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Do acute coronary syndrome patients with depression have low blood cell membrane omega-3 fatty acid levels? To determine the extent to which levels of membrane eicosapentaenoic (EPA)+docosahexaenoic acids (DHA) (the omega-3 index) were associated with depression in patients with acute coronary syndrome (ACS). Depression is associated with worse cardiovascular (CV) outcomes in patients with ACS. Reduced levels of blood cell membrane omega-3 (n-3) fatty acids (FAs), an emerging risk factor for both CV disease and depression, may help to explain the link between depression and adverse CV outcomes. We measured membrane FA composition in 759 patients with confirmed ACS. The analysis included not only EPA and DHA but also the n-6 FAs linoleic and arachidonic acids (LA and AA). Depressive symptoms were measured with the Patient Health Questionnaire-9 (PHQ). Multivariable linear regression was used to adjust for demographic and clinical characteristics. There was a significant inverse relationship between the n-3 index and depressive symptoms (PHQ) in the fully adjusted model (p = .034). For every 4.54% point rise in the n-3 index, there was a 1-point decline in depressive symptoms. In contrast to the n-3 FAs, membrane levels of the n-6 FAs LA and AA were not different between depressed and nondepressed ACS patients.

We found an inverse relationship between the n-3 index and the prevalence of depressive symptoms in patients with ACS. Therefore, this study supports the hypothesis that reduced n-3 FA tissue levels are a common and potentially modifiable link between depression and adverse CV outcomes.

Do cell-cycle markers improve discrimination of EORTC and CUETO risk models in predicting recurrence and progression of non-muscle-invasive high-grade bladder cancer? To assess if a panel of cell-cycle markers could improve the discrimination of European Organization for Research and Treatment of Cancer (EORTC) and Spanish Urological Club for Oncological Treatment (CUETO) models in predicting recurrence and progression of high-grade non-muscle-invasive bladder cancer (NMIBC). Between January 2007 and January 2012, every patient with high-grade NMIBC treated with transurethral resection of bladder underwent immunohistochemical staining for 5 biomarkers (p21, p27, p53, KI-67, and cyclin E1). We excluded patients who had muscle-insvasive disease, underwent early cystectomy, and those with incomplete follow-up. Kaplan-Meier curves assessed recurrence and progression-free survival. Univariate and multivariate Cox regression analysis assessed the predictive ability of markers after correcting for EORTC or CUETO risk scores. Harrel concordance index assessed for discrimination. There were 131 patients with a median follow-up of 31.1 months. Stage was Ta (50%), T1 (44%), and Tis (8%). For 95 patients this was the primary tumor. Intravesical therapy was used in 76% of cases of which 45% had maintenance. Recurrence-free survival rates at 6, 12, and 24 months were 68.9%, 52.1%, and 33.2%, respectively, whereas progression-free survival rate at 6, 12, and 24 months were 93.8%, 88%, and 84.3%, respectively. No differences in survival based on number of altered markers were noted. Biomarker status was neither a significant predictor of recurrence nor progression. Marker alterations marginally improved discrimination of EORTC and CUETO models, which were confirmed to be mediocre.

Markers were not significant predictors of recurrence nor progression in patients with high-grade NMIBC and their addition to prediction models is of little benefit.

Does erythropoietin attenuate oxidative stress and apoptosis in Schwann cells isolated from streptozotocin-induced diabetic rats? High glucose-evoked oxidative stress and apoptosis within Schwann cells (SCs) are mechanisms facilitating the procession of diabetic peripheral neuropathy (DPN). Although erythropoietin (EPO) was demonstrated to have neuroprotective effects in neurodegenerative diseases, the effects of EPO on glucose-evoked oxidative stress and apoptosis of SCs remain unknown. Primary cultured SCs isolated from streptozotocin (STZ)-induced diabetic peripheral neuropathic rats and normal control rats were exposed to high or normal glucose condition with or without EPO incubation for 72 h. Cell viability, apoptotic rate, cellular reactive oxygen species (ROS) level, total glutathione (GSH) level, EPO mRNA and erythropoietin receptor (EPOR) mRNA levels were assayed. SCs from diabetic rats showed a lower cell viability and a higher apoptotic rate. High glucose culture condition elevated ROS level and diminished total GSH level of SCs. EPO improved cell viability and decreased cell apoptotic rate of SCs. EPO also elevated total GSH level and decreased intracellular ROS level. SCs from diabetic rats exhibited higher EPO mRNA and EPOR mRNA levels than SCs from normal control rats.

