ylO-β-D-glucopyranosyl-(1→4)-β-D-glucopyranosyl-(1 → 4)-3-methoxy-β-D-ribopyranoside, and as compound 2: 7-O-acetyl-12-O-benzoyl-3β,7β,12β,14β-tetrahydroxy-17β-(3-methylbutyl-O-acetyl-1-yl)-androstan-3-ylO-β-D-glucopyranosyl-(1 → 4)-6-deoxy-β-D-allopyranosyl-(1 → 4)-β-D-cymaropyranosyl-(1 → 4)-β-D-cymapyranosyl-(1→ 4)-β-D-cymaropyranoside. Compound 1 (pregnane glycoside) and compound 2 (androstan glycoside) induced apoptosis at <25 μM after 48 h as assessed by cell shrinkage, PARP cleavage, DNA fragmentation, and reversal with the caspase inhibitor. ### Long_Answer: Two novel steroid glycosides isolated from Caralluma tuberculata possess moderate, micromolar cytotoxic activity on breast cancer and other cells in vitro, which may indicate a source of activity in vivo of interest to future drug design. ### Final_Prediction: yes

### Question: Is the white blood cell count an independent predictor of no-reflow and mortality following acute myocardial infarction in the coronary interventional era? ### Context: In the era before the use of coronary reperfusion therapy, an elevated white blood cell (WBC) count was associated with a higher risk of adverse events following acute myocardial infarction (AMI). However, the relationship between WBC count and prognosis after AMI has not been investigated since coronary intervention was introduced.To evaluate whether a high WBC count within 48 hours of the onset of AMI predicts future adverse events in patients undergoing percutaneous coronary intervention (PCI).We evaluated 1,016 patients who underwent PCI in the acute phase of MI using the Japanese Acute Coronary Syndrome Study (JACSS) database. RESULTS. WBC count was significantly associated with smoking, sudden onset AMI, and the no-reflow phenomenon during PCI, as were age, peak creatine kinase level, and Killip class. An elevated WBC count was significantly associated with higher risk of in-hospital mortality. Patients in the highest quartile of WBC count were about three times more likely to have a poor prognosis after AMI compared to those in the lowest quartile. ### Long_Answer: The WBC count is of great significance for stratifying patient risk and can be used as a universal marker for predicting future adverse events following any treatment for AMI. ### Final_Prediction: yes

### Question: Do tetracyclines inhibit nitrosothiol production by cytokine-stimulated osteoarthritic synovial cells? ### Context: To evaluate the capacity of doxycycline and minocycline to inhibit NO production and N-nitrosation reactions in vitro.Synovial cells obtained from 6 patients with osteoarthritic joint disease were incubated for 24 hours with (i) or without (ii) IL-1beta (1 ng/ml), TNF-alpha (500 pg/ml), IFN-gamma (10(4) U/ml) plus minocycline or doxycycline (10(-4) to 10(-6) M), diclofenac (10(-5) M), or cortisol (10(-5) M). Nitrosothiols were determined by fluorimetry, nitrite by the Griess reaction, nitrate by a spectrophotometric assay using oxidation by nitrate reductase and iNOS by immunoblotting.After 24 hours of stimulation, the level of NO production was much higher than that in untreated cells: about 5.5 times higher for nitrosothiols, 5.2 times higher for nitrate and about 3.5 times higher for nitrite. Doxycycline and minocycline induced a dose-dependent decrease in the production of nitrosothiols, nitrate and nitrite, and inhibited the synthesis of the iNOS protein. Doxycycline and minocycline inhibited the N-nitrosation reaction of DAN effectively, with IC50 values close to 100 microM. Diclofenac and cortisol had no effect. ### Long_Answer: This study provides new information on the mechanism by which tetracyclines exert anti-inflammatory effects, via inhibiting nitrosothiols. ### Final_Prediction: yes

### Question: Is cD36 AA genotype associated with decreased lipid taste perception in young obese , but not lean , children? ### Context: Obesity is an alarming threat for all age groups, including children. Fat overconsumption is one of the factors that directly influences this pathology. Recent studies have suggested that a common variant in the CD36 gene, that is, single-nucleotide polymorphism (SNP) rs1761667-A allele, that reduces CD36 expression, associates with high oral fat detection thresholds in some obese subjects. The objective was to assess fatty acid sensitivity in relation to CD36 SNP in young lean and obese children.We studied lingual detection thresholds for emulsions, containing oleic acid, in Algerian children (n=116, age=8±0.5 years) who were divided into two groups: obese (n=57; body mass index (BMI) z-score=2.513±0.490) and lean children (n=59; BMI z-score=-0.138±0.601) by alternative-forced choice method. To correlate the lipid taste perception thresholds with CD36 SNP, the children were genotyped for A/G SNP rs1761667 in 5'UTR region of CD36 by using PCR and restriction fragment length polymorphism.We noticed significantly higher CD36 A-allele frequency (P=0.036) in young obese children compared with leans. CD36 A-allele was associated with higher lipid taste perception thresholds than G-allele in obese children, but not in lean controls. Moreover, waist circumference was positively correlated with reduced fat taste sensitivity in these children. ### Long_Answer: CD36 SNP A-allele, being present both in young lean and in obese children, is associated with high threshold for fatty acid taste sensitivity only in obese children. ### Final_Prediction: yes

### Question: Anal lesions: any significant prognosis in Crohn's disease? ### Context: One hundred and one patients (46 males, 55 females, aged 34 +/- 14 years; range: 15-79) were consecutively referred to our institution (May 1991 to May 1994) for intestinal symptoms related to Crohn's disease (mean duration 66 +/- 66 months). They all underwent a proctological examination regardless of perineal symptoms. The Cardiff classification was used to describe anoperineal lesions. Patients with anal lesions (64) differed from those without (37): male predisposition (53% vs. 32%, P<0.05), more frequent rectal involvement (75% vs. 24%, P<0.001) and more acute lesions observed at proctoscopic examination (42% vs. 16%, P<0.05). Age of onset, surgical past history of Crohn's disease, colonic or ileal involvement, or Harvey-Bradshaw score were not different between groups.Patients with anal ulceration (43) as compared to patients having anal involvement without ulceration experienced pain more frequently (constant pain: 56 vs. 14%; defecatory pain: 35 vs. 19%) and a more severe evolution of intestinal (40 vs. 22%, P<0.05) and anal (42 vs. 12%, P<0.05) involvement. In those with an aggressive ulceration (U2, 28 patients), daily stool frequency (5.1 +/- 3 vs. 3.6 +/- 2.5, P<0.05) and clinical score (9 +/- 5 vs. 7 +/- 3) were more pronounced. Steroid therapy dependency occurred more frequently in the group with anal ulceration (35 vs. 16% and 40 vs. 17%, respectively, P<0.05). Similar associations were observed for cases of anal involvement (34 vs. 5%, P<0.01) and azathioprine was more frequently required (39 vs. 5%, P<0.01) than in those free of anal lesions. During follow-up, eight other patients required azathioprine (steroid dependence in six) and seven of them had anal lesions at referral. At the endpoint of the study, one out of two patients with anal lesions required azathioprine most often due to steroid dependency of the intestinal involvement (30/64 vs. 4/37, P<0.005). ### Long_Answer: Anal ulcerations are a reliable severity index of Crohn's disease in both short- and long-term prognosis but their link to the steroid status of the intestinal disease remains unclear. ### Final_Prediction: nan

### Question: Ethical considerations of mobile phone use by patients in KwaZulu-Natal: Obstacles for mHealth? ### Context: mHealth has the potential to facilitate telemedicine services, particularly in the developing world. Concern has been expressed about the confidentiality of health information that is relayed by mobile phone.AIM: We examined the habits and practices of mobile phone use by patients in KwaZulu-Natal, South Africa.We conducted a descriptive survey of two patient populations: 137 urban patients attending private practitioners and 139 patients in remote rural areas attending outpatient departments in Government-funded hospitals. The questionnaire covered several domains: demographics, mobile phone use, privacy and confidentiality and future use for health-related matters.Two hundred and seventy-six patients completed the questionnaire. We found that a third of our participants shared their mobile phone with others, 24% lent their phone to others and more than half received health-related messages for other people. Mobile phone theft was common, as was number changing. Thirty-eight percent of the people were not able to afford airtime for more than a week in the past year and 22% of rural patients were unable to keep their phone charged. Mobile phone signal coverage was significantly worse in the rural areas than in urban areas. ### Long_Answer: This study highlights the legal and ethical ramifications that these practices and findings will have on mHealth programmes in our setting. Healthcare providers and regulators will need to consider how patients use and manage their mobile phones when developing services and regulations. ### Final_Prediction: nan

### Question: Does long interspersed nuclear element ORF-1 protein promote proliferation and resistance to chemotherapy in hepatocellular carcinoma? ### Context: To clarify the specific roles and mechanisms of long interspersed nuclear element-1 ORF-1 protein [human long interspersed nuclear element-1 (LINE-1), ORF-1p] in chemotherapeutic drug resistance and cell proliferation regulation in hepatocellular carcinoma (HCC) cells.MTT assays were performed to identify the effect of the chemotherapeutic drug toxicity on HepG2 cells. Cell proliferation inhibition and the IC50 were calculated by the Origin 8.0 software. Western blotting assays were performed to investigate whether LINE-1 ORF-1p modulates the expression of some important genes, including p53, p27, p15, Bcl-2, mdr, and p-gp. To corroborate the proliferation and anchor-independent growth results, the HepG2 cells were analyzed by flow cytometry to investigate the effect of LINE-1 ORF-1p on the apoptosis regulation.LINE-1 ORF-1p contributed to the resistance to several chemotherapeutic drugs (cisplatin and epirubicin) in HepG2 cells. The IC50 of the epirubicin and cisplatin increased from 36.04 nmol/L to 59.11 nmol/L or from 37.94 nmol/L to 119.32 nmol/L. Repression of LINE-1 ORF-1p expression by the siRNA could markedly enhance the response of HepG2 cells to the epirubicin and cisplatin. The IC50 correspondingly decreased from 28.06 nmol/L to 3.83 nmol/L or from 32.04 nmol/L to 2.89 nmol/L. Interestingly, down-regulation of LINE-1 ORF-1p level by siRNA could promote the response of HepG2 cells to the paclitaxel. The IC50 decreased from 35.90 nmol/L to 7.36 nmol/L. However, overexpression of LINE-1 ORF-1p did not modulate the paclitaxel toxicity in HepG2 cells. Further Western blotting revealed that LINE-1 ORF-1p enhanced mdr and p-gp gene expression. As a protein arrested in the nucleus, LINE-1 ORF-1p may function through modulating transcriptional activity of some important transcription factors. Indeed, LINE-1 ORF-1p promoted HepG2 cell proliferation, anchor-independent growth and protected the cells against apoptosis through modulating the expression of p15, p21, p53, and Bcl-2 genes. ### Long_Answer: LINE-1 ORF-1p promotes HepG2 cell proliferation and plays an important role in the resistance of chemotherapeutic drugs. By establishing novel roles and defining the mechanisms of LINE-1 ORF-1p in HCC chemotherapeutic drug resistance and cell proliferation regulation, this study indicates that LINE-1 ORF-1p is a potential target for overcoming HCC chemotherapeutic resistance. ### Final_Prediction: yes

### Question: Does gene expression meta-analysis identify metastatic pathways and transcription factors in breast cancer? ### Context: Metastasis is believed to progress in several steps including different pathways but the determination and understanding of these mechanisms is still fragmentary. Microarray analysis of gene expression patterns in breast tumors has been used to predict outcome in recent studies. Besides classification of outcome, these global expression patterns may reflect biological mechanisms involved in metastasis of breast cancer. Our purpose has been to investigate pathways and transcription factors involved in metastasis by use of gene expression data sets.We have analyzed 8 publicly available gene expression data sets. A global approach, "gene set enrichment analysis" as well as an approach focusing on a subset of significantly differently regulated genes, GenMAPP, has been applied to rank pathway gene sets according to differential regulation in metastasizing tumors compared to non-metastasizing tumors. Meta-analysis has been used to determine overrepresentation of pathways and transcription factors targets, concordant deregulated in metastasizing breast tumors, in several data sets.The major findings are up-regulation of cell cycle pathways and a metabolic shift towards glucose metabolism reflected in several pathways in metastasizing tumors. Growth factor pathways seem to play dual roles; EGF and PDGF pathways are decreased, while VEGF and sex-hormone pathways are increased in tumors that metastasize. Furthermore, migration, proteasome, immune system, angiogenesis, DNA repair and several signal transduction pathways are associated to metastasis. Finally several transcription factors e.g. E2F, NFY, and YY1 are identified as being involved in metastasis. ### Long_Answer: By pathway meta-analysis many biological mechanisms beyond major characteristics such as proliferation are identified. Transcription factor analysis identifies a number of key factors that support central pathways. Several previously proposed treatment targets are identified and several new pathways that may constitute new targets are identified. ### Final_Prediction: yes

### Question: Does acute exposure to waterpipe tobacco smoke induce changes in the oxidative and inflammatory markers in mouse lung? ### Context: Tobacco smoking represents a global public health threat, claiming approximately 5 million lives a year. Waterpipe tobacco use has become popular particularly among youth in the past decade, buttressed by the perception that the waterpipe "filters" the smoke, rendering it less harmful than cigarette smoke.In this study, we examined the acute exposure of waterpipe smoking on lung inflammation and oxidative stress in mice, and compared that to cigarette smoking.Mice were divided into three groups; fresh air control, cigarette and waterpipe. Animals were exposed to fresh air, cigarette, or waterpipe smoke using whole body exposure system one hour daily for 7 days.Both cigarette and waterpipe smoke exposure resulted in elevation of total white blood cell count, as well as absolute count of neutrophils, macrophages, and lymphocytes (P < 0.01). Both exposures also elevated proinflammatory markers such as TNF-α and IL-6 in BALF (P < 0.05), and oxidative stress markers including GPx activity in lungs (P < 0.05). Moreover, waterpipe smoke increased catalase activity in the lung (P < 0.05). However, none of the treatments altered IL-10 levels. ### Long_Answer: Results of cigarette smoking confirmed previous finding. Waterpipe results indicate that, similar to cigarettes, exposure to waterpipe tobacco smoke is harmful to the lungs. ### Final_Prediction: yes

### Question: Does heterogeneity of isolated mononuclear cells from patients with acute myeloid leukemia affect cellular accumulation and efflux of daunorubicin? ### Context: Pharmacologic studies on blasts from patients with leukemia are generally performed on density gradient isolated blood or bone marrow cells. Thereby, cellular drug accumulation and efflux are determined as mean values of the entire cell population. The objective of the present study was to characterize the heterogeneity in the accumulation and efflux of daunorubicin in various subpopulations of mononuclear cells isolated from patients with acute myeloid leukemia (AML).Mononuclear cells from 33 patients with AML were isolated from peripheral blood by density gradient centrifugation on Lymphoprep (1. 077 g/mL). Cellular accumulation of fluorescent daunorubicin was determined by flow cytometry after incubation of the cells at +37C for 1 hour. Thereafter, the cells were washed and reincubated in drug-free medium. Kinetics of drug efflux were determined by frequent determination of cellular fluorescence during 30 min. Daunorubicin accumulation and efflux were compared in the total isolated mononuclear cell population and in the various blast cell populations gated on FSC/SSC according to the results of immunophenotyping.In 8 of these 33 (24%) patient samples, two distinct blast cell populations could be identified. In 7 out of 8 these cases the more immature blasts had a lower drug accumulation and in 6 out of the 8 cases also a higher efflux rate than the differentiating cell population. Cyclosporin A increased daunorubicin accumulation and reduced efflux in the immature blast population. In the differentiating cell population cyclosporin A increased both the accumulation and the efflux. In patients with a single blast cell population, the gated blast cells had a significantly lower drug accumulation but also a lower drug efflux rate than the total cell population. ### Long_Answer: The results imply that drug transport studies on cells isolated from patients with AML give somewhat different results depending on the cell population studied. Some, but not all, of these differences in daunorubicin accumulation and efflux as well as in the effect of cyclo-sporin A can be explained by a heterogenous expression of the mdr1-gene. The observed heterogeneity may be of special relevance with regard to drug resistance. The presence of even a small resistant cell clone may jeopardize the effect of the chemotherapy due to expansion resulting in relapse of disease. ### Final_Prediction: yes

### Question: Does risk factors and correlate of violence among acutely ill adult psychiatric inpatients? ### Context: The purpose of the study was to identify risk factors and correlates of violence committed by patients in an acute adult psychiatric inpatient unit in a district general hospital of the United Kingdom's National Health Service.Incidents of violence committed by inpatients over a one-year period in 1997-1998 were retrospectively analyzed. The clinical characteristics of 49 violent patients were compared with those of all patients admitted to the unit during the study period (N=474) and with a random sample of nonviolent patients (N=140). Logistic regression analysis was used to identify clinical variables that predicted violent behavior.Violence was not positively associated with schizophrenia or negatively associated with depression. Frequent medication change, high use of sedative drugs, past violent behavior, an ICD-10 diagnosis of dissocial personality disorder or emotionally unstable personality disorder (DSM-IV antisocial personality disorder or borderline personality disorder), and long hospitalization were the most powerful predictors of violence. Together these variables had a sensitivity of 76 percent, a specificity of 97 percent, and a positive predictive value of 90 percent in predicting which patients became violent. Compulsory (involuntary) admission, comorbid diagnoses, past self-harm, and nonalcohol drug abuse were also associated with violent behavior. ### Long_Answer: Clinicians' judgment about an inpatient's potential for violence may be augmented by knowledge of the risk factors identified in this study. Medication variables could be especially useful predictors, particularly when information about other risk factors is not available. Factors other than mental illness per se may be crucial determinants of violence in acute inpatient settings. ### Final_Prediction: yes