The data of this study offered fresh viewpoints for interpreting the pathogenesis of DPN and novel pharmacological principles implicit in the therapeutic effect of EPO.

Are hunger and thirst numeric rating scales valid estimates for gastric content volumes : a prospective investigation in healthy children? A rating scale for thirst and hunger was evaluated as a noninvasive, simple and commonly available tool to estimate preanesthetic gastric volume, a surrogate parameter for the risk of perioperative pulmonary aspiration, in healthy volunteer school age children. Numeric scales with scores from 0 to 10 combined with smileys to rate thirst and hunger were analyzed and compared with residual gastric volumes as measured by magnetic resonance imaging and fasting times in three settings: before and for 2 h after drinking clear fluid (group A, 7 ml/kg), before and for 4 vs 6 h after a light breakfast followed by clear fluid (7 ml/kg) after 2 vs 4 h (crossover, group B), and before and for 1 h after drinking clear fluid (crossover, group C, 7 vs 3 ml/kg). In 30 children aged 6.4-12.8 (median 9.8) years, participating on 1-5 (median two) study days, 496 sets of scores and gastric volumes were determined. Large inter- and intra-individual variations were seen at baseline and in response to fluid and food intake. Significant correlations were found between hunger and thirst ratings in all groups, with children generally being more hungry than thirsty. Correlations between scores and duration of fasting or gastric residual volumes were poor to moderate. Receiver operating characteristic (ROC) analysis revealed that thirst and hunger rating scales cannot predict gastric content.

Hunger and thirst scores vary considerably inter- and intra-individually and cannot predict gastric volume, nor do they correlate with fasting times in school age children.

Do periadventitial rapamycin-eluting microbeads promote vein graft disease in long-term pig vein-into-artery interposition grafts? Neointima formation and atherosclerosis compromise long-term graft patency in aortocoronary and peripheral vein bypass grafts. We investigated the short- and long-term effects of periadventitial application of a sustained-release formulation of rapamycin on experimental pig vein grafts with similar dimensions and kinetics to human saphenous vein bypass grafts. Periadventitial application of rapamycin-eluting polyvinyl alcohol microspheres (60 microg . cm(-2)) to porcine saphenous vein-to-carotid artery interposition grafts inhibited vein graft positive and vascular smooth muscle cell proliferation in 1-week grafts. It also decreased neointima formation and wall thickening in 4-week vein grafts compared with controls. The inhibition of vein graft thickening was not sustained; however, a catch-up phenomenon was observed, and there was no therapeutic benefit evident in 12-week grafts. Increasing the dose of rapamycin to 120 microg . cm(-2) was associated with significant local toxicity manifest by high rates of graft rupture (25%), inhibition of adventitial neoangiogenesis, and a paradoxical acceleration of vein graft disease as evidenced by increased vascular smooth muscle cell proliferation.

Local toxicity and poor long-term efficacy limits the clinical applicability of locally applied, sustained rapamycin release in vein graft disease.

Is abnormal cervical cytology associated with increased nitric oxide release in the uterine cervix? The human uterine cervix is capable of producing nitric oxide (NO). We studied the impact of cytological changes on the release of cervical NO. Population-based case-control study. City of Helsinki, Finland. Cervical cytology tests and cervical fluid samples were collected in 297 women. Cervical cytology tests, classified according to Bethesda criteria, were specifically analyzed for changes typically seen in human papillomavirus (HPV) infection, and the level of NO metabolites (NOx) in cervical fluid was assessed by Griess reaction. The difference in cervical fluid NOx between normal and abnormal cytology. Cervical cytology was normal in 219 women and abnormal in 78 women. Among women with abnormal cytology there was both a higher detection rate (89% vs. 71%) and a higher concentration of NOx (median 22.5 micromol/l, 95% CI 14.6-31.9 vs. 11.0 micromol/l, 95% CI 8.0-16.7) compared to women with normal cytology. Age, parity, use of oral contraceptives, phase of the menstrual cycle, or history of miscarriage or termination of early pregnancy were not linked to an increased cervical NOx level.

Cervical cell changes (suggestive of HPV infection) are accompanied by an increased release of NO in the human cervix. The significance of this finding remains uncertain, but in theory, increased release of NO could modify the outcome of cervical infection.

Does diclazuril protect against Maternal Gastrointestinal Syndrome and Congenital Toxoplasmosis? Toxoplasmosis is a common cause of foodborne, gastrointestinal and congenital syndrome with particularly severe or unknown health consequences. There is no safe and effective preventive or therapeutic modality against congenital toxoplasmosis or to eliminate the persistent chronic infection. Diclazuril to be safe in pregnancy and effective against gastrointestinal toxoplasmosis. CD1 programmed pregnant mice were divided into groups and administered a diet containing diclazuril, or sham control. Treatments were initiated on Day 5 of pregnancy and continued until Day 16 when dams were euthanatized. On Day 8 of pregnancy dams were infected intraperitoneally with escalating doses of tachyzoites (0, 100, 300, 600) from Type II strain. Dams were monitored daily for distress, pain, and abortion and samples collected at the end of the experiments. Infected dams developed moderate to severe

This is the first report describing of diclazuril safety in pregnancy as well as efficacy against mild to moderate hepato-gastrointestinal syndrome in dams and fetal toxoplasmosis (Special issue, "Treatment of Liver Diseases").

Does [ Architectural modernization of psychiatric hospitals influence the use of coercive measures ]? Coercive measures are widely applied in psychiatric hospitals as a last resort to prevent patients seriously harming themselves or others, with negative psychological and somatic consequences for those affected. In a naturalistic observational study it was investigated whether relocation of the structural milieu of a psychiatric hospital to an architectonically improved new building influenced the application of coercive measures. The frequency and duration of coercive measures (e.g. fixation, coercive medication and preventive restraints) were routinely documented and compared in the periods before and after the relocation. After the relocation the utilization of coercive measures was significantly reduced by 48-84 %.

Despite the limitations of the study design the results suggest that the architectural improvements reduced the application of coercive measures. It is speculated that the positive structural milieu enhanced the well-being of patients and staff and their social relations, which in turn prevented coercive measures.

Do positive- and negative peer modelling effects on young children 's consumption of novel blue foods? The effects of positive- and negative peer modelling on children's consumption of a novel blue food, presented in each of four snack meals during an "activity" day, were evaluated. It was predicted that: (i) novel food consumption would increase after positive modelling, but decrease after negative modelling; (ii) modelling effects would generalise to a second novel blue food when participants were alone when they ate their snack; (iii) that positive modelling would reverse the effects of negative modelling. A mixed design was employed with random assignment to either Groups A, B, or C (equal numbers of males and females per group). Within groups, each participant received the novel food on four snack occasions. Group A received positive modelling of blue food consumption on the first and third occasions, but were alone when they received the foods on the second and fourth occasions; Group B had negative modelling on the first occasion, positive modelling on the third, and ate alone on the second and fourth; Group C ate alone on all four occasions. To measure generalisation, an additional blue food was presented in all second and fourth "alone" occasions. Thirty-five 5-7-year olds took part in Study 1, and 44 3-4-year olds in Study 2. All main predictions were confirmed except that positive peer modelling did not reverse the effects of negative modelling in the 3-4-year olds.

Negative peer modelling inhibits novel food consumption, and its effects are particularly difficult to reverse in younger children.