### Question: Does malaria infection appear to modify the risk of bronchiolitis early in life? ### Context: The observation of an increased prevalence of allergic disorders coinciding with a decreasing frequency of infectious diseases in early childhood has led to the speculation that infections may prevent allergic sensitization. Information on the role of parasites in this context is limited. Bronchiolitis in infancy has been linked with asthmatic symptoms later in childhood, although the underlying cause of this association is unknown.To test the hypothesis that early parasitic infections in infancy might prevent the development of allergic manifestations later in life, the effect of malaria infections during the first year of life on the risk of bronchiolitis was studied in 675 Tanzanian children at 18 months of age. The study was conducted as part of an intervention trial of malaria chemoprophylaxis and/or iron supplementation for the prevention of malaria and anemia in infants.The incidence of bronchiolitis up to 18 months of age in the 675 children was 0.58 episode per child per year. The risk factors analysis was based on 470 children with complete data. There was no difference in the incidence of bronchiolitis between those who had received malaria chemoprophylaxis during the first year of life and those who had not. However, the proportion of children who had bronchiolitis was lower among those who had had malaria episodes than among those who had not (48% vs. 55%, P = 0.05). ### Long_Answer: This study does not support the hypothesis that reduced exposure to parasites may modulate the development of bronchiolitis early in life. ### Final_Prediction: no

### Question: Is involvement of ER-α36 in the malignant growth of gastric carcinoma cells associated with GRP94 overexpression? ### Context: This study aimed to examine the involvement of glucose-regulated protein 94 (GRP94) in oestrogen receptor-α36 (ER-α36)-mediated oestrogen signalling in gastric cancer development.A total of 130 formalin-fixed and paraffin-embedded gastric tumour samples with corresponding normal gastric and tumour-adjacent tissues were used. High levels of GRP94 expression (2+ or 3+) were observed in 109 of 130 gastric carcinomas (83.85%) by immunohistochemistry, and in 13 of 18 tumour specimens (72.22%) with Western blot analysis. GRP94 expression was correlated positively with gender, tumour stage, lymph node metastasis and ER-α36 expression (P < 0.05). Oestrogen treatment up-regulated both GRP94 and ER-α36 expression in gastric cancer SGC7901 cells. In addition, steady state levels of GRP94 protein were decreased in established gastric cancer SGC7901 cells with knocked-down levels of ER-α36 expression and in xenograft tumours formed by these cells. Forced expression of recombinant ER-α36 in SGC7901 cells, however, up-regulated the levels of GRP94 expression. ### Long_Answer: Glucose-regulated protein 94 is a downstream effector of ER-α36-mediated oestrogen signalling, and may be involved in ER-α36 function during gastric carcinogenesis. ### Final_Prediction: yes

### Question: Does identification of technical item flaws lead to improvement of the quality of single best Multiple Choice Questions? ### Context: The purpose of the study was to identify technical item flaws in the multiple choice questions submitted for the final exams for the years 2009, 2010 and 2011.This descriptive analytical study was carried out in Islamic International Medical College (IIMC). The Data was collected from the MCQ's submitted by the faculty for the final exams for the year 2009, 2010 and 2011. The data was compiled and evaluated by a three member assessment committee. The data was analyzed for frequency and percentages the categorical data was analyzed by chi-square test.Overall percentage of flawed item was 67% for the year 2009 of which 21% were for testwiseness and 40% were for irrelevant difficulty. In year 2010 the total item flaws were 36% and 11% testwiseness and 22% were for irrelevant difficulty. The year 2011 data showed decreased overall flaws of 21%. The flaws of testwisness were 7%, irrelevant difficulty were 11%. ### Long_Answer: Technical item flaws are frequently encountered during MCQ construction, and the identification of flaws leads to improved quality of the single best MCQ's. ### Final_Prediction: yes

### Question: Hypointense hepatocellular nodules on hepatobiliary phase of Gd-EOB-DTPA-enhanced MRI: can increasing the flip angle improve conspicuity of lesions? ### Context: To compare the conspicuity of hypointense hepatocellular nodules in patients with chronic liver disease on hepatobiliary phase (HP) of gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) acquired with low to high flip angles (FAs).A total of 95 patients with chronic liver disease who underwent Gd-EOB-DTPA-enhanced MRI were included. HP images were obtained at 20 minutes, with 15°, 20°, and 30° FAs. For the detected hepatocellular nodule, liver-to-lesion contrast-to-phantom ratios (CPR) and lesion conspicuity (LCS) were assessed.In all examinations, 96 hepatocellular nodules showing hypointensity on HP were identified. These lesions included 39 hypovascular nodules and 57 hypervascular nodules. Mean CPR and LCS showed the highest value on the 30° FA, followed by 20° and 15° FAs. CPR and LCS of 15° FA were significantly lower than those of 20° and 30° FAs (P<0.001 to P = 0.007). CPR of 30° FA for hypervascular nodules was significantly greater than that of 20° FA (P<0.001). ### Long_Answer: In the evaluation of hypointense hepatocellular nodules on HP of Gd-EOB-DTPA-enhanced MRI, higher FA such as 30° should be used rather than low FA such as 15°. ### Final_Prediction: nan

### Question: Do lectins detect changes of the glycosylation status of plasma membrane constituents during late apoptosis? ### Context: Mechanisms governing the normal resolution processes of inflammation are poorly understood, yet their elucidation may lead to a greater understanding of the pathogenesis of chronic inflammation. The removal of apoptotic cell material and their potentially histotoxic contents is a prerequisite of resolution. Engulfment by macrophages is an important disposal route, and changes in the apoptotic cells that are associated with their recognition by macrophages are the subject of this report.Apoptosis and necrosis in primary cells and cell lines were induced by various stimuli. The binding profile of 23 different lectins for vital, apoptotic, and necrotic cells were analyzed by flow cytometry.We observed that lectins were able to attach to the cell surfaces of vital and dying cells. Some lectins exhibited membrane destructive properties and, consecutively, changed the morphology of the cells as detected by flow cytometry. Other lectins did not show differences in their binding to viable and apoptotic cells. Those lectins were, therefore, not used for analyses of surface changes. The lectins Griffonia simplificolia II (GSL II), Narcissus pseudonarcissus (NPn), and Ulex europaeus I (UEA I) showed no cytotoxic activity and bound preferentially to dying cells. Primary and secondary necrotic cells displayed an equal staining intensity, which was substantially higher than for apoptotic cells. The binding of GSL II, NPn, and UEA to dying cells increased in a time-dependent manner and was delayed to AxV positivity and the decrease in the mitochondrial membrane potential of apoptotic cells. The kinetic of the lectin staining correlated with the increase in subG1-DNA. GSL II, NPn, and UEA are specific for N-acetylglucosamine, mannose, and fucose, respectively. ### Long_Answer: According to their binding specificity, we conclude that N-acetylglucosamine-, mannose-, and fucose-containing epitopes are increasingly exposed on cells undergoing apoptosis. ### Final_Prediction: yes

### Question: Does salsalate treatment improve glycemia without altering adipose tissue in nondiabetic obese hispanics? ### Context: Salsalate treatment has well-known effects on improving glycemia, and the objective of this study was to examine whether the mechanism of this effect was related to changes in adipose tissue.A randomized double-blind and placebo-controlled trial in obese Hispanics (18-35 years) was conducted. The intervention consisted of 4 g day(-1) of salsalate (n = 11) versus placebo (n = 13) for 4 weeks. Outcome measures included glycemia, adiposity, ectopic fat, and adipose tissue gene expression and inflammation.In those receiving salsalate, plasma fasting glucose decreased by 3.4% (P < 0.01), free fatty acids decreased by 42.5% (P = 0.06), and adiponectin increased by 27.7% (P < 0.01). Salsalate increased insulin AUC by 38% (P = 0.01) and HOMA-B by 47.2% (P < 0.01) while estimates of insulin sensitivity/resistance were unaffected. These metabolic improvements occurred without changes in total, abdominal, visceral, or liver fat. Plasma markers of inflammation/immune activation were unchanged following salsalate. Salsalate had no effects on adipose tissue including adipocyte size, presence of crown-like structures, or gene expression of adipokines, immune cell markers, or cytokines downstream of NF-κB with the exception of downregulation of IL-1β (P < 0.01). ### Long_Answer: Findings suggest that metabolic improvements in response to salsalate occurred without alterations in adiposity, ectopic fat, or adipose tissue gene expression and inflammation. ### Final_Prediction: yes

### Question: Are abnormal involuntary movements linked to psychosis-risk in children and adolescents : Results of a population-based study? ### Context: Altered motor behavior has consistently been reported in medication-naive adult patients with schizophrenia and first episode psychosis and adults at clinical high risk for psychosis (CHR). This study is the first to evaluate the prevalence of abnormal involuntary movements in a community sample of children and adolescents with and without CHR.We examined CHR in 102 children and adolescents aged 8-17years from the general population of the Canton Bern. Attenuated and brief intermittent psychotic symptoms, as well as basic symptoms, were assessed using the Structured Interview for Psychosis Risk Syndromes and the Schizophrenia Proneness Instrument, Child & Youth Version. Motor symptoms were assessed using the Abnormal Involuntary Movement Scale (AIMS). Additionally, psychosocial functioning, a neurocognitive test battery, and DSM-IV Axis I disorders were examined.Eleven (10.8%) participants met CHR criteria, 13 (12.7%, 5 with and 8 without CHR) met criteria for increased abnormal involuntary movements (AIMS≥2). Both AIMS total scores and the percentage of children with AIMS≥2 were significantly higher in the CHR group. Psychosocial functioning was reduced in subjects with abnormal involuntary movements, and movement abnormalities were linked to deficits in attention and perception but not to the presence of non-psychotic mental disorders. ### Long_Answer: Our findings suggest that abnormal involuntary movements are linked to psychosis risk in children and adolescents from the general population. Thus, abnormal involuntary movements might represent an additional useful and easily accessible predictor of psychosis. ### Final_Prediction: yes

### Question: Do laminin-rich blood vessels display activated growth factor signaling and act as the proliferation centers in Dupuytren 's contracture? ### Context: Dupuytren's contracture (DC) is a chronic fibroproliferative disease of the hand, which is characterized by uncontrolled proliferation of atypical myofibroblasts at the cellular level. We hypothesized that specific areas of the DC tissue are sustaining the cell proliferation and studied the potential molecular determinants that might contribute to the formation of such niches.We studied the expression pattern of cell proliferation marker Ki67, phosphorylated AKT (Ak mouse strain thymoma) kinase, DC-associated growth factors (connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), insulin-like growth factor 2 (IGF-2)) and extracellular matrix components (laminins, fibronectin, collagen IV) in DC tissue and normal palmar fascia using immunofluorescence microscopy and quantitative real-time polymerase chain reaction (qPCR).We found that proliferative cells in the DC nodules were concentrated in the immediate vicinity of small blood vessels and localized predominantly in the myofibroblast layer. Correspondingly, the DC-associated blood vessels contained increased levels of phosphorylated AKT, a hallmark of activated growth factor signaling. When studying the expression of potential activators of AKT signaling we found that the expression of bFGF was confined to the endothelium of the small blood vessels, IGF-2 was present uniformly in the DC tissue and CTGF was expressed in the DC-associated sweat gland acini. In addition, the blood vessels in DC nodules contained increased amounts of laminins 511 and 521, which have been previously shown to promote the proliferation and stem cell properties of different cell types. ### Long_Answer: Based on our findings, we propose that in the DC-associated small blood vessels the presence of growth factors in combination with favorable extracellular matrix composition provide a supportive environment for sustained proliferation of myofibroblasts and thus the blood vessels play an important role in DC pathogenesis. ### Final_Prediction: yes

### Question: Is one patient out of four with newly diagnosed erectile dysfunction a young man -- worrisome picture from the everyday clinical practice? ### Context: Erectile dysfunction (ED) is a common complaint in men over 40 years of age, and prevalence rates increase throughout the aging period. Prevalence and risk factors of ED among young men have been scantly analyzed.Assessing sociodemographic and clinical characteristics of young men (defined as ≤ 40 years) seeking first medical help for new onset ED as their primary sexual disorder.Complete sociodemographic and clinical data from 439 consecutive patients were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). Patients completed the International Index of Erectile Function (IIEF).Descriptive statistics tested sociodemographic and clinical differences between ED patients ≤ 40 years and >40 years.New onset ED as the primary disorder was found in 114 (26%) men ≤ 40 years (mean [standard deviation [SD]] age: 32.4 [6.0]; range: 17-40 years). Patients ≤ 40 years had a lower rate of comorbid conditions (CCI = 0 in 90.4% vs. 58.3%; χ(2) , 39.12; P < 0.001), a lower mean body mass index value (P = 0.005), and a higher mean circulating total testosterone level (P = 0.005) as compared with those >40 years. Younger ED patients more frequently showed habit of cigarette smoking and use of illicit drug, as compared with older men (all P ≤ 0.02). Premature ejaculation was more comorbid in younger men, whereas Peyronie's disease was prevalent in the older group (all P = 0.03). At IIEF, severe ED rates were found in 48.8% younger men and 40% older men, respectively (P > 0.05). Similarly, rates of mild, mild-to-moderate, and moderate ED were not significantly different between the two groups. ### Long_Answer: This exploratory analysis showed that one in four patients seeking first medical help for new onset ED was younger than 40 years. Almost half of the young men suffered from severe ED, with comparable rates in older patients. Overall, younger men differed from older individuals in terms of both clinical and sociodemographic parameters. ### Final_Prediction: yes

### Question: Does oral delivery of IL-27 recombinant bacteria attenuate immune colitis in mice? ### Context: Treatment of inflammatory bowel disease would benefit from specific targeting of therapeutics to the intestine. We developed a strategy for localized delivery of the immunosuppressive cytokine interleukin (IL)-27, which is synthesized actively in situ by the food-grade bacterium Lactococcus lactis (LL-IL-27), and tested its ability to reduce colitis in mice.The 2 genes encoding mouse IL-27 were synthesized with optimal codon use for L lactis and joined with a linker; a signal sequence was added to allow for product secretion. The construct was introduced into L lactis. Colitis was induced via transfer of CD4(+)CD45RB(hi) T cells into Rag(-/-) mice to induce colitis; 7.5 weeks later, LL-IL-27 was administered to mice via gavage. Intestinal tissues were collected and analyzed.LL-IL-27 administration protected mice from T-cell transfer-induced enterocolitis and death. LL-IL-27 reduced disease activity scores, pathology features of large and small bowel, and levels of inflammatory cytokines in colonic tissue. LL-IL-27 also reduced the numbers of CD4(+) and IL-17(+) T cells in gut-associated lymphoid tissue. The effects of LL-IL-27 required production of IL-10 by the transferred T cells. LL-IL-27 was more effective than either LL-IL-10 or systemic administration of recombinant IL-27 in reducing colitis in mice. LL-IL-27 also reduced colitis in mice after administration of dextran sodium sulfate. ### Long_Answer: LL-IL-27 reduces colitis in mice by increasing the production of IL-10. Mucosal delivery of LL-IL-27 could be a more effective and safer therapy for inflammatory bowel disease. ### Final_Prediction: yes

### Question: Does oral sorbent AST-120 increase renal NO synthesis in uremic rats? ### Context: The urine level of nitric oxide (NO) metabolites, i.e., nitrates/nitrites (NOx), in chronic renal failure (CRF) is decreased because of reduced renal synthesis of NO. We determined whether the administration of an oral sorbent, AST-120, increases the urine level of NOx and the renal expression of nitric oxide synthase (NOS) isoforms in CRF rats.Chronic renal failure rats were produced by 4/5 nephrectomy. Rats were randomized into two groups: CRF control rats, and AST-120-treated CRF rats. The AST-120 was administered to the rats at a dose of 4 g/kg with powder chow for 16 weeks, whereas powder chow alone was administered to control rats. The urine levels of NOx were measured by using a NOx colorimetric assay kit. The expression of endothelial NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS) in the kidney was determined by immunohistochemistry. Serum and urine levels of indoxyl sulfate were determined by high-performance liquid chromatography.Urine levels of NOx and the expression of glomerular eNOS and tubulointerstitial nNOS were significantly decreased in CRF rats compared with normal rats. The administration of AST-120 to CRF rats significantly increased urine levels of NOx and the expression of glomerular eNOS and tubulointerstitial nNOS. The administration of AST-120 to CRF rats significantly decreased urine and serum levels of indoxyl sulfate. ### Long_Answer: The oral sorbent AST-120 increases NO synthesis in the kidneys of uremic rats by increasing the renal expression of eNOS and nNOS, through alleviation of indoxyl sulfate overload on the kidney. ### Final_Prediction: yes

### Question: Are stunted young Indonesian children more likely to be overweight, thin, or have high blood pressure in adolescence? ### Context: To determine whether stunted young children are at greater risk of (1) overweight/obesity or thinness, and (2) high blood pressure (HBP) in adolescence.A secondary data analysis using the Indonesian Family Life Survey waves 1 (1993) to 4 (2007). We generated a 14-year follow-up cohort (1993-2007) and two 7-year cohorts (1993-2000 and 2000-2007) of children aged 2.0-4.9 years. Stunting (HAZ < -2), thinness (BMIZ < -2), and overweight/obesity (BMIZ > +1) were determined based upon the WHO Child Growth Standards. HBP (>90th percentile) was interpreted using the 4th Report on the Diagnosis of HBP in Children and Adolescents.765, 1083, and 1589 children were included in the 14-year cohort, and the two 7-year cohort analyses, respectively. In the 7-year cohorts, early life stunting was inversely associated with overweight/obesity (prevalence ratio 0.32 and 0.38, respectively; P < 0.05), but no significant association was found with the 14-year cohort. There was no significant association between childhood stunting and thinness at adolescence or in the odds/likelihood of having high systolic or diastolic blood pressure. ### Long_Answer: We found no association between early life stunting and overweight/obesity, thinness and HBP in adolescence. ### Final_Prediction: nan

### Question: Multiple, simultaneous trauma patients: Are they worse off? ### Context: The simultaneous management of multiple severely injured patients has the potential to overwhelm trauma center resources. We hypothesize that trauma patients presenting in clusters of two or more patients within a short time period have worse outcomes.From the registry at our urban Level I trauma center, we reviewed 4,619 "major" trauma patients admitted during a span of 5.5 years (January 1998 through June 2003). A multidisciplinary team led by an in-house trauma surgery attending evaluated all patients. Pairs of two patients presenting less than 10 minutes apart (PAIRS) and clusters of three patients presenting within 30 minutes (CLUSTERS) were compared with patients arriving alone presenting over 4 hours apart (ALONE) and to other patients that did not meet any of the above criteria (OTHER). Multivariate regression was performed to determine differences in likelihood of direct operating room admissions, hospital, and intensive care unit (ICU) length of stay, and mortality.PAIRS made up 8.9% (413) and CLUSTERS made up 2.7% (126) of patients; 42% (1,939) arrived ALONE; 48.3% (2,229) of patients were classified as OTHER. Multivariate regression showed no significant differences in ICU or hospital length of stay, or mortality for PAIRS or CLUSTERS compared with patients presenting ALONE. PAIR and CLUSTER patients were more likely to undergo immediate surgery than the ALONE group (odds ratio 1.37, 95% confidence interval 1.03-1.83 and 1.61, 95% CI 1.00-2.58, respectively). ### Long_Answer: When PAIRS or CLUSTERS of seriously injured patients arrive in close time proximity, they are more likely to be directly admitted to the operating room than patients arriving ALONE. This difference in management does not appear to affect patient outcomes. ### Final_Prediction: nan

### Question: Are red-blood-cell to plasma ratios transfused during massive transfusion associated with mortality in severe multiple injury : a retrospective analysis from the Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie? ### Context: To test whether an acute transfusion practice of packed red blood cells (pRBC) : fresh-frozen plasma (FFP) 1 : 1 would be associated with reduced mortality in acute bleeding multiply injury.Retrospective analysis using the TR-DGU database (Trauma Registry of the Deutsche Gesellschaft für Unfallchirurgie 2002-2006) on primary admissions with substantial injury (Injury Severity Score > 16) and massive transfusion (> 10 pRBCs). Seven hundred thirteen patients were divided into three groups according to the pRBC : FFP ratio transfused, that is, (i) pRBC : FFP > 1.1; (ii) pRBC : FFP 0.9-1.1 (1 : 1); and (iii) pRBC : FFP < 0.9, and mortality rates were compared.Four hundred ninety-seven (69.7%) of patients were male, the mean age was 40.1 (+/- 18.3) years. Injury characteristics and pathophysiological state upon emergency room arrival were comparable between groups. Out of 713, 484 patients had undergone massive transfusion with pRBC : FFP > 1.1, 114 with pRBC : FFP 0.9-1.1 (1 : 1), and 115 with pRBC : FFP < 0.9 ratios. Acute mortality (< 6 h) rates for pRBC : FFP > 1.1, pRBC : FFP 0.9-1.1 (1 : 1), and pRBC : FFP < 0.9 ratios were 24.6, 9.6 and 3.5% (P < 0.0001), 24-h mortality rates were 32.6, 16.7 and 11.3% (P < 0.0001), and 30-day mortality rates were 45.5, 35.1 and 24.3% (P < 0.001). The frequency for septic complications and organ failure was higher in the pRBC : FFP 0.9-1.1 (1 : 1) group, ventilator days and length of stays for intensive care unit and overall in-hospital were highest in the pRBC : FFP < 0.9 ratio group (P < 0.0005). ### Long_Answer: An association between pRBC : FFP transfusion ratios and mortality to favour early aggressive FFP administration was observed. Further investigation is necessary prior to recommending routine 1 : 1 or more aggressive FFP use in exsanguinating patients. ### Final_Prediction: yes

### Question: Do parameters used to clear noncritically injured polytrauma patients for extremity surgery predict complications? ### Context: In multiply injured patients, definitive stabilization of major fractures is performed whenever feasible, depending on the clinical condition.QUESTIONS/We therefore asked whether (1) any preoperative indicators predict major complications after major extremity surgery; (2) perioperative routine parameters other than those indicative of hemorrhagic shock predict postoperative complications; and (3) any postoperative clinical findings can predict major complications in the further course of the patient.We prospectively followed patients with femoral midshaft fracture, Injury Severity Score (ISS)>16 points, or three fractures and Abbreviated Injury Scale (AIS) ≥ 2 points and another injury (AIS ≥ 2 points), and age 18 to 65 years. We recorded multiple clinical parameters. End points were pneumonia, sepsis, acute respiratory distress syndrome, acute lung injury, and multiple organ failure.Forty-three of 165 patients developed complications. (1) Patients with complications had a decreased initial Glasgow Coma Scale and tended to have a lower ISS. (2) None of the assessed perioperative parameters was able to sufficiently predict postoperative complications. (3) The presence of a lung contusion and ventilation>48 hours were associated with complications in the further course. ### Long_Answer: In stable multiply injured patients, none of the individual routine clinical parameters was able to predict complications. Severe head and thoracic injuries seem to be important drivers for the development postoperative complications. ### Final_Prediction: nan

### Question: Does the novel PARP inhibitor 5-aminoisoquinolinone reduce the liver injury caused by ischemia and reperfusion in the rat? ### Context: This study was designed to investigate the effects of 5-aminoisoquinolinone (5-AIQ), a water-soluble potent inhibitor of poly-(ADP-ribose) polymerase (PARP) in a rat model of liver ischemia-reperfusion injury.Male Wistar rats were anesthetised with sodium pentobarbital (60 mg/kg, i.p.) and subjected to liver ischemia (for 30 minutes) and reperfusion (for 2 hours). Liver injury was assessed by measuring (i). the serum levels of transaminases, lactate dehydrogenase, gamma-glutamyl transferase, (ii). lipid peroxidation in liver tissue and (iii). by immunohistochemistry for PARP and intracellular adhesion molecule 1 (ICAM-1).Pre-treatment of rats (five minutes prior to onset of liver ischemia) with the PARP inhibitor 5-AIQ (3 mg/kg, i.v.) rather than vehicle reduced the rise in the serum levels of transaminases, lactate dehydrogenase, and gamma-glutamyl transferase as well as the degree of lipid peroxidation (measured as levels of malondialdehyde in the liver) caused by ischemia-reperfusion of the liver. Liver sections obtained from 5-AIQ treated rats showed reduced PARP activation and less staining for ICAM-1. ### Long_Answer: Taken together, these results show that 5-AIQ, a new water-soluble potent inhibitor of poly-(ADP-ribose) polymerase, reduces the tissue injury associated with ischemia-reperfusion of the liver. We propose that 5-AIQ may be useful in the therapy conditions associated with ischemia-reperfusion of the liver which remains an important clinical problem during shock, liver surgery, and liver transplantation. ### Final_Prediction: yes

### Question: Does this patient need to be evaluated today? ### Context: Physicians and nurses often make judgments about the urgency with which patients require evaluation, yet few explicit process-of-care criteria are available to guide these decisions. Using a multidisciplinary expert physician panel and explicit, quantitative group judgment methods, standardized, clinically detailed deferred care criteria were developed to guide emergency department and ambulatory care triage decisions for same-day versus deferred care for patients with respiratory infection symptoms.Using a modified Delphi process, an eight-member multidisciplinary expert physician panel rated the safety of deferred care for standardized clinical scenarios. The ratings were converted into explicit criteria and then compared with usual implicit judgment in terms of nurse triage times.The panel achieved 100% consensus on 36 critical clinical factors, each of which precludes deferring care for a patient with respiratory infection symptoms. Based on combinations of 12 additional clinical factors, 48 clinical scenarios were created that the panel rated for deferred care safety. Panelists' ratings agreed for 90% of clinical scenarios. These were formatted into screening criteria. Near-perfect interrater agreement (kappa = 0.9) was found in reproducibility testing. The difference in mean nurse triage times using the criteria compared with implicit nurse judgment was 0.4 minutes (95% confidence interval = -2.1 to 2.9 minutes). ### Long_Answer: Application of explicit criteria for deferring care of patients with respiratory infection symptoms did not lengthen triage time. This approach may facilitate more efficient resource management for ambulatory settings. However, widespread use before these criteria's, our systematic criteria-based triage should be validated in multicenter clinical trials against an outcome standard and the more common implicit approach. ### Final_Prediction: nan

### Question: Does kATP channel closure ameliorate the impaired insulinotropic effect of glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes? ### Context: The reduced incretin effect in subjects with type 2 diabetes is accompanied by a severely impaired insulinotropic effect of the incretin hormone glucose-dependent insulinotropic polypeptide (GIP). The K(ATP) channels of the beta-cell appear to be essential for the function of GIP in mice, and mutations in the gene encoding these channels have been linked to the development of type 2 diabetes. With this study we therefore aimed at clarifying the role of K(ATP) channel malfunction in the impaired function of GIP.We examined 12 subjects with type 2 diabetes using a 2-h (15 mM) hyperglycemic clamp on 4 separate days with concomitant infusion of one of the following: GIP; GIP + 10 mg sulfonylurea (SU, glipizide) taken orally 1 h before the clamp; saline + 10 mg SU; or saline alone. Blood was sampled to measure plasma concentrations of glucose, intact GIP, insulin, C-peptide, and glucagon.Compared to the results of GIP alone, SU alone, or those results added together, coadministration of GIP and SU resulted in a more-than-additive increase in the peripheral insulin (P = 0.002) and C-peptide (P = 0.028) responses and furthermore, a more-than-additive increase in total (P = 0.01), early (P = 0.02), and late-phase (P = 0.02) insulin secretion. ### Long_Answer: We have demonstrated that inhibiting the K(ATP) channels of the diabetic beta-cell acutely using SU significantly increases both the peripheral insulin response to GIP and GIP-induced insulin secretion, indicating an ameliorated insulinotropic effect of GIP. ### Final_Prediction: yes

### Question: Are high EGFR protein expression and exon 9 PIK3CA mutations independent prognostic factors in triple negative breast cancers? ### Context: Triple negative breast cancers (TNBC) are a more aggressive subset of breast cancer. A better understanding of its biology could allow the rational development of targeted therapies.We extensively analyzed the EGFR/PI3K/PTEN axis in a large, homogeneous population of TNBC to help defining the putative role of anti-EGFR and -PI3K targeted therapies in this setting. EGFR gene amplification, EGFR protein expression, PIK3CA and PTEN gene alterations (two members of EGFR downstream pathways) and their clinicopathological and prognostic implications were analyzed in 204 TNBC samples from European patients.EGFR amplification was detected in 18 of the 204 TNBC specimens (8.9 %) and was significantly associated with higher EGFR protein levels. Fourteen PIK3CA mutations were identified in exon 9 (6.7 %), and 17 in exon 20 (8.3 %). PIK3CA mutations, especially in exon 9, were significantly associated with grade I-II tumors. PTEN deletions were detected in 43 samples (21.50 %) and were significantly associated with grade III tumors (p < 0.001). Univariate analysis showed a significant association between relapse-free survival (RFS), T and N stage and exon 9 PIK3CA mutations. Overall survival was significantly associated with T stage, N stage and adjuvant chemotherapy, which was administered to 70.3 % of patients. In multivariate analyses, T stage, N stage, presence of exon 9 PIK3CA mutations and high EGFR protein level were independent poor prognostic factors for RFS, while adjuvant chemotherapy was associated with a better outcome. ### Long_Answer: High EGFR protein expression and exon 9 PIK3CA activating mutations are independent prognostic factors in TNBC. The efficacy of anti-PI3K targeted therapies needs to be evaluated in this setting. ### Final_Prediction: yes

### Question: Does glucose-regulated protein 78 ( Grp78 ) confer chemoresistance to tumor endothelial cells under acidic stress? ### Context: This study was designed to investigate the activation of the unfolded protein response (UPR) in tumor associated endothelial cells (TECs) and its association with chemoresistance during acidic pH stress.Endothelial cells from human oral squamous cell carcinomas (OSCC) were excised by laser capture microdissection (LCM) followed by analysis of UPR markers (Grp78, ATF4 and CHOP) using quantitative PCR. Grp78 expression was also determined by immunostaining. Acidic stress was induced in primary human dermal microvascular endothelial cells (HDMECs) by treatment with conditioned medium (CM) from tumor cells grown under hypoxic conditions or by adjusting medium pH to 6.4 or 7.0 using lactic acid or hydrochloric acid (HCl). HDMEC resistance to the anti-angiogenic drug Sunitinib was assessed with SRB assay.UPR markers, Grp78, ATF4 and CHOP were significantly upregulated in TECs from OSCC compared to HDMECs. HDMECs cultured in acidic CM (pH 6.0-6.4) showed increased expression of the UPR markers. However, severe acidosis led to marked cell death in HDMECs. Alternatively, HDMECs were able to adapt when exposed to chronic acidosis at pH 7.0 for 7 days, with concomittant increase in Grp78 expression. Chronic acidosis also confers drug resistance to HDMECs against Sunitinib. Knockdown of Grp78 using shRNA resensitizes HDMECs to drug treatment. ### Long_Answer: UPR induction in ECs under acidic pH conditions is related to chemoresistance and may contribute to therapeutic failures in response to chemotherapy. Targeting Grp78, the key component of the UPR pathway, may provide a promising approach to overcome ECs resistance in cancer therapy. ### Final_Prediction: yes

### Question: Is inflammation-based prognostic score a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma? ### Context: Recent studies have revealed that the Glasgow prognostic score (GPS), an inflammation-based prognostic score, is useful for predicting outcome in a variety of cancers. This study sought to investigate the significance of GPS for prognostication of patients who underwent surgery with extrahepatic cholangiocarcinoma.We retrospectively analyzed a total of 62 patients who underwent resection for extrahepatic cholangiocarcinoma. We calculated the GPS as follows: patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a score of 2; patients with one or none of these abnormalities were allocated a s ore of 1 or 0, respectively. Prognostic significance was analyzed by the log-rank test and a Cox proportional hazards model.Overall survival rate was 25.5 % at 5 years for all 62 patients. Venous invasion (p = 0.01), pathological primary tumor category (p = 0.013), lymph node metastasis category (p < 0.001), TNM stage (p < 0.001), and GPS (p = 0.008) were significantly associated with survival by univariate analysis. A Cox model demonstrated that increased GPS was an independent predictive factor with poor prognosis. ### Long_Answer: The preoperative GPS is a useful predictor of postoperative outcome in patients with extrahepatic cholangiocarcinoma. ### Final_Prediction: yes

### Question: Does [ The analysis of the test result in HIV screening laboratory of Beijing Friendship Hospital in 2008 ]? ### Context: According to test results of the Hospital of AIDS screening laboratory in 2008, after counting analysis to assess the prevalence of AIDS, we can early detect positive cases in the future and effectively control the spread of AIDS.All serum samples were screened by ELISA method and we reexaminated the samples by PA. As long as one result is positive by the two methods, then we sent the positive samples to Beijing Center for Disease Control and Prevention by Western Blot method to confirm the result.A total of 21 467 samples were detected and 29 (13.5% 0) were positive screening results. We confirm there were 7 (24.1%) positive samples and 12 (41.4%) suspected samples. We researched the epidemiology of the specimens by its source and age and sex. ### Long_Answer: Application of ELISA method for HIV screening test has a practical significance, it is accurate and fit to record the results of the screening test for AIDS. ### Final_Prediction: yes