Are aortic and mitral annular calcifications predictive of all-cause and cardiovascular mortality in patients with type 2 diabetes? To examine the association of aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) with all-cause and cardiovascular mortality in type 2 diabetic individuals. We retrospectively analyzed the data from 902 type 2 diabetic outpatients, who had undergone a transthoracic echocardiography for clinical reasons during the years 1992-2007. AVS and MAC were diagnosed by echocardiography, and a heart valve calcium (HVC) score was calculated by summing up the AVS and MAC variables. The study outcomes were all-cause and cardiovascular mortality. At baseline, 477 (52.9%) patients had no heart valves affected (HVC-0), 304 (33.7%) had one valve affected (HVC-1), and 121 (13.4%) had both valves affected (HVC-2). During a mean follow-up of 9 years, 137 (15.2%) patients died, 78 of them from cardiovascular causes. Compared with patients with HVC-0, those with HVC-2 had the highest risk of all-cause and cardiovascular mortality, whereas those with HVC-1 had an intermediate risk (P < 0.0001 by the log-rank test). After adjustment for sex, age, BMI, systolic blood pressure, diabetes duration, A1C, LDL cholesterol, estimated glomerular filtration rate, smoking, history of myocardial infarction, and use of antihypertensive and lipid-lowering drugs, the hazard ratio of all-cause mortality was 2.3 (95% CI 1.1-4.9; P < 0.01) for patients with HVC-1 and 9.3 (3.9-17.4; P < 0.001) for those with HVC-2. Similar results were found for cardiovascular mortality.

Our findings indicate that AVS and MAC, singly or in combination, are independently associated with all-cause and cardiovascular mortality in type 2 diabetic patients.

Does rNA binding protein QKI inhibit the ischemia/reperfusion-induced apoptosis in neonatal cardiomyocytes? RNA-binding protein QKI is abundantly expressed in the brain and heart. The role of QKI in the nervous system has been well characterized, but its function in cardiac muscle is still poorly understood. The present study was to investigate the role of QKI in ischemia/reperfusion-induced apoptosis in cardiomyocytes. A simulated ischemia/reperfusion model was established in neonatal cardiomyocytes and adult rat heart. After QKI5 or QKI6 was expressed by adenovirus and QKI was knocked down QKI by RNAi in the cardiomyocytes, RT-PCR, western blot and immunofluorescence staining were applied to detect gene expression alterations. Apoptosis was evaluated by PARP degradation, DNA fragmentation (DNA laddering) and flow cytometry. Our study demonstrated that both QKI5 and QKI6 were present in cardiomyocytes, while QKI5 expression was greatly inhibited by simulated ischemia/reperfusion. Knocking down endogenous QKI by RNAi enhanced cell susceptibility to apoptosis, whereas overexpression of either QKI5 or QKI6 suppressed IR-induced apoptosis substantially. The pro-apoptotic transcription factor FoxO1, a potential QKI target, was induced by ischemia/reperfusion at both total amount and nuclear distribution. Accordingly, FOXO1 downstream target genes were negatively affected by the presence of QKI with IR treatment.

In summary, our study supports that both QKI-5 and 6 are anti-apoptotic proteins in cardiomyocytes, favoring cardiac survival via antagonizing the elevation of some pro-apoptotic factors in cardiac injury.

Does pancreatic-duct stent placement facilitate difficult common bile duct cannulation? Cannulation of the common bile duct can be difficult in certain instances. Difficult cannulation has been demonstrated to be a risk factor for post-ERCP pancreatitis. We report a technique to facilitate difficult cannulation that uses a pancreatic-duct stent to guide biliary cannulation. A retrospective review of all ERCPs performed at our institution from October 1, 2000 to June 30, 2004 (1638) was performed to identify all cases in which a pancreatic-duct stent was placed to guide common bile duct cannulation. Charts on these patients then were reviewed to assess cannulation success and complications. In addition, indications for the ERCP and previously failed cannulation attempts by outside physicians were documented. Thirty-nine patients had pancreatic-duct stents placed as an aid to guide common bile duct cannulation. Successful cannulation of the bile duct was achieved in 38 of the 39 patients (97.4%) Procedure-related pancreatitis occurred in two patients and was mild in both. There were no procedure-related deaths.