### Question: Does the direction of pedicle screw rotation affect the biomechanics of direct transverse plane vertebral derotation? ### Context: In vitro biomechanical investigation using human cadaveric vertebrae.Evaluate the biomechanical differences in transverse plane vertebral body derotation maneuvers of thoracic pedicle screws in both medial and lateral directions.Thoracic pedicle screws are thought to have better vertebral rotation control and better segmental scoliosis correction compared to hooks and wires. Little data exists regarding the biomechanical stability of pedicle screws when derotated in either medial or lateral directions.Vertebral bodies (T4-L5) from 12 cadavers were instrumented with appropriate length pedicle screws while measuring insertion torque. Each body was anchored for independent loading in medial or lateral directions. Each screw was rotated around a rod using a constant length lever arm (30.5 cm) rigidly attached to the screw head simulating the posterior vertebral derotation maneuver. Yield torques (Nm) were analyzed using a one-way analysis of variance (P<0.05).Yield torques for both directions were significantly related to screw insertion torque (both P<0.01). There were no statistical differences in yield torque between medial (12.0 +/- 4.9 Nm) or lateral (11.5 +/- 5.1 Nm) directions. There were no significant differences after normalization for insertion torque or screw length. Tests rotating the screw tip laterally demonstrated structural failure in the following percentages (anterolateral failure = 67%, posterior element failure = 33%, additional screw bending = 42%). Rotation medially demonstrated structural failures in the following percentages (canal penetration = 51%, posterior element failure = 49%, additional screw bending = 44%). ### Long_Answer: From these data, a surgeon performing a direct vertebral derotation using a 30 cm (12 in) lever would need to apply roughly 40 N (9 lbs) to causeanatomic failure. Adolescent patients would likely tolerate a greater force without bone failure given a greater bone density, yet, extreme caution is still recommended to prevent screw rotation either medially into the spinal canal or laterally into the chest. ### Final_Prediction: nan

### Question: Does clear cell renal cell carcinoma induce fibroblast-mediated production of stromal periostin? ### Context: Increase in periostin (PN) was reported in clear cell renal cell carcinoma (ccRCC). But how PN contributes to ccRCC pathogenesis remains unclear. This research will investigate the underlying mechanism.The PN protein in 37 adjacent non-tumour kidney (ANK) tissues, their respective ccRCCs, 16 cases of metastasised ccRCC and xenograft tumours was analysed by immunohistochemistry. PN expression in ccRCC cells and NIH3T3 fibroblasts was examined by real time PCR (polymerase chain reaction) and western blot.PN was detected at low levels in the tubular epithelial cells of ANKs. PN was robustly increased in the ccRCC-associated stroma of both organ-confined and metastasised ccRCCs. Furthermore, despite A498 ccRCC cells and their-derived xenograft tumour cells expressing a low level of PN, a strong presence of stromal PN was observed especially in the boundary region between xenograft tumour mass and non-tumour tissue. Collectively, these results suggest that the ccRCC-associated PN was derived from stroma instead of tumours. This notion was supported by the co-existence of PN with α-smooth muscle actin (αSMA), a marker of activated fibroblasts, in both local and metastasised ccRCC. Furthermore, co-culture of NIH3T3 mouse fibroblasts with either human A498 or 786-0 ccRCC cells dramatically enhanced PN transcription only in NIH3T3 cells as well as NIH3T3 cell-mediated accumulation of extracellular PN. In return, extracellular PN significantly enhanced A498 cell attachment. Elevation of PN promotes NIH3T3 cell proliferation and enhanced AKT activation. ### Long_Answer: ccRCC induces fibroblast-mediated accumulation of stromal PN; stromal PN enhances ccRCC cell attachment and fibroblast proliferation. ### Final_Prediction: yes

### Question: Do rat multipotent mesenchymal stromal cells lack long-distance tropism to 3 different rat glioma models? ### Context: Viral gene therapy of malignant brain tumors has been restricted by the limited vector distribution within the tumors. Multipotent mesenchymal stromal cells (MSCs) and other precursor cells have shown tropism for gliomas, and these cells are currently being explored as potential vehicles for gene delivery in glioma gene therapy.To investigate MSC migration in detail after intratumoral and extratumoral implantation through syngeneic and orthotopic glioma models.Adult rat bone marrow-derived MSCs were transduced to express enhanced green fluorescent protein and implanted either directly into or at a distance from rat gliomas.We found no evidence of long-distance MSC migration through the intact striatum toward syngeneic D74(RG2), N32, and N29 gliomas in the ipsilateral hemisphere or across the corpus callosum to gliomas located in the contralateral hemisphere. After intratumoral injection, MSCs migrated extensively, specifically within N32 gliomas. The MSCs did not proliferate within tumors, suggesting a low risk of malignant transformation of in vivo grafted cell vectors. Using a model for surgical glioma resection, we found that intratumorally grafted MSCs migrate efficiently within glioma remnants after partial surgical resection. ### Long_Answer: The findings point to limitations for the use of MSCs as vectors in glioma gene therapy, although intratumoral MSC implantation provides a dense and tumor-specific vector distribution. ### Final_Prediction: yes

### Question: Does constitutive Activation of DNA Damage Checkpoint Signaling contribute to Mutant p53 Accumulation via Modulation of p53 Ubiquitination? ### Context: Many mutant p53 proteins exhibit an abnormally long half-life and overall increased abundance compared with wild-type p53 in tumors, contributing to mutant p53's gain-of-function oncogenic properties. Here, a novel mechanism is revealed for the maintenance of mutant p53 abundance in cancer that is dependent on DNA damage checkpoint activation. High-level mutant p53 expression in lung cancer cells was associated with preferential p53 monoubiquitination versus polyubiquitination, suggesting a role for the ubiquitin/proteasome system in regulation of mutant p53 abundance in cancer cells. Interestingly, mutant p53 ubiquitination status was regulated by ataxia-telangectasia mutated (ATM) activation and downstream phosphorylation of mutant p53 (serine 15), both in resting and in genotoxin-treated lung cancer cells. Specifically, either inhibition of ATM with caffeine or mutation of p53 (serine 15 to alanine) restored MDM2-dependent polyubiquitination of otherwise monoubiquitinated mutant p53. Caffeine treatment rescued MDM2-dependent proteasome degradation of mutant p53 in cells exhibiting active DNA damage signaling, and ATM knockdown phenocopied the caffeine effect. Importantly, in cells analyzed individually by flow cytometry, p53 levels were highest in cells exhibiting the greatest levels of DNA damage response, and interference with DNA damage signaling preferentially decreased the relative percentage of cells in a population with the highest levels of mutant p53. These data demonstrate that active DNA damage signaling contributes to high levels of mutant p53 via modulation of ubiquitin/proteasome activity toward p53. ### Long_Answer: The ability of DNA damage checkpoint signaling to mediate accumulation of mutant p53 suggests that targeting this signaling pathway may provide therapeutic gain. Mol Cancer Res; 14(5); 423-36. ©2016 AACR. ### Final_Prediction: yes

### Question: Is time between the first day of chemotherapy and the last day of chest radiation the most important predictor of survival in limited-disease small-cell lung cancer? ### Context: To identify time factors for combined chemotherapy and radiotherapy predictive for long-term survival of patients with limited-disease small-cell lung cancer (LD-SCLC).A systematic overview identified suitable phase III trials. Using meta-analysis methodology to compare results within trials, the influence of the timing of chest radiation and the start of any treatment until the end of radiotherapy (SER) on local tumor control, survival, and esophagitis was analyzed. For comparison between studies, the equivalent radiation dose in 2-Gy fractions, corrected for the overall treatment time of chest radiotherapy, was analyzed.The SER was the most important predictor of outcome. There was a significantly higher 5-year survival rate in the shorter SER arms (relative risk [RR] = 0.62; 95% CI, 0.49 to 0.80; P = .0003), which was more than 20% when the SER was less than 30 days (upper bound of 95% CI, 90 days). A low SER was associated with a higher incidence of severe esophagitis (RR = 0.55; 95% CI, 0.42 to 073; P < .0001). Each week of extension of the SER beyond that of the study arm with the shortest SER resulted in an overall absolute decrease in the 5-year survival rate of 1.83% +/- 0.18% (95% CI). ### Long_Answer: A low time between the first day of chemotherapy and the last day of chest radiotherapy is associated with improved survival in LD-SCLC patients. The novel parameter SER, which takes into account accelerated proliferation of tumor clonogens during both radiotherapy and chemotherapy, may facilitate a more rational design of combined-modality treatment in rapidly proliferating tumors. ### Final_Prediction: yes

### Question: Does topical administration of orbital fat-derived stem cells promote corneal tissue regeneration? ### Context: Topical administration of eye drops is the major route for drug delivery to the cornea. Orbital fat-derived stem cells (OFSCs) possess an in vitro corneal epithelial differentiation capacity. Both the safety and immunomodulatory ability of systemic OFSC transplantation were demonstrated in our previous work. In this study, we investigated the safety, therapeutic effect, and mechanism(s) of topical OFSC administration in an extensive alkali-induced corneal wound.Corneal injury was created by contact of a piece of 0.5 N NaOH-containing filter paper on the corneal surface of a male Balb/c mouse for 30 s. The area of the filter paper covered the central 70% or 100% of the corneal surface. OFSCs (2 × 10(5)) in 5 μl phosphate-buffered saline (PBS) were given by topical administration (T) twice a day or by two intralimbal (IL) injections in the right cornea, while 5 μl of PBS in the left cornea served as the control.Topical OFSCs promoted corneal re-epithelialization of both the limbal-sparing and limbal-involved corneal wounds. In the first three days, topical OFSCs significantly reduced alkali-induced corneal edema and stromal infiltration according to a histopathological examination. Immunohistochemistry and immunofluorescence staining revealed that transplanted cells were easily detectable in the corneal epithelium, limbal epithelium and stroma, but only some of transplanted cells at the limbal epithelium had differentiated into cytokeratin 3-expressing cells. OFSCs did not alter neutrophil (Ly6G) levels in the cornea, but significantly reduced macrophage (CD68) infiltration and inducible nitrous oxide synthetase (iNOS) production during acute corneal injury as quantified by a Western blot analysis. Continuous topical administration of OFSCs for seven days improved corneal transparency, and this was accompanied by diffuse stromal engraftment of transplanted cells and differentiation into p63-expressing cells at the limbal area. The therapeutic effect of the topical administration of OFSCs was superior to that of the IL injection. OFSCs from the IL injection clustered in the limbal area and central corneal epithelium, which was associated with a persistent corneal haze. ### Long_Answer: Topical OFSC administration is a simple, non-surgical route for stem cell delivery to promote corneal tissue regeneration through ameliorating acute inflammation and corneal epithelial differentiation. The limbal area serves as a niche for OFSCs differentiating into corneal epithelial cells in the first week, while the stroma is a potential site for anti-inflammation of OFSCs. Inhibition of corneal inflammation is related to corneal transparency. ### Final_Prediction: yes

### Question: Is sPARC expression in CML associated to imatinib treatment and to inhibition of leukemia cell proliferation? ### Context: SPARC is a matricellular glycoprotein with growth-inhibitory and antiangiogenic activity in some cell types. The study of this protein in hematopoietic malignancies led to conflicting reports about its role as a tumor suppressor or promoter, depending on its different functions in the tumor microenvironment. In this study we investigated the variations in SPARC production by peripheral blood cells from chronic myeloid leukemia (CML) patients at diagnosis and after treatment and we identified the subpopulation of cells that are the prevalent source of SPARC.We evaluated SPARC expression using real-time PCR and western blotting. SPARC serum levels were detected by ELISA assay. Finally we analyzed the interaction between exogenous SPARC and imatinib (IM), in vitro, using ATP-lite and cell cycle analysis.Our study shows that the CML cells of patients at diagnosis have a low mRNA and protein expression of SPARC. Low serum levels of this protein are also recorded in CML patients at diagnosis. However, after IM treatment we observed an increase of SPARC mRNA, protein, and serum level in the peripheral blood of these patients that had already started at 3 months and was maintained for at least the 18 months of observation. This SPARC increase was predominantly due to monocyte production. In addition, exogenous SPARC protein reduced the growth of K562 cell line and synergized in vitro with IM by inhibiting cell cycle progression from G1 to S phase. ### Long_Answer: Our results suggest that low endogenous SPARC expression is a constant feature of BCR/ABL positive cells and that IM treatment induces SPARC overproduction by normal cells. This exogenous SPARC may inhibit CML cell proliferation and may synergize with IM activity against CML. ### Final_Prediction: yes

### Question: Is optimal angiotensin-converting enzyme inhibitor dosing neglected in elderly patients with heart failure? ### Context: The benefit of angiotensin-converting enzyme (ACE) inhibitors on mortality in heart failure has been proved in randomized controlled trials.We prospectively evaluated the prescribing of ACE inhibitors and the prescribing of target ACE inhibitor doses in 43 ambulatory patients with heart failure to identify differences in ACE inhibitor utilization among elderly and nonelderly patients. The prescribed ACE inhibitor dose and other variables were assessed by direct patient interview and information contained in the medical record. Telephone calls were conducted at 3 months to identify the occurrence of clinical events.Fewer elderly patients were prescribed target ACE inhibitor doses compared with nonelderly patients (21.4% vs 68.8%; p = 0.0136). Elderly patients were more likely to experience an event than nonelderly patients (11 vs 4; p = 0.0074). Elderly patients not receiving target ACE inhibitor doses demonstrated a trend toward more events than elderly patients who were at target doses. ### Long_Answer: The data suggest that this group of elderly patients with heart failure who received lower ACE inhibitor doses appeared to be at higher risk for clinical events. ### Final_Prediction: nan

### Question: Is the transcription factor Krüppel homolog 1 linked to hormone mediated social organization in bees? ### Context: Regulation of worker behavior by dominant queens or workers is a hallmark of insect societies, but the underlying molecular mechanisms and their evolutionary conservation are not well understood. Honey bee and bumble bee colonies consist of a single reproductive queen and facultatively sterile workers. The queens' influences on the workers are mediated largely via inhibition of juvenile hormone titers, which affect division of labor in honey bees and worker reproduction in bumble bees. Studies in honey bees identified a transcription factor, Krüppel-homolog 1 (Kr-h1), whose expression in worker brains is significantly downregulated in the presence of a queen or queen pheromone and higher in forager bees, making this gene an ideal candidate for examining the evolutionary conservation of socially regulated pathways in Hymenoptera.In contrast to honey bees, bumble bees foragers do not have higher Kr-h1 levels relative to nurses: in one of three colonies levels were similar in nurses and foragers, and in two colonies levels were higher in nurses. Similarly to honey bees, brain Kr-h1 levels were significantly downregulated in the presence versus absence of a queen. Furthermore, in small queenless groups, Kr-h1 levels were downregulated in subordinate workers with undeveloped ovaries relative to dominant individuals with active ovaries. Brain Kr-h1 levels were upregulated by juvenile hormone treatment relative to a vehicle control. Finally, phylogenetic analysis indicates that KR-H1 orthologs are presence across insect orders. Though this protein is highly conserved between honey bees and bumble bees, there are significant differences between orthologs of insects from different orders. ### Long_Answer: Our results suggest that Kr-h1 is associated with juvenile hormone mediated regulation of reproduction in bumble bees. The expression of this transcription factor is inhibited by the queen and associated with endocrine mediated regulation of social organization in two species of bees. Thus, KR-H1 may transcriptionally regulate a conserved genetic module that is part of a pathway that has been co-opted to function in social behavior, and adjusts the behavior of workers to their social environmental context. ### Final_Prediction: yes

### Question: Does prostate cancer biomarker annexin A3 detected in urines obtained following digital rectal examination present antigenic variability? ### Context: Annexin A3 (ANXA3) is a potential marker for prostate cancer (PCa). We aimed to develop robust immunoassays suitable for quantifying ANXA3 in urine samples obtained following digital rectal examination (DRE) in order to facilitate the diagnostic performance evaluation of this marker.Anti-ANXA3 monoclonal antibodies were generated and their epitopes mapped. Two different ANXA3 assay prototypes were established on the VIDAS® automated immunoanalyser and analytical validation was carried out using post-DRE urine samples obtained from patients with PCa (n=23) or benign prostate hyperplasia (n=31).The assays had the same capture antibody (TGC44) but different detection antibodies (13A12 or 5C5), recognizing novel distinct epitopes. Both had a lower limit of quantification <1ng/mL and were highly specific for ANXA3, not cross-reacting with other annexins. Interassay imprecision was ≤11% and ≤15% for 13A12 and 5C5 assays, respectively. Surprisingly, a total lack of correlation was observed between ANXA3 levels measured by these two assays in post-DRE urines, indicating detection of distinct antigenic variants. Two freeze-thaw cycles did not affect analyte stability in either assay, whereas a lack of stability of antigenic variants was observed when samples were stored at -80°C for 1month. ### Long_Answer: Two different antigenic variants of ANXA3 are present in post-DRE urines and their clinical significance for diagnosis of prostate cancer should be further investigated. These variants are not stable over time in samples preserved at -80°C. Until this issue is resolved, ANXA3 should only be measured in freshly collected samples. ### Final_Prediction: yes

### Question: Does french mothers ' milk deficient in DHA contain phospholipid species of potential interest for infant development? ### Context: An insufficient human milk docosahexaenoic acid (DHA) level was reported worldwide, which leads to the question of the sufficiency of the DHA supply for infant development in the French Mediterranean area. Also, among milk lipids, phospholipids may be of high potential interest for infant brain development, being a specific vector of DHA and providing plasmalogens. We aimed to estimate the consumption of such milk compounds by preterm and term infants.Milk samples from 22 lactating French women living in a port city, Marseille, were collected in a neonatology department from a single full-breast expression using an electric pump. Amounts of triglycerides, total phospholipids and plasmalogens, and fatty acid profile were determined by gas chromatography, and cholesterol by enzymatic assay.Depending on the infant dietary guidelines we referred to, 46% or 82% of milk samples were below the recommended DHA level (0.4% or 0.7%), and a majority exhibited high linoleic acid/α-linolenic acid and n-6/n-3 ratios, probably resulting from high linoleic acid together with low fish and seafood products consumption. DHA carried by phospholipids in a majority of specimens met the requirements for brain development for term but not for premature infants. Milk plasmalogen levels ranged from 3.4 to 39.2  mg/L. ### Long_Answer: Our results support the recommendation of DHA supplementation to French mothers living in a Mediterranean port city, and of decreased linoleic acid intake, to reach optimal milk composition for infant health. DHA-containing phospholipids including plasmalogen species may represent important bioactive human milk compounds. ### Final_Prediction: yes

### Question: Does treatment of AG129 mice with antisense morpholino oligomers increase survival time following challenge with dengue 2 virus? ### Context: To determine the antiviral activity of phosphorodiamidate morpholino oligomers (PMO) and peptide-conjugated PMO (PPMO) in AG129 mice infected with dengue 2 virus (DENV-2).Antisense PMO and PPMO were designed against the 5' terminal region (5'SL) or the 3'-cyclization sequence region (3'CS) of DENV genomic RNA and administered to AG129 mice before and/or after infection with DENV-2. In addition, cell culture evaluations designed to determine optimum PPMO length, and pharmacokinetic and toxicity analysis of PPMO were also carried out.Mock-treated AG129 mice lived for 9-17 days following intraperitoneal (ip) infection with 10(4)-10(6) pfu of DENV-2 (strain New Guinea C). Intraperitoneal administration of 5'SL or 3'CS PPMO before and after DENV infection produced an increase in the average survival time of up to 8 days. Animals receiving only post-infection PPMO treatment did not benefit significantly. Cell culture studies showed that PPMO of 22-24 bases long produced substantially higher DENV titre reductions than did PPMO that were either shorter or longer. Pharmacokinetic and toxicology analysis with non-infected animals showed that nine consecutive once-daily ip treatments of 10 mg/kg PPMO resulted in high concentrations of PPMO in the liver and caused little impact on overall health. ### Long_Answer: The data indicate that PPMO had considerable antiviral efficacy against DENV-2 in the AG129 mouse model and that PPMO treatment early in the course of an infection was critical to extending the survival times of DENV-2-infected mice in the AG129 model system. ### Final_Prediction: yes

### Question: Is the small leucine rich proteoglycan fibromodulin overexpressed in human prostate epithelial cancer cell lines in culture and human prostate cancer tissue? ### Context: Fibromodulin is a small leucine-rich proteoglycan important for extracellular matrix organization and essential for tissue repair in multiple organs. The main function of this proteoglycan is the regulation of collagen fibrillogenesis; however, more recently described roles for fibromodulin have expanded to include regulation of angiogenesis, reprogramming of human fibroblasts into pluripotent cells, modulation of TGF-β activity, inflammatory processes and association with metastatic phenotypes. Additionally, fibromodulin has been identified as a novel tumor-associated antigen in leukemia, lymphoma, and leiomyoma. Knowledge about its expression in the prostate is limited.Fibromodulin expression was analyzed in two different malignant and one non-tumorigenic prostatic cell lines in culture, and in benign and malignant human prostate tissue. Expression was analyzed by real time PCR, immunocytochemistry, and immunohistochemistry. DNA sequencing was performed on a PCR fragment amplified with primers specific for the FMOD gene from cDNA obtained from the cultured cell lines.Both immunostaining and real time PCR analysis of cell lines indicated that fibromodulin was differentially expressed in the cancerous cell lines compared to the non-tumorigenic cell line. Likewise, cancerous tissue expressed significantly higher levels of intracellular fibromodulin compared to matched, benign tissue from the same patients, as well as compared to tissue from patients with only benign disease. ### Long_Answer: The expression of fibromodulin was higher in prostatic cancer cells (cell-lines and human tissue) than in normal/benign prostatic cells. Additional studies are required to determine the biological and clinical significance and whether this proteoglycan has a role in carcinogenesis of the prostate or in prostate cancer related inflammatory processes. ### Final_Prediction: yes

### Question: Does she1-mediated inhibition of dynein motility along astral microtubules promote polarized spindle movements? ### Context: Cytoplasmic dynein motility along microtubules is critical for diverse cellular processes ranging from vesicular transport to nuclear envelope breakdown to mitotic spindle alignment. In yeast, we have proposed a regulated-offloading model to explain how dynein motility drives microtubule sliding along the cortex, powering transport of the nucleus into the mother-bud neck [1, 2]: the dynein regulator She1 limits dynein offloading by gating the recruitment of dynactin to the astral microtubule plus end, a prerequisite for offloading to the cortex. However, whether She1 subsequently affects cortically anchored dynein activity during microtubule sliding is unclear.Using single-molecule motility assays, we show that She1 strongly inhibits dynein movement along microtubules, acting directly on the motor domain in a manner independent of dynactin. She1 has no effect on the motility of either Kip2, a kinesin that utilizes the same microtubule track as dynein, or human kinesin-1, demonstrating the specificity of She1 for the dynein motor. At single-molecule resolution, She1 binds tightly to and exhibits diffusional behavior along microtubules. Diffusive She1 collides with and pauses motile dynein motors, prolonging their attachment to the microtubule. Furthermore, Aurora B/Ipl1 directly phosphorylates She1, and this modification appears to enhance the diffusive behavior of She1 along microtubules and its potency against dynein. In cells, She1 dampens productive microtubule-cortex interactions specifically in the mother compartment, polarizing spindle movements toward the bud cell. ### Long_Answer: Our data reveal how inhibitory microtubule-associated proteins selectively regulate motor activity to achieve unidirectional nuclear transport and demonstrate a direct link between cell-cycle machinery and dynein pathway activity. ### Final_Prediction: yes

### Question: Does maternal deprivation enhance behavioral vulnerability to stress associated with miR-504 expression in nucleus accumbens of rats? ### Context: In this study, the effect of maternal deprivation (MD) and chronic unpredictable stress (CUS) in inducing depressive behaviors and associated molecular mechanism were investigated in rats.Maternal deprivation was established by separating pups from their mothers for 6 hours daily from postnatal day 1 to day 14. Chronic unpredictable stress was established by water deprivation, elevated open platform, food deprivation, restraint stress and electric foot shock. The depressive behaviors were determined by use of sucrose preference test and forced swim test.Rats in MD/CUS group exhibited lower sucrose preference rate, longer immobility time, and lighter body weights than rats in other groups (MD/control, non-MD/CUS and non-MD/control group). Meanwhile, higher miR-504 expression and lower dopamine receptor D1 (DRD1) and D2 (DRD2) expression were observed in the nucleus accumbens of rats in the MD/CUS group than in the other three groups. MiR-504 expression correlated negatively with DRD1 gene expression and sucrose preference rate in the sucrose preference test, but correlated positively with immobility time in forced swim test. Both DRD2 mRNA and protein expression correlated negatively with immobility time in forced swim test. ### Long_Answer: These results suggest that MD enhances behavioral vulnerability to stress during adulthood, which is associated with the upregulation of miR-504 and downregulation of DRD2 expression in the nucleus accumbens. ### Final_Prediction: yes

### Question: Does losartan affect the substrate for atrial fibrillation maintenance in a rabbit model? ### Context: Atrial fibrosis causes abnormal conduction through the atria, creating a substrate for atrial fibrillation (AF). In a rabbit model, rapid atrial pacing produces significant atrial fibrosis and the substrate for AF maintenance. This atrial remodeling is a potential therapeutic target.To evaluate the effects of the losartan on atrial fibrosis.Thirty rabbit AF models were produced by rapid atrial stimulation. They were randomly divided into three groups: sham group, rapid atrial pacing group, and rapid atrial pacing with losartan group. We performed AF vulnerability studies, atrial histologic, and molecular analyses after 4 weeks.Only rabbits in the rapid atrial pacing group developed sustained AF (30 min, 4of 10 rabbits). Treatment with losartan resulted in a significant reduction in left atrial fibrosis and AF duration (P<.01). real-time polymerase chain reaction analyses demonstrated the drug's effects on the expression of Collagen I, Collagen III, and TGF-β/Smads signaling pathway. ### Long_Answer: The treatment of losartan results in significantly reduced atrial fibrosis and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF. ### Final_Prediction: yes

### Question: Are hypoxic cells critical for the outcome of fractionated radiotherapy in a slow-growing mouse tumor? ### Context: To investigate the significance of hypoxic cells, reoxygenation and repopulation for the outcome of fractionated radiotherapy of a slow-growing subline of a murine fibrosarcoma and to compare the results with those previously obtained from the original fast-growing tumor.A slow-growing subline, 457-O, was obtained among the tumors that recurred after a single irradiation to the third generation isotransplants of a mouse fibrosarcoma, FSa-II. The single cell suspensions were transplanted into the mouse foot and when the tumors reached an average diameter of 4 mm, they were subjected to one to 20 equal daily y-ray doses given in air (A) or under hypoxic conditions (H). The TCD50 (50% tumor control radiation dose) was calculated according to the tumor control frequency within 180 days. The linear-quadratic plus time model was fitted to these data by logistic regression analysis.The volume doubling time of the 457-O tumors was approximately 2.2 times slower than that of the original FSa-II tumors. The TCD50(H) (single dose) was 52.3 Gy and increased with an increasing number of fractions to a TCD50(H) (20 doses) of 90.8 Gy. This increase of 38.5 Gy was much smaller than that of 149 Gy for the original FSa-II. The TCD50(A) (single dose) and TCD50(A) (20 doses) were 41.3 and 50.6 Gy, respectively. This small difference of 9.3 Gy contrasted with a significant increase of 52.9 Gy for the FSa-II.These results suggested no repopulation of 457-O tumor clonogens during the course of up to 20 daily doses, while the original FSa-II tumor cells repopulated substantially. Hypoxic clonogens in the slow-growing tumor reoxygenated but some fractions remained critical. ### Long_Answer: The present data together with those obtained from the fast-growing FSa-II suggested that hypoxic clonogens were critical for the outcome of fractionated radiotherapy. Repopulation was insignificant in this slow-growing tumor during five to 20 daily doses. ### Final_Prediction: nan

### Question: Does perception of improvement in patients with rheumatoid arthritis vary with disease activity levels at baseline? ### Context: To analyze the minimum clinically important improvement (MCII) of disease activity measures in rheumatoid arthritis (RA) using patient-derived anchors, and to assess whether criteria for improvement differ with baseline disease activity.We used data from a Norwegian observational database comprising 1,050 patients (73% women, 65% rheumatoid factor-positive, mean duration of RA 7.7 years). At 3 months after initiation of therapy, patients indicated whether their condition had improved, had considerably improved, was unchanged, had worsened, or had considerably worsened. We used receiver operating characteristic curve analysis to determine the MCII for the Disease Activity Score based on the assessment of 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI), and analyzed the effects of different levels of baseline disease activity on the MCII.On average, patients started with high disease activity and improved significantly during treatment (American College of Rheumatology 20%, 50%, and 70% improvement criteria responses were 37%, 17%, and 5%, respectively). The overall mean (95% confidence interval [95% CI]) thresholds for MCII after 3 months for the DAS28, SDAI, and CDAI were 1.20 (95% CI 1.18-1.22), 10.95 (95% CI 10.69-11.20), and 10.76 (95% CI 10.49-11.04), respectively, and the mean (95% CI) thresholds for major responses were 1.82 (95% CI 1.80-1.83), 15.82 (95% CI 15.65-16.00), and 15.00 (95% CI 14.82-15.18), respectively. With increasing disease activity, much higher changes in disease activity were needed to achieve MCII according to patient judgment. ### Long_Answer: The perception of improvement of disease activity of patients with RA is considerably different depending on the disease activity level at which they start. ### Final_Prediction: yes

### Question: Does statin therapy help to control blood pressure levels in hypertensive dyslipidemic patients? ### Context: Aside from lowering lipid levels; statins improve endothelial function, decrease platelet aggregation, reduce procoagulant blood factors, and decrease vascular tone. This study was conducted to investigate the possible effect of atorvastatin on blood pressure (BP) in a group of hypertensive and dyslipidemic patients.Thirty-six hypertensive and dyslipidemic patients with inadequately controlled lipid levels by diet were treated with atorvastatin 20 mg/day for 8 weeks and compared with 24-patient matched controls treated with diet alone. The type and dosage of antihypertensive medications were not altered during statin therapy. Blood lipid profile including total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) levels were noted at inclusion and after 8 weeks. Ambulatory BP monitoring (ABPM) was carried out at study entry and at the end of week eight.A total of 49 patients (32 patients in the atorvastatin group and 17 patients in the control group) completed the 3-month follow-up period of observation. The ABPM studies indicated significant reductions in total average systolic BP, total average diastolic BP, total average mean BP, day average systolic BP, day average diastolic BP, night average systolic BP, night average diastolic BP, and night average mean BP levels in the atorvastatin group, whereas these reductions were not observed in the control group. ### Long_Answer: Our results indicate that atorvastatin therapy significantly improves BP control in hyperlipidemic hypertensive patients. However, the effects of other statins on BP, as well as, the different dosages need to be further investigated. ### Final_Prediction: yes

### Question: Does fucoidan from seaweed Fucus vesiculosus inhibit migration and invasion of human lung cancer cell via PI3K-Akt-mTOR pathways? ### Context: Recently there has been an increased interest in the pharmacologically active natural products associated with remedies of various kinds of diseases, including cancer. Fucoidan is a polysaccharide derived from brown seaweeds and has long been used as an ingredient in some dietary supplement products. Although fucoidan has been known to have anti-cancer activity, the anti-metastatic effects and its detailed mechanism of actions have been poorly understood. Therefore, the aims of this study were to demonstrate the anti-metastatic functions of fucoidan and its mechanism of action using A549, a highly metastatic human lung cancer cell line.Fucoidan inhibits the growth of A549 cells at the concentration of 400 µg/ml. Fucoidan treatment of non-toxic dose (0-200 µg/ml) exhibits a concentration-dependent inhibitory effect on the invasion and migration of the cancer cell via decreasing its MMP-2 activity. To know the mechanism of these inhibitory effects, Western blotting was performed. Fucoidan treatment down-regulates extracellular signal-related kinase 1 and 2 (ERK1/2) and phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (PI3K-Akt-mTOR) pathways. Furthermore, fucoidan decreases the cytosolic and nuclear levels of Nuclear Factor-kappa B (p65). ### Long_Answer: The present study suggests that fucoidan exhibits anti-metastatic effect on A549 lung cancer cells via the down-regulation of ERK1/2 and Akt-mTOR as well as NF-kB signaling pathways. Hence, fucoidan can be considered as a potential therapeutic reagent against the metastasis of invasive human lung cancer cells. ### Final_Prediction: yes

### Question: Does tetrahydrobiopterin improve endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease? ### Context: We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis.Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF).Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF (%ACBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 microg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine.The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with "diminished" (%deltaCBF <300%, n = 8) and "normal" (%deltaCBF >300%, n = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. ### Long_Answer: We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease. ### Final_Prediction: yes

### Question: Does a single mutation in the core domain of the lac repressor reduce leakiness? ### Context: The lac operon provides cells with the ability to switch from glucose to lactose metabolism precisely when necessary. This metabolic switch is mediated by the lac repressor (LacI), which in the absence of lactose binds to the operator DNA sequence to inhibit transcription. Allosteric rearrangements triggered by binding of the lactose isomer allolactose to the core domain of the repressor impede DNA binding and lift repression. In Nature, the ability to detect and respond to environmental conditions comes at the cost of the encoded enzymes being constitutively expressed at low levels. The readily-switched regulation provided by LacI has resulted in its widespread use for protein overexpression, and its applications in molecular biology represent early examples of synthetic biology. However, the leakiness of LacI that is essential for the natural function of the lac operon leads to an increased energetic burden, and potentially toxicity, in heterologous protein production.Analysis of the features that confer promiscuity to the inducer-binding site of LacI identified tryptophan 220 as a target for saturation mutagenesis. We found that phenylalanine (similarly to tryptophan) affords a functional repressor that is still responsive to IPTG. Characterisation of the W220F mutant, LacIWF, by measuring the time dependence of GFP production at different IPTG concentrations and at various incubation temperatures showed a 10-fold reduction in leakiness and no decrease in GFP production. Cells harbouring a cytotoxic protein under regulatory control of LacIWF showed no decrease in viability in the early phases of cell growth. Changes in responsiveness to IPTG observed in vivo are supported by the thermal shift assay behaviour of purified LacIWF with IPTG and operator DNA. ### Long_Answer: In LacI, long-range communications are responsible for the transmission of the signal from the inducer binding site to the DNA binding domain and our results are consistent with the involvement of position 220 in modulating these. The mutation of this single tryptophan residue to phenylalanine generated an enhanced repressor with a 10-fold decrease in leakiness. By minimising the energetic burden and cytotoxicity caused by leakiness, LacIWF constitutes a useful switch for protein overproduction and synthetic biology. ### Final_Prediction: yes