In cases of difficult common bile duct cannulation, placement of a pancreatic-duct stent as a guide to aid common bile duct cannulation appears to be an effective and safe technique.

Are systemic factors trophic in Thiry-Vella loop in the absence of luminal contents? Mucosal histology, crypt cell proliferation and brush border enzymes were measured in rats with varying degrees of Thiry-Vella fistulas, in order to compare the effect of systemic and luminal factors on adaptive growth and differentiation (brush border enzymes) in small intestinal epithelium. Twenty-four male Wistar rats (300-350 g) were divided with three groups of eight which underwent the following operations: 20% Thiry-Vella fistula, 80% Thiry-Vella fistula and sham operation. 80% Thirty-Vella fistulas caused a functional short gut; in intestine remaining in continuity there were significant increases in segmental weight, protein, Alp activity and villus height, compared with sham-operated controls and 20% Thiry-Vella fistulas. There was a significant fall in villus height, crypt cell production in loops of 20% Thiry-Vella fistula rats not exposed to luminal contents compared with control segments of sham-operated rats. In contrast, loops of the 80% Thiry-Vella fistula rats were not atrophied despite the much greater distance from luminal nutrients; the villus height and PCNA-LI were higher than in 20% Thiry-Vella fistula rats, and at least as great as in sham-operated rats.

This study indicates that atrophy does not occur in loops after 80% Thiry-Vella fistula because crypt cell proliferation is maintained in Thiry-Vella fistulas. Thus, the atrophic effect of diversion of luminal nutrients can be counteracted by systemic growth factors released as part of the adaptive response; luminal factors are not essential for maintenance of normal cellular turnover when there is a powerful stimulus to cell proliferation.

Do higher-order contrast functions improve performance of independent component analysis of fMRI data? To evaluate the performance of different contrast functions used in Independent Component Analysis (ICA) of functional magnetic resonance imaging (fMRI) data at low signal-to-noise ratio (SNR), present in fMRI paradigms such as resting-state acquisitions. Metrics were defined to estimate both the accuracy and robustness of contrast functions under varying source distributions. Simulations were performed to compare the performance of lower-order (such as ln cosh) to higher-order (such as kurtosis) contrast functions using Laplacian source distributions corrupted with Gaussian noise. The ln cosh and kurtosis contrast functions were also compared using resting-state fMRI data from 10 normal adult volunteers. Higher-order contrast functions provided superior performance compared to lower-order contrast functions in the evaluation of metrics and via the simulations in the presence of a significant amount of noise. The performance of kurtosis was not statistically significantly different from that of a theoretically optimized contrast function. The choice of contrast function was found to result in substantial (R < 0.9) differences in 40% of the components found from the resting-state fMRI data.

The use of higher-order contrast functions, such as kurtosis, may provide superior performance in ICA analysis of fMRI data with low SNR.

Does clotting factor concentrate given to prevent bleeding and bleeding-related complications in people with hemophilia A or B? People with severe hemophilia A or B, X-linked bleeding disorders due to decreased blood levels of coagulants, suffer recurrent bleeding into joints and soft tissues. Before clotting factor concentrates were available, most people with severe hemophilia developed crippling musculoskeletal deformities. Clotting factor concentrate prophylaxis aims to preserve joint function by converting severe hemophilia (factor VIII or IX less than 1%) into a clinically milder form of the disease. Prophylaxis has long been used in Sweden, but not universally adopted because of medical, psychosocial, and cost controversies. Use of clotting factor concentrates is the single largest predictor of cost in treating hemophilia. To determine the effectiveness of clotting factor concentrate prophylaxis in the management of people with hemophilia A or B. We searched the Cystic Fibrosis and Genetic Disorders Group's Trials Register comprising references from comprehensive electronic database searches and handsearches of journals and abstract books. Reference lists of relevant articles were reviewed. Most recent search: January 2002. Randomized controlled trials (RCTs) evaluating people with severe hemophilia A or B, receiving prophylactic clotting factor concentrates. Two reviewers independently reviewed studies for eligibility, assessed methodological quality and extracted data. Twenty-nine studies were identified, of which four (including 37 participants) were eligible for inclusion. Three studies evaluated hemophilia A; one showed a decrease in frequency of joint bleeds with prophylaxis compared to placebo (non-physiological dose), with a rate difference (RD) -10.80 (95% confidence interval (CI) -16.33 to -5.27) bleeds per year. The remaining two studies evaluating hemophilia A compared two prophylaxis regimens, one study showed no difference in joint bleed frequency, RD -5.04 (95%CI -17.02 to 6.94) bleeds per year and another failed to demonstrate an advantage of factor VIII dosing based on individual pharmacokinetic data over the standard prophylaxis regimen with RD -0.14 (95% CI -1.34 to 1.05) bleeds per year. The fourth study evaluated hemophilia B and showed fewer joint bleeds with weekly (15 IU/kg) versus bi-weekly (7.5 IU/kg) prophylaxis, RD -3.30 (95% CI -5.50 to - 1.10) bleeds per year.