### Question: Does treatment of infertility increase the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation? ### Context: To evaluate the relationship between use of fertility medication (i.e., selective estrogen receptor [ER] modulator, gonadotropin, or other) or infertility treatment (i.e., IVF or IUI) and the risk of ovarian cancer among women with a BRCA1 or BRCA2 mutation.A matched case-control study of 941 pairs of BRCA1 or BRCA2 mutation carriers with and without a diagnosis of ovarian cancer.Genetic clinics.Detailed information regarding treatment of infertility was collected from a routinely administered questionnaire.None.Conditional logistic regression was used to estimate odds ratios and 95% confidence intervals associated with fertility treatment.There was no significant relationship between the use of any fertility medication or IVF treatment (odds ratio, 0.66; 95% confidence interval 0.18-2.33) and the subsequent risk of ovarian cancer. ### Long_Answer: Our findings suggest that treatment for infertility does not significantly increase the risk of ovarian cancer among women with a BRCA mutation. ### Final_Prediction: no

### Question: Does prenatal care at community-based health centers result in infant primary care at these sites? ### Context: To describe where women receiving prenatal care (PNC) at community-based health centers (CBHCs) go for infant primary care, and to assess reasons for and factors associated with leaving CBHCs and using other practices for infant care.A prospective survey of women receiving PNC at CBHCs from February 2000 to February 2002 was conducted. In-person, prepartum, and postpartum surveys included questions about sociodemographic and health characteristics, and health services use.Among 1,107 primarily low-income, African American mothers, 60% of women left CBHCs and used other practices for their infants due to dissatisfaction, inconvenience, referral to and perceived expertise at other sites, and insurance changes. Leaving CBHCs was associated with being white, Latina, US born, educated beyond high school, single, owning a car, using non-CBHC practices for prepregnancy care, and having child health insurance. Among those who left, 48% used hospital-based clinics (HBCs) and 52% used private practices (PPs). Mothers using HBCs, when compared to those using PPs, were more likely to be African American (AOR = 6.83; 95% CI: 3.82, 12.22) or Latina (AOR = 5.60; 95% CI: 2.79, 11.24), dissatisfied with their PNC (AOR = 2.02; 95% CI: 1.05, 3.89) and to leave CBHCs because of insurance changes (AOR = 2.27; 95% CI: 1.18, 4.39) and perceived pediatric expertise at other sites (AOR = 4.81; 95% CI: 2.53, 9.11). ### Long_Answer: The majority of women in our study left CBHCs and used other sites for pediatric care. Higher education, having child health insurance, and car ownership were associated with leaving CBHCs. Among women who left, race/ethnicity and perceived pediatric expertise were major factors associated with using HBCs rather than PPs. ### Final_Prediction: nan

### Question: Does inhibitor for advanced glycation end products formation attenuate hypertension and oxidative damage in genetic hypertensive rats? ### Context: A recent study demonstrated that free radicals were involved in the maintenance of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). Advanced glycation end-products (AGEs) accumulate progressively in the vasculature with ageing, and have been identified to be relevant mediators for various vascular complications. To elucidate the role of AGEs in genetic hypertension, we investigated the effect of OPB-9195, a novel inhibitor of AGEs, on hypertension and oxidative damage in SHRSP.Five-week-old male SHRSP were divided into a control group, fed a control diet and two, OPB-9195, (+/-)-2-isopropylidenehydrazono-4-oxo-thiazolidin-5-ylacetanilide, treatment groups, fed a diet supplemented with OPB-9195 at the concentration of 0.5 (OPB-L) or 2 mg/g (OPB-H) mixed chow for 10 weeks.The plasma of OPB-9195-treated SHRSP had lower levels of glycated albumin as compared with that of control SHRSP. OPB-9195 lowered the systolic blood pressure (SBP) by the fourth week of administration, and this effect was maintained throughout the study. We also confirmed SBP and diastolic blood pressure (DBP) rhythms, monitored by telemetry, were significantly lower in the OPB-H group than in the control group. Urinary nitric oxide (NO) excretion as well as the expression of endothelial NO synthase (eNOS) mRNA, and eNOS activity in the aorta were significantly increased in OPB-9195-treated groups compared with the control group. The levels of 8-hydroxydeoxyguanosine (8-OHdG), produced from deoxyguanosine under conditions of oxidative stress, in the urine of OPB-9195-treated SHRSP was significantly lower than in the control SHRSP. We also confirmed that the expression of glutathione peroxidase in the aorta was significantly increased in OPB-9195 treated SHRSP. ### Long_Answer: Because long-term administration of a AGEs inhibitor reduces blood pressure and oxidative damage in SHRSP, this study suggests a role for AGEs in the progression or maintenance of hypertension and related diseases in genetic hypertension. ### Final_Prediction: yes

### Question: Is visual perfusion-diffusion mismatch equivalent to quantitative mismatch? ### Context: The concept of stroke MRI mismatch based on qualitative evaluation of diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) has been applied in clinical practice for several years. The benefit of MRI in providing pathological evidence of ischemia before thrombolytic treatment has been demonstrated. The purpose of this study is to determine the reliability of the qualitative method and compare it with quantitative mismatch measurement in thrombolytic-treated patients.Patients (n=70) were selected from the Lesion Evolution of Stroke and Ischemic On Neuroimaging (LESION) database if they: (1) were treated with intravenous recombinant tissue plasminogen activator; (2) had a pretreatment MRI with evaluable DWI and PWI; and (3) had acute ischemic lesion volume >10 mL on DWI as determined by core imaging laboratory measurements. Quantitative mismatch was defined as a difference of >50 mL between abnormal mean transit time and DWI volumes. Sample characteristics and postdischarge modified Rankin Scale for the positive mismatch patients were compared between the subgroups identified by qualitative versus quantitative methods.Patient characteristics and thrombolytic outcomes (sex, age, National Institutes of Health Stroke Scale, mismatch volume, and modified Rankin Scale) did not differ for mismatch patients identified by qualitative versus quantitative methods. Qualitative mismatch selection among neurologists had a high sensitivity (0.82), specificity (0.80), accuracy (0.81), and positive predictive value (0.88) compared with quantitative measurements. ### Long_Answer: We observed that qualitative evaluation of mismatch identified the same thrombolytic-treated patients compared with retrospective quantitative mismatch measurements. ### Final_Prediction: yes

### Question: Does nuclear factor-κB predict outcome in locally advanced rectal cancer patients receiving neoadjuvant radio-chemotherapy? ### Context: NF-κB expression has been shown to be responsible for resistance to antineoplastic agents.The aim of our study was to investigate the importance of NF-κB expression as prognostic factor in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy.We retrospectively analysed the immunoreactivity for NF-κB in patients with locally advanced rectal cancer who underwent neoadjuvant treatment (chemotherapy and/or radiotherapy) in our Institution between March 2003 and June 2006.Seventy-four consecutive patients were enrolled into this study. Immunohistochemistry analysis for NF-κB was performed both in biopsies and in primary tumour samples. NF-κB was considered positive when at least 1% of the tumour cells showed nuclear positivity. A significant correlation between a positive NF-κB nuclear expression, both in biopsies and in tumour samples, and a worse overall survival was observed. Moreover, median time to progression was significantly shorter in the NF-κB-positive subgroup of patients. ### Long_Answer: Globally, our findings seem to suggest that NF-κB could represent an important parameter able to predict the outcome in patients receiving neoadjuvant treatment for rectal cancer. It also could be useful in order to select patients to receive adjuvant chemotherapy, intensifying the adjuvant therapy and, in the next future, obviating the use of drugs involving NF-κB system in their mechanism of action in NF-κB-positive patients. ### Final_Prediction: yes

### Question: Do infant and young child feeding practices differ by ethnicity of Vietnamese mothers? ### Context: Limited studies have examined ethnic variation in breastfeeding and complementary feeding practices in developing countries. This study investigated ethnic variation in feeding practices in mothers with children 0-23 months old in Vietnam.We used data on 1875 women who came from the ethnic majority, Kinh (n = 989, randomly sampled from 9875 surveyed Kinh mothers, 10 % from each province) and three ethnic minorities: E De-Mnong (n = 309), Thai-Muong (n = 229) and Tay-Nung (n = 348). Ethnic minorities were compared with the Kinh group using logistic regression model.Prevalence of breastfeeding initiation within an hour of birth was 69 % in Thai-Muong, but ~50 % in other ethnicities. In logistic regression, the prevalence of breastfeeding within one hour was lower in Tay-Nung (OR: 0.54; 95 % CI: 0.38, 0.77) than the majority Kinh. Prevalence of exclusive breastfeeding under 6 months was 18, 10, 17, and 33 % in Kinh, Thai-Muong, Tay-Nung, and E De-Mnong, respectively; compared to the majority Kinh, the prevalence was lower in Thai-Muong (OR: 0.42; 95 % CI: 0.25, 0.71) and higher in E De-Mnong (OR: 1.99; 95 % CI: 1.04, 3.82). Overall prevalence of bottle feeding in Thai-Muong and E De-Mnong (~20 %) was lower than in Kinh (~33 %): Thai-Muong (OR: 0.50; 95 % CI: 0.37, 0.68) and E De-Mnong (OR: 0.69; 95 % CI: 0.50, 0.95). Compared with Kinh (75 %), fewer ethnic minority children received minimum acceptable diets (33 % in Thai-Muong, 46 % in E De-Mnong, and 52 % in Tay-Nung; P < 0.05). Prevalence of minimum acceptable diet (met both dietary frequency and diversity) was lower in Thai-Muong (OR: 0.23; 95 % CI: 0.11, 0.46), Tay-Nung (OR: 0.52; 95 % CI: 0.39, 0.69), and E De-Mnong (OR: 0.55; 95 % CI: 0.33, 0.89) than the majority Kinh. ### Long_Answer: Breastfeeding practices were suboptimal and differed by ethnicity, which suggests need for tailored interventions at multiple levels to address ethnic-specific challenges and norms. Complementary feeding practices were less optimal among ethnic minorities compared to Kinh, which suggests need for broad intervention including improved food availability, accessibility, and security. ### Final_Prediction: yes

### Question: Is extreme drug resistance common after prior exposure to paclitaxel? ### Context: The platinum-free interval (PFI) is an important entity in the treatment of women with epithelial ovarian cancer. The purpose of this study was to determine on clinical samples whether a taxane-free interval (TFI), as defined by in vitro extreme drug resistance assay, existed in women previously exposed to platinum and taxane chemotherapy.Records were examined from 2003 to 2006 to find all patients with epithelial ovarian cancer who had previous exposure to platinum and taxane therapy. Further examination was done to find all patients who underwent secondary cytoreduction and had their tumor submitted for extreme drug resistance assay.Thirty-four women meeting the above criteria were found. The mean PFI was 25 months (median 18). The mean TFI was 27 months (median 20). Over 44% of the patients have been exposed to more than just a course of platinum and a course of a taxane. In patients having a PFI of >or=12 months, 38.8% had extreme drug resistance (EDR) to carboplatin and 41.9% EDR to cisplatin. Conversely, in patients having a TFI of >or=12 months, 89.7% had EDR to paclitaxel and 82.8% EDR to docetaxel. ### Long_Answer: While only a small percentage have EDR to carboplatin and cisplatin after a PFI of >or=12 months, almost 90% of patients with a TFI>or=12 months showed EDR to paclitaxel in vitro. ### Final_Prediction: yes

### Question: Does serum resistin correlate with central obesity but weakly with insulin resistance in Chinese children and adolescents? ### Context: Resistin has been linked with obesity and hypothesized as a potential marker of insulin resistance in addition to being linked with acute inflammation. However, these links are still highly controversial in humans. Our goal was to examine resistin levels in relation to obesity, insulin resistance and inflammation markers in a large population of Asian children and adolescents.Children and adolescents (n=3472) aged 6-18 years, boys (n=1765) and girls (n=1707), were assessed for body size parameters, pubertal development, blood lipids, glucose, insulin, resistin, C-reactive protein (CRP), adiponectin and complement C3 (C3) levels.Resistin increased with central obesity in both genders but not with simple adiposity in boys. Several markers associated with central obesity correlated in a gender-specific fashion with plasma resistin. Waist circumference, fat-mass percentage, waist-to-height ratio and body mass index (BMI) positively correlated with resistin in both genders. Blood lipids such as triglycerides, nonesterified fatty acids (NEFA) and low-density lipoprotein cholesterol, diastolic and systolic blood pressure correlated positively with resistin in boys. NEFA, high-density lipoprotein cholesterol (negatively) and inflammation markers, such as CRP and C3, positively correlated with resistin in girls. There was no correlation between resistin and adiponectin, and no association of adiponectin with resistin quintiles in either boys or girls. In both boys and girls, resistin tended to decrease with age, with girls having higher levels than boys. Few indices of insulin resistance were linked with plasma resistin in either gender. ### Long_Answer: In this population, plasma resistin levels are a weak biochemical marker of metabolic dysfunction defined by central obesity, adiposity and inflammation and does not predict insulin resistance. Only a small proportion of resistin variation can be explained by factors related to metabolic syndrome, suggesting that resistin is not strongly implicated in a concentration-dependent fashion in any of the examined pathologies. ### Final_Prediction: yes

### Question: Do sevoflurane and isoflurane impair edrophonium reversal of vecuronium-induced neuromuscular block? ### Context: A dose-response relationship study for edrophonium to examine the modification of volatile anaesthetics on reversal of vecuronium block.One hundred and twenty ASA (I-II) patients were anaesthetized with sevoflurane, isoflurane (1 minimum alveolar anaesthetic concentration [MAC] end-tidal concentration), or fentanyl-diazepam anaesthesia, in combination with 66% nitrous oxide (n = 40 for each group). The evoked electromyogram (EMG) response of the abductor digiti minimi was monitored at 20 sec intervals following train-of-four (TOF) stimulation of the ulnar nerve. The initial neuromuscular block was produced by vecuronium 100 micrograms.kg-1. When the amplitude of the first response (T1) had spontaneously recovered to 10% of the control, edrophonium (0, 125, 400, 700 or 1000 micrograms.kg-1; eight patients each) was randomly administered, and the ratio of the fourth TOF to the first response (TOFR) was monitored at one minute intervals for 10 min.Sevoflurane and isoflurane impaired the edrophonium-assisted TOFR recovery in an edrophonium dose and time dependent manner. The dose-response curves at 10 min exhibited a greater shift to the right in the sevoflurane and isoflurane groups than in the fentanyl-diazepam-nitrous oxide group (P < 0.05). Higher ED50 values (the edrophonium dose required to obtain TOFR value of 50%) in the sevoflurane (> 1000 micrograms.kg-1) and isoflurane groups (851 micrograms.kg-1) were observed than in the fentanyl-diazepam-nitrous oxide group (339 micrograms.kg-1) (P < 0.05). ### Long_Answer: One MAC sevoflurane and isoflurane anaesthesia impair edrophonium reversal of vecuronium block to a similar degree. ### Final_Prediction: yes

### Question: Is low serum adropin associated with coronary atherosclerosis in type 2 diabetic and non-diabetic patients? ### Context: Diabetes increases the risk and severity of atherosclerosis. Adropin, a metabolic homeostasis-related protein, has been implicated in the maintenance of metabolic homeostasis. We examined the relationship between serum adropin level and angiographic severity of coronary atherosclerosis in diabetic and non-diabetic patients.A total of 392 patients with suspected coronary artery disease, who underwent coronary angiography, were assigned into the type 2 diabetic and non-diabetic groups and also classified into four groups according to the quartiles of adropin level. Venous serum samples were collected for adropin measurement by enzyme-linked immunosorbent assay and for biochemistry assay. The angiographic severity of coronary atherosclerosis was assessed by Gensini, Friesinger, and SYNTAX scores.Compared with non-diabetic patients, diabetic patients had lower serum adropin level and higher Gensini, Friesinger and SYNTAX scores (all p<0.001). Serum adropin level was inversely correlated with the Gensini, Friesinger and SYNTAX scores (rs=-0.389, -0.390 and -0.386, respectively, all p<0.001) among all patients. Low adropin level was an independent predictor of clinically relevant coronary atherosclerosis (SYNTAX score >11), both in diabetic patients [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.53-0.83; p<0.001] and in non-diabetic patients (OR 0.51, 95% CI 0.35-0.74; p<0.001). ### Long_Answer: Serum adropin level was significantly lower in type 2 diabetic patients than in non-diabetic patients and was inversely and independently associated with angiographic severity of coronary atherosclerosis, suggesting that serum adropin serves as a novel predictor of coronary atherosclerosis. ### Final_Prediction: yes

### Question: Is noise exposure increased with neonatal helmet CPAP in comparison with conventional nasal CPAP? ### Context: in adults, noninvasive ventilation via a helmet is associated with significantly greater noise than nasal and facial masks. We hypothesized that noise exposure could be increased with neonatal helmet continuous positive airway pressure (CPAP) in comparison with conventional nasal CPAP (nCPAP). Our primary objective was to compare the noise intensity produced by a neonatal helmet CPAP and a conventional nCPAP system. Furthermore, we aimed to evaluate the effect of the gas flow rate and the presence of the humidifier and the filter on noise levels during neonatal helmet CPAP treatment.in this bench study, noise intensity was measured in the following settings: helmet CPAP, nCPAP, incubator and the neonatal intensive care unit. In helmet CPAP, noise measurements were performed at different gas flow rates (8, 10 and 12 l/min), while in nCPAP, the flow rate was 8 l/min. For both CPAP systems, the level of pressure was maintained constant at 5 cmH(2) O.during neonatal helmet CPAP, the median (interquartile range) noise levels were significantly higher than those during nCPAP: 70.0 dB (69.9-70.4) vs. 62.7 dB (62.5-63.0); P<0.001. In the helmet CPAP, the noise intensities changed with increasing flow rate and with the presence of a humidifier or a filter. ### Long_Answer: noise intensities generated by the neonatal helmet CPAP were significantly higher than those registered while using a conventional nCPAP system. In the helmet, the noise intensity depends on the gas flow rate, and the presence of a humidifier and a filter in the system. ### Final_Prediction: yes

### Question: Do patients with localized non-small cell lung cancer miss out on curative surgery with distance from specialist care? ### Context: To determine whether increasing distance to the nearest accessible specialist hospital (NASH, a public hospital with a thoracic surgical service) increases a patient's likelihood of missing out on curative surgery for localized non-small cell lung cancer (NSCLC).Population-based study of cancer registry records for 27 033 people with lung cancer diagnosed in New South Wales, Australia, between 2000 and 2008 linked to hospital admission records. This analysis includes 3240 patients with localized NSCLC admitted to hospital within 12 months of diagnosis.Patients who lived 100+ km from the NASH were more likely to have no surgery (50.6%) than those living 0-39 km away (37.6%) and more likely to attend general hospitals for their care (52.2% at 100+ km, 14.8% at 0-39 km). Relative to patients living 0-39 km from the NASH and attending a specialist hospital for their care, the odds ratio (OR) of not having surgery was high if patients attended a general hospital (adjusted OR 5.99, 95% confidence interval (CI) 3.87-9.26, for those 0-39 km distant) and even higher as distance from the NASH increased (24.68, 95% CI 12.37-49.13 for 40-49 km and 30.10, 95% CI 18.2-49.40 for 100+ km). For patients treated in specialist hospitals (public or private), the trend with distance was opposite: relative to 0-39 km, the OR was 0.29 (95% CI 0.15-0.50) at 40-99 km and 0.14 (95% CI 0.08-0.26) at 100+ km. ### Long_Answer: Patients with localized NSCLC are most likely to have no potentially curative surgery if they live distant from a specialist hospital and attend a general hospital for their care. ### Final_Prediction: yes

### Question: Do mutations causing low HDL-C promote increased carotid intima-media thickness? ### Context: Although observational data support an inverse relationship between high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD), genetic HDL deficiency states often do not correlate with premature CHD.Carotid intima-media thickness (cIMT) measurements were obtained in cases comprising 10 different mutations in LCAT, ABCA1 and APOA1 to further evaluate the relationship between low HDL resulting from genetic variation and early atherosclerosis.In a 1:2 case-control study of sex and age-related (+/-5 y) subjects (n=114), cIMT was nearly identical between cases (0.66+/-0.17 cm) and controls (0.65+/-0.18 cm) despite significantly lower HDL cholesterol (0.67 vs. 1.58 mmol/l) and apolipoprotein A-I levels (96.7 vs. 151.4 mg/dl) (P<0.05) ### Long_Answer: Genetic variants identified in the present study may be insufficient to promote early carotid atherosclerosis. ### Final_Prediction: no

### Question: Do ejection fraction and other gated stress rest myocardial perfusion parameters differ by age and gender? ### Context: We have studied the end-diastolic volume (EDV), the end-systolic volume (ESV), and the ejection fraction (EF) for patients who had normal results on treadmill exercise tests and perfusion scans. We also studied normal wall motion as diagnosed by gated myocardial perfusion imaging with the quantitative gated single photon emission tomography (QGSPECT) software set to launch a range of normal values. In addition, we evaluated differences based on age and gender.All subjects with normal results on Bruce exercise and myocardial perfusion imaging QGSPECT using the 2-days stress-rest technetium-99m (99mTc) sestamibi protocol were enrolled in the study. The quantitated functional data of EDV, ESV, and EF using the QGSPECT software were assessed in the rest and stress studies. The association of quantitated functional data with age and sex at both stress and rest was studied in 78 subjects with no symptoms from the cardiovascular system and normal QGSPECT imaging, 29 males (mean age: 58.41 ± 9.0 years) and 49 females (mean age: 58.18 ± 9.0 years). Also studied were differences between males and females.Our results showed that in women compared with men only stress EF showed a significantly higher value (P = 0.02), whereas all other parameters including REF, SESV, SEDV, RESV, and REDV did not demonstrate a significant difference between men and women (P value>0.05). ### Long_Answer: The study showed that EF as determined by the QGSPECT technique should be considered as gender-matched normative parameter. ### Final_Prediction: nan

### Question: Can Flemish women in semi-rural areas be motivated to attend organized breast cancer screening? ### Context: The implementation of organized breast cancer screening in Flanders was prepared by means of pilot projects within a multicenter study. In the semi-rural district of Kontich (Province of Antwerp, Flanders) a pilot project was performed using a mobile screening unit. Compared to international standards, the attendance rate for this pilot project (i.e. 34%) was low. Non-organized screening, which already exists in Flanders, at least partly explains this low attendance rate for the organized screening. The main purpose of our study was to investigate the experience of the pilot target group with respect to the organized breast cancer screening in the district of Kontich, in order to maximize the conditions for a high attendance rate in the organized breast cancer screening programme throughout Flanders.With a random numbers procedure, performed by the computer, 500 women were selected among those who were invited to the first screening round of the breast cancer screening programme in the district of Kontich (n = 6,897). These 500 randomly selected women were asked to cooperate with a face-to-face interview. The questionnaire used dealt with the different aspects of the organized mammographic screening which were expected to influence the decision to attend.There were 348 women who responded to the questionnaire (69.6%): 138 of them were attenders and 210 were non-attenders at the organized breast cancer screening. Attenders and non-attenders at the organized breast cancer screening in the district of Kontich had different views about various aspects of the screening programme. The percentages of those who thought that an item was important or very important to them, were for the 138 attenders and the 210 non-attenders respectively: "to receive a personal invitation letter": 90.6 vs. 48.1% (p<0.05); "a preliminary visit to the GP": 9.4 vs. 34.3% (p<0.05); "possibility of examination outside business hours": 15.9 vs. 30.0% (p<0.05). ### Long_Answer: Although the putting into action of a mobile unit in the semi-rural area of the district of Kontich was productive, the attendance rate was still too low compared to international standards. To increase the attendance rate, the following interventions should be considered: devising the personal invitation letter in a more attractive way, activating and stimulating the important motivational role of the GP in persuading women to attend the organized screening programme and offering the invited population the possibility to have a mammographic examination performed outside business hours. Appropriate measures are being explored. ### Final_Prediction: nan

### Question: Does a new improved accelerated diagnostic protocol safely identify low-risk patients with chest pain in the emergency department? ### Context: To assess whether the accelerated diagnostic protocol (ADP) studied in the Asia Pacific Evaluation of Chest Pain Trial (ASPECT) could be optimized to effectively risk stratify patients with symptoms suggestive of acute coronary syndrome (ACS) and allow early discharge of very-low-risk patients.Patients presenting to the emergency department (ED) with chest pain were prospectively enrolled between November 2007 and April 2010. Blood samples were analyzed at 0 and 2 hours postpresentation with a point-of-care multimarker panel (POC-MMP; troponin I [TnI], creatine kinase myocardial band [CKMB] isoenzyme fraction, and myoglobin) and a high-sensitivity cardiac troponin T assay (hsTnT). Patients received standard care. The original ADP (Thrombolysis in Myocardial Infarction [TIMI] risk score = 0, no ischemic electrocardiogram [ECG] changes, and the multimarker panel negative) was compared with an ADP using the point of care TnI only, hsTnT only, or TIMI risk score = 0 to 1. Primary outcome was ACS within 30 days.Of the 1,000 patients recruited, 362 (36.2%) had ACS. There were 12.3% identified as low risk by the original ADP with a sensitivity for ACS of 99.2% (95% confidence interval [CI] = 97.5% to 99.8%). The ADP with the point of care TnI only or hsTnT had the same sensitivity, but identified more patients for discharge (15.0% vs. 12.3%). Including patients with a TIMI risk score of 1 identified more patients as low risk (19.7%), but with a lower sensitivity (97.0% vs. 99.2%). ### Long_Answer: An ADP consisting of a TIMI risk score of 0, no new ECG changes, and negative troponin at 0 and 2 hours postpresentation safely identifies patients at low risk of ACS, in whom discharge without further evaluation can be considered. ### Final_Prediction: yes

### Question: Does albumin infusion after reperfusion prevent gut ischemia-reperfusion-induced gut-associated lymphoid tissue atrophy? ### Context: Our recent study clarified that gut ischemia-reperfusion (I/R) causes gut-associated lymphoid tissue (GALT) mass atrophy, a possible mechanism for increased morbidity of infectious complications after severe surgical insults. Because albumin administration reportedly reduces hemorrhagic shock-induced lung injury, we hypothesized that albumin treatment prevents GALT atrophy due to gut I/R.Male mice (n = 37) were randomized to albumin, normal saline, and sham groups. All groups underwent jugular vein catheter insertion. The albumin and normal saline groups underwent 75-minute occlusion of the superior mesenteric artery. During gut ischemia, all mice received normal saline infusions at 1.0 mL/h. The albumin group was given 5% bovine serum albumin in normal saline at 1.0 mL/h for 60 minutes after reperfusion, whereas the normal saline group received 0.9% sodium chloride at 1.0 mL/h. The sham group underwent laparotomy only. Mice were killed on day 1 or 7, and the entire small intestine was harvested. GALT lymphocytes were isolated and counted. Their phenotypes (alphabetaTCR, gammadeltaTCR, CD4, CD8, B220) were determined by flow cytometry.On day 1, the gut I/R groups showed significantly lower total lymphocyte and B cell numbers in Peyer's patches and the lamina propria than the sham group. However, the albumin infusion partially but significantly restored these cell numbers. On day 7, there were no significant differences in any of the parameters measured among the 3 groups. ### Long_Answer: Albumin infusion after a gut ischemic insult may maintain gut immunity by preventing GALT atrophy. ### Final_Prediction: yes

### Question: Do a human factors approach to observation chart design can trump health professionals ' prior chart experience? ### Context: To determine whether experienced health professionals recognise patient deterioration more accurately and efficiently using (a) novel observation charts, designed from a human factors perspective, or (b) chart designs with which they have long-term experience.Participants were 101 health professionals experienced in using either a multiple parameter track-and-trigger chart or a graphical chart with no track-and-trigger system. Participants were presented with realistic abnormal and normal patient observations recorded on six hospital observation charts of varying design quality, including the chart that participants were familiar with (or a very similar design). Across 48 trials, the participant was asked to specify if any of the vital sign observations were abnormal, or if all of the observations were normal. Participants' overall error rates (i.e., proportion of incorrect responses) and response times, the main outcome measures, were calculated for each observation chart.Participants made significantly fewer errors and responded significantly faster when using a novel user-friendly chart compared with all the other designs, including the charts that they were experienced with in a clinical setting. ### Long_Answer: The findings suggest that, at least in the contexts examined, superior observation chart design appears to trump familiarity. Hence, hospitals motivated to improve the detection of patient deterioration should implement charts designed from a human factors perspective, rather than simply maintaining the status quo of reliance on clinical experience. ### Final_Prediction: yes

### Question: Endovascular management of unruptured intracranial aneurysms: does outcome justify treatment? ### Context: The appropriate management of unruptured intracranial aneurysms depends on a complete understanding of their natural history and on the risks and efficacy of treatment options. There is little current data on the risks of endovascular therapy for these aneurysms. The aim of this study was to assess outcome of endovascular treatment of unruptured intracranial aneurysms.A retrospective analysis was performed on all unruptured aneurysms treated by Guglielmi detachable (GD) coils at this institution from 1994 to 2000.Seventy three unruptured aneurysms were treated in 62 patients. There were 52 female and 10 male patients, with a median age of 55.7 years. Clinical background was: subarachnoid haemorrhage due to rupture of an additional aneurysm (40), headache (4), third nerve palsy (four), familial (four), and incidental (10). There were 14 technical failures with no clinical sequelae. Four procedural complications occurred (5.5%, 95% confidence interval (95% CI) 0.3% to 10.9%). One patient had temporary clinical sequelae (1.4%, 95% CI 0% to 2.7%); 79% of treated aneurysms had stable occlusions at follow up, 10.5% showed improved occlusion grade, 10.5% showed some recurrence, and three patients have required retreatment. Follow up modified Glasgow outcome scores were grade 1, 71%; grade 2, 18%; grade 3, 3%; grade 4, 3%. There were no deaths or haemorrhages during the follow up period. Two patients died as a result of complications from subarachnoid haemorrhage. ### Long_Answer: The endovascular treatment of patients with unruptured aneurysms is safe with few clinical or procedural complications. Poor outcomes were only seen in those patients who presented with subarachnoid haemorrhage due to rupture of an aneurysm at another site. ### Final_Prediction: nan

### Question: Is hexavalent chromium carcinogenic to F344/N rats and B6C3F1 mice after chronic oral exposure? ### Context: Hexavalent chromium [Cr(VI)] is a human carcinogen after inhalation exposure. Humans also ingest Cr(VI) from contaminated drinking water and soil; however, limited data exist on the oral toxicity and carcinogenicity of Cr(VI).We characterized the chronic oral toxicity and carcinogenicity of Cr(VI) in rodents.The National Toxicology Program (NTP) conducted 2-year drinking water studies of Cr(VI) (as sodium dichromate dihydrate) in male and female F344/N rats and B6C3F1 mice.Cr(VI) exposure resulted in increased incidences of rare neoplasms of the squamous epithelium that lines the oral cavity (oral mucosa and tongue) in male and female rats, and of the epithelium lining the small intestine in male and female mice. Cr(VI) exposure did not affect survival but resulted in reduced mean body weights and water consumption, due at least in part to poor palatability of the dosed water. Cr(VI) exposure resulted in transient microcytic hypochromic anemia in rats and microcytosis in mice. Nonneoplastic lesions included diffuse epithelial hyperplasia in the duodenum and jejunum of mice and histiocytic cell infiltration in the duodenum, liver, and mesenteric and pancreatic lymph nodes of rats and mice. ### Long_Answer: Cr(VI) was carcinogenic after administration in drinking water to male and female rats and mice. ### Final_Prediction: yes

### Question: Is aerosol delivery to the lung more efficient using an extension with a standard jet nebulizer than an open-vent jet nebulizer? ### Context: Open-vent jet nebulizers are frequently used to promote drug deposition in the lung, but their clinical efficacy and indications are not clear. Our study compared lung deposition of amikacin using two different configurations of a jet nebulizer (Sidestream(®)): one vented (N1) and one unvented with a corrugated piece of tubing (N2).In vitro nebulizer performance was assessed by laser diffraction and filtering. Lung delivery was evaluated by scintigraphy in baboons as a child model, and by amikacin urinary drug concentration in seven healthy spontaneously breathing volunteers. Subjects were randomly assigned to the two nebulizer systems (N1 and N2). ### Long_Answer: In vitro results showed a higher efficiency of N2 than N1 in terms of lung deposition prediction (95±3 mg vs. 70±0 mg; p<0.0001). Radioactivity deposition in the baboons' lungs was lower with N1 than with N2 (1.8% vs. 4.7% of nebulizer charge; p<0.05). The total daily amount of amikacin urinary excretion was lower with N1 than with N2 (29.5 mg vs. 40.1 mg; p<0.01). Conversely, in vivo drug output rate was higher with N1 than with N2 (3.1 mg/min vs. 2.2 mg/min; p<0.05). Using a corrugated piece of tubing with standard jet nebulizers delivers higher doses to the lungs than open-vent jet nebulizers. The open-vent jet nebulizer might be recommended for rapid administration of a lower dose to the lungs and the standard jet nebulizer with corrugated piece of tubing for a higher dose in the lungs. ### Final_Prediction: yes

### Question: Are biochemical recurrence outcomes similar after radical prostatectomy and radiation therapy? ### Context: Due to the protracted natural history of the clinical progression of prostate cancer, biochemical recurrence (BCR) is often used to compare treatment modalities. However, BCR definitions and posttreatment prostate-specific antigen kinetics vary considerably among treatments, calling into the question the validity of such comparisons.To analyze prostate cancer-specific mortality (PCSM) according to treatment-specific nomogram-predicted risk of BCR for men treated by radical prostatectomy (RP), external-beam radiation therapy (EBRT), and brachytherapy.A total of 13 803 men who underwent RP, EBRT, or brachytherapy at two US high-volume hospitals between 1995 and 2008.RP, EBRT, and brachytherapy.The 5-yr progression-free probability (5Y-PFP) was calculated for each patient based on the treatment received using a validated treatment-specific nomogram. Fine and Gray competing risk analysis was then used to estimate PCSM by a patient's predicted 5Y-PFP. Multivariable competing risk regression analysis was used to determine the association of treatment with PCSM after adjusting for nomogram-predicted 5Y-PFP.Men receiving EBRT had higher 10-yr PCSM compared with those treated by RP across the range of nomogram-predicted risks of BCR: 5Y-PFP>75%, 3% versus 0.9%; 5Y-PFP 51-75%, 6.8% versus 5.9%; 5Y-PFP 26-50%, 12.2% versus 10.6%; and 5Y-PFP ≤25%, 26.6% versus 21.2%. After adjusting for nomogram-predicted 5Y-PFP, EBRT was associated with a significantly increased PCSM risk compared with RP (hazard ratio: 1.5; 95% confidence interval, 1.1-2.0; p=0.006). No statistically significant difference in PCSM was observed between patients treated by brachytherapy and RP, although patient selection factors and lack of statistical power limited this analysis. ### Long_Answer: EBRT patients with similar nomogram-predicted 5Y-PFP appear to have a significantly increased risk of PCSM compared with those treated by RP. Comparison of treatments using nomogram-predicted BCR end points may not be valid. ### Final_Prediction: nan