There is insufficient evidence to determine whether prophylactic clotting factor concentrates decrease bleeding and bleeding-related complications in hemophilia A or B, compared to placebo, on-demand treatment, or prophylaxis based on pharmacokinetic data from individuals. Well-designed RCTs are needed to assess the effectiveness of prophylactic clotting factor concentrates. Two clinical trials are ongoing.

Is carotid endothelial shear stress reduction with aging associated with plaque development in twelve years? Atherosclerosis is associated with clinical, biochemical and haemodynamic risk factors. In a group of subjects studied twelve years apart, we evaluated carotid plaque development in relation to baseline and to changes at follow-up in common carotid haemodynamic profile. Forty-eight participants were recruited to a cardiovascular disease prevention programme. Atherosclerotic plaques were evaluated and scored by echography. Endothelial shear stress, circumferential wall tension, and Peterson's elastic modulus as an index of arterial stiffness, were computed by echo-Doppler, along with blood viscosity data. Binary logistic regression analyses were used to test the association among the development of atherosclerosis, cardiovascular risk factors and haemodynamic variations. Analyses were also performed on participants who presented at the follow-up with carotid haemodynamic variations in the left or right common carotid only. Participants (69% male) were aged 64.5 ± 9.7 years at follow-up. Peak and mean endothelial shear stress was significantly lower at follow-up as previously reported; circumferential wall tension and arterial stiffness were significantly higher. Carotid plaque scores increased after 12 years (0.39 ± 0.72 vs. 0.67 ± 0.86, p < 0.01). Of the 96 common carotids analysed, shear stress reduction with aging was an independent predictor of carotid atherosclerosis (B = -0.063; odds ratio = 0.94; p = 0.01). Out of 48 participants, 21 (44%) showed shear stress reduction with aging in only one side of the body and, on this side, the plaque score increased (0.52 ± 0.98 vs. 0.90 ± 0.94, p < 0.05), remaining unchanged in the contralateral carotid tree.

Aging-related shear stress reduction is an independent predictor of atherosclerosis development.

Are cannabinoid receptors 1 and 2 associated with bladder dysfunction in an experimental diabetic rat model? To investigate diabetes-associated changes in urinary bladder expression of cannabinoid receptors 1 and 2 (CB1 and CB2) and the functional role of CB agonists and antagonists in mediating phasic contractions of isolated bladder strips using a streptozotocin-induced diabetic rat model. The bladder and dorsal root ganglion (DRG) were removed from diabetic rats and age-matched controls 8-10 weeks after diabetes induction. Expression of CB1 and CB2 mRNA was studied using quantitative real-time PCR and protein levels were determined by Western blot analysis. The effect of increasing concentrations (0.1-100 μM) of the mixed CB1/CB2 agonist R(+)-WIN 55,212-2 (WIN), selective CB1 antagonist (AM251) and selective CB2 antagonist (AM630) on carbachol-evoked contraction of bladder strips from control and diabetic rats was investigated. WIN-induced alterations of bladder strip contraction were then studied after pre-incubation with AM251 and AM630. Diabetes induced decreased CB1 protein and mRNA expression in both the bladder and DRG (P < 0.05), while decreased CB2 expression was observed in the bladder (P < 0.05). WIN decreased the amplitude, but not frequency, of carbachol-induced phasic contractions of bladder strips in a concentration-dependent manner and this effect was diminished in the diabetic state. AM630 and AM251 had no effect on isolated detrusor muscle function. Moreover, pre-incubation with AM251 partially counteracted the effect of WIN on detrusor muscle contraction.

The results indicate that CB1 and CB2 are responsible for the pathogenesis of bladder dysfunction in diabetes mellitus and represent a viable target for pharmacological treatment of bladder cystopathy.

Is catastrophizing associated with clinical examination findings , activity interference , and health care use among patients with temporomandibular disorders? To examine whether catastrophizing is associated with clinical examination findings, pain-related activity interference, and health care use among patients with pain related to temporomandibular disorders (TMD). Patients with TMD (n = 338; 87% female; mean age, 37 years) completed measures of pain, pain-related activity interference, health care use, and depression, and received a Research Diagnostic Criteria/ Temporomandibular Disorders (RDC/TMD) clinical examination from an oral medicine specialist. Catastrophizing was not significantly associated with the more objective clinical examination measures of maximum assisted jaw opening and jaw-joint sounds, but it was associated with the more subjective examination measures (unassisted opening without pain, extraoral muscle site palpation pain severity, joint site palpation pain severity) and with increased TMD-related activity interference and number of health care visits (P values for all < .01). Even after controlling for demographic variables, pain duration, and depression severity, catastrophizing remained significantly associated with extraoral muscle and joint site palpation pain severity and with activity interference and number of health care visits.

TMD patients who catastrophize have higher scores on clinical examination measures reflecting more widely dispersed and severe pain upon palpation of TMD-related facial muscle and joint sites, as well as greater TMD-related activity interference and health care use. Clinicians should consider screening patients with moderate or greater TMD pain and activity interference for catastrophizing. Cognitive-behavioral interventions may help reduce pain, disability, and health care use of patients who catastrophize.

Is near-target caloric intake in critically ill medical-surgical patients associated with adverse outcomes? The objective of this study was to determine whether caloric intake independently influences mortality and morbidity of critically ill patients. The study was conducted as a nested cohort study within a randomized controlled trial in a tertiary care intensive care unit (ICU). The main exposure in the study was average caloric intake/target for the first 7 ICU days. The primary outcomes were ICU and hospital mortality. Secondary outcomes included ICU-acquired infections, ventilator-associated pneumonia (VAP), duration of mechanical ventilation days, and ICU and hospital length of stay (LOS). The authors divided patients (n = 523) into 3 tertiles according to the percentage of caloric intake/target: tertile I <33.4%, tertile II 33.4%-64.6%, and tertile III >64.6%. To adjust for potentially confounding variables, the authors assessed the association between caloric intake/target and the different outcomes using multivariate logistic regression for categorical outcomes (tertile I was used as reference) and multiple linear regression for continuous outcomes. Tertile III was associated with higher adjusted hospital mortality, higher risk of ICU-acquired infections, and a trend toward higher VAP rate. Increasing caloric intake was independently associated with a significant increase in duration of mechanical ventilation, ICU LOS, and hospital LOS.

The data demonstrate that near-target caloric intake is associated with significantly increased hospital mortality, ICU-acquired infections, mechanical ventilation duration, and ICU and hospital LOS. Further studies are needed to explore whether reducing caloric intake would improve the outcomes in critically ill patients.