### Question: Is improving antibiotic use in the hospital : Focusing on positive blood cultures an effective option? ### Context: The unsolicited and systematic evaluation of positive blood cultures (pBC) after laboratory report by a single infectious disease specialist (IDS) was evaluated during one year, using a computer-generated alert by the laboratory. The main objectives of IDS counselling were to improve antibiotic use for bloodstream infection (i.e., initiating or modifying therapy) and to stop unjustified therapy for contaminated pBC.During the first part of the study (4 months), all pBC in patients from ICUs, medical and surgical wards were analyzed. After an interim analysis, only pBC from medical and surgical wards were evaluated during the second part (8 months).Overall, 1090 episodes of pBC (representing 866 patients) were evaluated and classified as bloodstream infection (65.5%), contamination (29%) or undetermined (5.5%). Forty-three percent of episodes prompted IDS counselling, including initiation (5%), modification (27.5%), withdrawal (3.5%) and diagnosis workup (5%). Restricting the evaluation to medical and surgical wards increased the rate of counselling (61.2% vs. 27.7%, P<0.0001), notably for de-escalating (20% vs. 8%, P<0.0001), initiating (9% vs. 2%, P<0.0001), oral switch (6% vs. 2%, P<0.0001), withdrawing (5% vs. 2%, P=0.002) or reducing the duration of therapy (5% vs. 2%, P=0.002). ### Long_Answer: In complement to the laboratory report, a computer-generated alert used by the IDS was useful for the management of pBC in hospital. The impact of IDS counselling was more effective when the evaluation was restricted to medical and surgical wards. ### Final_Prediction: yes

### Question: Is higher 25-hydroxyvitamin D associated with lower relapse risk in multiple sclerosis? ### Context: A protective association between higher vitamin D levels and the onset of multiple sclerosis (MS) has been demonstrated; however, its role in modulating MS clinical course has been little studied. We investigated whether higher levels of serum 25-hydroxyvitamin D (25-OH-D) were associated with a lower risk of relapses in people with MS.We conducted a prospective cohort study of 145 participants with relapsing-remitting MS from 2002 to 2005. Serum 25-OH-D levels were measured biannually, and the hazard of relapse was assessed using survival analysis.There was an inverse linear relationship between 25-OH-D levels and the hazard of relapse over the subsequent 6 months, with hazard ratio (HR) 0.91 (95% confidence interval [CI]: 0.85-0.97) per 10 nmol/l increase in 25-OH-D level (p = 0.006). When variation due to timing of blood collection was removed by estimating 25-OH-D at the start of each season, this association persisted, with HR 0.90 (95% CI, 0.83-0.98) per 10 nmol/l increase (p = 0.016). Taking into account the biological half-life of 25-OH-D, we estimated 25-OH-D at monthly intervals, resulting in a slightly enhanced association, with HR 0.88 (95% CI, 0.82-0.95) per 10 nmol/l increase (p = 0.001). Adjusting for potential confounders did not alter these findings. ### Long_Answer: In this prospective population-based cohort study, in a cohort largely on immunomodulatory therapy, higher 25-OH-D levels were associated with a reduced hazard of relapse. This occurred in a dose-dependent linear fashion, with each 10 nmol/l increase in 25-OH-D resulting in up to a 12% reduction in risk of relapse. Clinically, raising 25-OH-D levels by 50 nmol/l could halve the hazard of a relapse. ### Final_Prediction: yes

### Question: Do 17beta-Estradiol and soy phytochemicals selectively induce a type 2 polarization in mesenteric lymph nodes of ovariectomized rats? ### Context: This study was designed to compare the effects of 17beta-estradiol (17beta-E2) and a phytoestrogen-containing soy extract on the immune system in an ovariectomized rat model of menopause. Specifically, T- and B-lymphocyte subsets, the balance of type 1 and 2 immune responses in the mesenteric lymph nodes, and serum levels of different classes of immunoglobulin were examined as study endpoints.Ovariectomized rats were treated with either the phytoestrogen-containing soy extract (50 or 100 mg/kg/day PO), 17beta-E2 (0.5 mg/kg/day PO), or vehicle; a sham control was included in the study. After the rats were killed, mesenteric lymph nodes and blood samples were collected. B- and T (CD4 and CD8)-lymphocyte subsets in mesenteric lymph nodes were evaluated by flow cytometry analysis. Cytokine-producing T lymphocytes were identified within each T-lymphocyte subset as TH1 (interferon-gamma CD4), TH2 (interleukin-4 CD4), TC1 (interferon-gamma CD8), and TC2 (interferon-4 CD8) lymphocytes. Serum levels of immunoglobulin classes were determined by enzyme-linked immunosorbent assay.There were no differences in the proportions of B lymphocytes and CD4 and CD8 T lymphocytes among groups. Treatment with 17beta-E2 and phytoestrogen-containing soy extract induced a reduction in TH1 and TC1 lymphocytes paralleled by a slight, nonsignificant, increase in the frequency of TH2. Data expressed as TH1/TH2 and TC1/TC2 ratios depicted a significant polarization of local immunity toward a humoral response. Evaluation of immunoglobulin serum levels did not show any significant difference among groups. ### Long_Answer: Here we show that estrogens and soy phytochemicals similarly polarize the immune system toward a type 2 immune response in a preclinical model of menopause; our data draw attention to the crucial need to evaluate in clinical studies the potential side effects on the immune system of the complex soy products that are actually consumed in the postmenopausal setting. ### Final_Prediction: yes

### Question: Does apurinic/apyrimidinic endonuclease 1 inhibit protein kinase C-mediated p66shc phosphorylation and vasoconstriction? ### Context: Phosphorylation of the adaptor protein p66shc is essential for p66shc-mediated oxidative stress. We investigated the role of the reducing protein/DNA repair enzyme apurinic/apyrimidinic endonuclease1 (APE1) in modulating protein kinase CβII (PKCβII)-mediated p66shc phosphorylation in cultured endothelial cells and PKC-mediated vasoconstriction of arteries.Oxidized low-density lipoprotein (oxLDL)induced p66shc phosphorylation at serine 36 residue and PKCβII phosphorylation in mouse endothelial cells. Adenoviral overexpression of APE1 resulted in reduction of oxLDL-induced p66shc and PKCβII phosphorylation. Phorbol 12-myristate 13-acetate (PMA), which stimulates PKCs, induced p66shc phosphorylation and this was inhibited by a selective PKCβII inhibitor. Adenoviral overexpression of PKCβII also increased p66shc phosphorylation. Overexpression of APE1 suppressed PMA-induced p66shc phosphorylation. Moreover, PMA-induced p66shc phosphorylation was augmented in cells in which APE1 was knocked down. PMA increased cytoplasmic APE1 expression, compared with the basal condition, suggesting the role of cytoplasmic APE1 against p66shc phosphorylation. Finally, vasoconstriction induced by phorbol-12,13, dibutylrate, another PKC agonist, was partially inhibited by transduction of Tat-APE1 into arteries. ### Long_Answer: APE1 suppresses oxLDL-induced p66shc activation in endothelial cells by inhibiting PKCβII-mediated serine phosphorylation of p66shc, and mitigates vasoconstriction induced by activation of PKC. ### Final_Prediction: yes

### Question: Does myocyte apoptosis occur early during the development of pressure-overload hypertrophy in infant myocardium? ### Context: Abnormal hemodynamic loading often accompanies congenital heart disease both before and after surgical repair. Adaptive and maladaptive myocardial responses to increased load are numerous. This study examined the hypothesis that myocyte loss occurs during compensatory hypertrophic growth in the developing infant myocardium subjected to progressive pressure overload.Pressure-overload left ventricular hypertrophy was induced in 7- to 10-day-old rabbits by banding the thoracic aorta. Left ventricular function and mechanics were quantified by serial echocardiography and noninvasive left ventricular wall stress analysis. Left ventricular tissue sections were examined for fibrosis by using Masson's trichrome stain and for myocyte apoptosis by using a myocyte-specific DNA fragmentation assay and caspase-3 activation (specific fluorescent substrate).Significant myocyte apoptosis (198 +/- 37/10(6) myocytes, P < .01 vs control) and caspase-3 activation were present in early hypertrophy when left ventricular contractility was preserved and compensatory hypertrophy had normalized wall stress. By 6 weeks, multiple indices of left ventricular contractility were reduced, and left ventricular wall stress was increased. Myocyte apoptosis was accelerated (361 +/- 56/10(6) myocytes), caspase-3 activity further increased, and the estimated total number of left ventricular myocytes was significantly reduced by 18% +/- 4%. ### Long_Answer: In experimental infant left ventricular hypertrophy, myocyte apoptosis is initiated in the face of normalized wall stress and preserved contractility. The ongoing rate of apoptosis causes a measurable decrease in myocyte number that is coincident with the onset of ventricular dysfunction. It thus appears that pressure overload, even at its earliest stages, is not well tolerated by the developing ventricle. ### Final_Prediction: yes

### Question: Does spinal radiation before surgical decompression adversely affect outcomes of surgery for symptomatic metastatic spinal cord compression? ### Context: A retrospective chart review was performed.To determine whether preoperative spinal radiation increases the number of major wound complications in patients with cancer who have symptomatic spinal cord compression.Many factors have increased the number of patients hospitalized with symptomatic spinal cord compression after spinal irradiation. The surgical management of metastatic spinal cord compression may be complicated by preoperative radiation.A retrospective review of 123 patients admitted with symptomatic metastatic spinal cord compression from 1970 through 1996 was conducted. The final study population of 85 patients was separated into three treatment groups: 1) radiation only, 2) radiation followed by surgery, and 3) de novo surgery followed by radiation.The major wound complication rate for patients who had radiation before surgical decompression and stabilization was 32%, or threefold, higher than the 12% observed in patients who had de novo surgery (P < 0.05). No other clinical factor or condition predicted the development of a major wound complication. Patients treated initially with surgery had superior functional outcomes in an analysis stratified by Frankel grade (P < 0.05). Of the ambulatory patients who underwent de novo surgery, 75% remained ambulatory and continent 30 days after treatment, whereas only 50% of those treated with radiation before surgery had similar outcomes. ### Long_Answer: Spinal radiation before surgical decompression for metastatic spinal cord compression is associated with a significantly higher major wound complication rate. In addition, preoperative spinal irradiation might adversely affect the surgical outcome. ### Final_Prediction: yes

### Question: Does oral uridine supplementation antagonize the peripheral neuropathy and encephalopathy induced by antiretroviral nucleoside analogues? ### Context: Peripheral neuropathy and central nervous system neurodegeneration may result from the mitochondrial toxicity of some antiretroviral nucleoside analogues. We investigated whether this neuropathology may be antagonized by uridine supplementation in vivo.Because of the obvious difficulties in obtaining human neural tissues, the mitochondrial neurotoxicity of the nucleoside analogues was studied in mice.BALB/C mice (7 weeks of age) were fed for 9 weeks with zalcitabine (13 mg/kg per day) or zidovudine (100 mg/kg per day) with or without mitocnol (340 mg/kg per day), a dietary supplement with high uridine bioavailability. Hippocampal and sciatic nerve mitochondria were analyzed.Zalcitabine and to a lesser extent zidovudine induced a significant peripheral neuropathy and encephalopathy with disrupted mitochondrial ultrastructure, depleted mitochondrial DNA, reduced levels of cytochrome c oxidase activity and diminished expression of mitochondrial DNA-encoded cytochrome c oxidase subunit I. Mitocnol had no intrinsic effects but attenuated or fully normalized all measured disorder of the peripheral and central nervous system. ### Long_Answer: Zidovudine and zalcitabine induce a mitochondrial disorder in the peripheral and central nervous system, both of which are antagonized by uridine supplementation. ### Final_Prediction: yes

### Question: Are urologists and radiologists equally effective in determining the RENAL Nephrometry score? ### Context: The RENAL nephrometry score (RNS) allows description of the anatomy and the complexity of renal masses. This study aimed to investigate the interobserver reproducibility of the RNS between a radiologist and a urologist.The computed tomography (CT) scans of patients undergoing partial nephrectomy in the authors' department between June 2010 and June 2013 were analyzed for determination of the RNS by a urologist and a radiologist blinded to the medical records. Cohen's kappa coefficient was used for interobserver reproducibility assessment. Correlations with per- and postoperative complication rates and renal function were assessed.The study included 52 consecutive patients with a mean age of 55 years. The average score was 7.4 ± 1.7 for the urologist and 7.3 ± 1.5 for the radiologist. The Cohen's kappa was 0.81 for R, 0.47 for E, 0.63 for N, 0.28 for A, and 0.21 for L. The Pearson's coefficient for the total RNS was 0.70. The operative time and the occurrence of major complications were significantly correlated with the complexity assessed by the score of both observers. In the univariate analysis, the RNS, the American Society of Anesthesiologists score, and the patient's age were significantly associated with major complication rates. In the multivariate analysis, the RNS remained significantly associated with major complications. No significant difference in postoperative renal function according to complexity group was found by either the urologist or the radiologist. ### Long_Answer: The reproducibility of the RNS between the radiologist and the urologist was not very good, especially for some items referring to the location of the tumor, although the major complication rates were significantly associated with the RNS for both observers. ### Final_Prediction: nan

### Question: Does glucose in bronchial aspirates increase the risk of respiratory MRSA in intubated patients? ### Context: The risk of nosocomial infection is increased in critically ill patients by stress hyperglycaemia. Glucose is not normally detectable in airway secretions but appears as blood glucose levels exceed 6.7-9.7 mmol/l. We hypothesise that the presence of glucose in airway secretions in these patients predisposes to respiratory infection.An association between glucose in bronchial aspirates and nosocomial respiratory infection was examined in 98 critically ill patients. Patients were included if they were expected to require ventilation for more than 48 hours. Bronchial aspirates were analysed for glucose and sent twice weekly for microbiological analysis and whenever an infection was suspected.Glucose was detected in bronchial aspirates of 58 of the 98 patients. These patients were more likely to have pathogenic bacteria than patients without glucose detected in bronchial aspirates (relative risk 2.4 (95% CI 1.5 to 3.8)). Patients with glucose were much more likely to have methicillin resistant Staphylococcus aureus (MRSA) than those without glucose in bronchial aspirates (relative risk 2.1 (95% CI 1.2 to 3.8)). Patients who became colonised or infected with MRSA had more infiltrates on their chest radiograph (p<0.001), an increased C reactive protein level (p<0.05), and a longer stay in the intensive care unit (p<0.01). Length of stay did not determine which patients acquired MRSA. ### Long_Answer: The results imply a relationship between the presence of glucose in the airway and a risk of colonisation or infection with pathogenic bacteria including MRSA. ### Final_Prediction: yes

### Question: Are low-abundant adiponectin receptors in visceral adipose tissue of humans and rats further reduced in diabetic animals? ### Context: Adipose tissue is an endocrine organ that releases various proteins that may also exert autocrine/paracrine effects. The antidiabetic adipokine adiponectin acts through two receptors, AdipoR1 and AdipoR2, but so far mainly mRNA expression has been measured in adipocytes and adipose tissues. Therefore, we aimed to analyze AdipoR1 and AdipoR2 proteins in adipocytes and paired samples of subcutaneous and visceral adipocytes/adipose tissue.AdipoR1 and AdipoR2 mRNA and protein expression were determined in adipocytes and paired samples of subcutaneous and visceral adipose tissue of humans and rats.AdipoR1 and AdipoR2 proteins were similarly abundant in preadipocytes and mature adipocytes despite an induction of mRNA expression during differentiation. Differentiation of 3T3-L1 cells in the presence of palmitic acid did not alter adiponectin receptor proteins but metformin and fenofibrate upregulated AdipoR2 within 24 h of incubation. AdipoR2 protein was significantly lower in human visceral compared to subcutaneous fat, and both receptors were reduced in visceral adipocytes. In rat tissues both receptors were reduced in visceral fat. In diabetic animals AdipoR2 protein, but not mRNA, was lower in both fat depots compared to similarly obese rats with normal glucose disposal. AdipoR1 was only reduced in subcutaneous adipose tissue of diabetic animals where mRNA expression was induced. ### Long_Answer: These data indicate that mRNA expression is not suitable to predict adiponectin receptor protein. Low adiponectin receptors in visceral adipocytes and adipose tissue and further suppression in adipose tissue of insulin-resistant animals indicate disturbed adiponectin bioactivity. ### Final_Prediction: yes