Is the best prostate biopsy scheme dictated by the gland volume : a monocentric study? Accuracy of biopsy scheme depends on different parameters. Prostate-specific antigen (PSA) level and digital rectal examination (DRE) influenced the detection rate and suggested the biopsy scheme to approach each patient. Another parameter is the prostate volume. Sampling accuracy tends to decrease progressively with an increasing prostate volume. We prospectively observed detection cancer rate in suspicious prostate cancer (PCa) and improved by applying a protocol biopsy according to prostate volume (PV). Clinical data and pathological features of these 1356 patients were analysed and included in this study. This protocol is a combined scheme that includes transrectal (TR) 12-core PBx (TR12PBx) for PV ≤ 30 cc, TR 14-core PBx (TR14PBx) for PV > 30 cc but < 60 cc, TR 18-core PBx (TR18PBx) for PV ≥ 60 cc. Out of a total of 1356 patients, in 111 (8.2%) PCa was identified through TR12PBx scheme, in 198 (14.6%) through TR14PBx scheme and in 253 (18.6%) through TR18PBx scheme. The PCa detection rate was increased by 44% by adding two TZ cores (TR14PBx scheme). The TR18PBx scheme increased this rate by 21.7% vs. TR14PBx scheme. The diagnostic yield offered by TR18PBx was statistically significant compared to the detection rate offered by the TR14PBx scheme (p < 0.003). The biopsy Gleason score and the percentage of core involvement were comparable between PCa detected by the TR14PBx scheme diagnostic yield and those detected by the TR18PBx scheme (p = 0.362).

The only PV parameter, in our opinion, can be significant in choosing the best biopsy scheme to approach in a first setting of biopsies increasing PCa detection rate.

Are k-ras mutations at codon 12 rare events in chronic pancreatitis? The activation of the K-ras gene at codon 12 is thought to be an early genetic event in the multistep pathogenesis of pancreatic cancer. Since the risk of pancreatic cancer is significantly elevated in subjects with chronic pancreatitis, the aim of the present study was to determine the frequency of K-ras mutations in chronic pancreatitis. Pancreatic DNA from intraoperatively resected tissues of 60 patients with chronic pancreatitis and 11 patients with histologically confirmed pancreatic carcinoma was evaluated by PCR amplification and restriction fragment length polymorphism analysis. In none of the 60 samples of chronic pancreatitis could K-ras mutations be identified using two independent PCR assays. In 5 of 11 patients with pancreatic carcinoma, K-ras mutations in codon 12 were detected.

These data indicate that K-ras mutations are rare events in chronic pancreatitis. Alternatively, it is possible that the time span between the occurrence of K-ras mutations and malignant transformation is rather short.

Is the HU regulon composed of genes responding to anaerobiosis , acid stress , high osmolarity and SOS induction? The Escherichia coli heterodimeric HU protein is a small DNA-bending protein associated with the bacterial nucleoid. It can introduce negative supercoils into closed circular DNA in the presence of topoisomerase I. Cells lacking HU grow very poorly and display many phenotypes. We analyzed the transcription profile of every Escherichia coli gene in the absence of one or both HU subunits. This genome-wide in silico transcriptomic approach, performed in parallel with in vivo genetic experimentation, defined the HU regulon. This large regulon, which comprises 8% of the genome, is composed of four biologically relevant gene classes whose regulation responds to anaerobiosis, acid stress, high osmolarity, and SOS induction.

The regulation a large number of genes encoding enzymes involved in energy metabolism and catabolism pathways by HU explains the highly pleiotropic phenotype of HU-deficient cells. The uniform chromosomal distribution of the many operons regulated by HU strongly suggests that the transcriptional and nucleoid architectural functions of HU constitute two aspects of a unique protein-DNA interaction mechanism.

Does a nonmetropolitan surgery clerkship increase interest in a surgical career? The optimal way to recruit the best and brightest medical students to fill the impending shortfall of general surgeons is uncertain. Forty-three students were placed into nonmetropolitan sites for their basic surgical clerkship over 3 years. We surveyed students and compared match trends. When students selected to participate in the nonmetropolitan clerkship were examined, only 22% of students reported interest in a surgical career before their clerkship. This interest in surgery increased to 63% after the nonmetropolitan clerkship, P < .05. When match numbers were examined, students who completed the nonmetropolitan clerkship were significantly more likely to match to a general surgical residency than students who completed the standard clerkship (17% vs 6%, P < .02).

These data challenge the perception that students should remain at a teaching university for their introductory clerkships. It may be that pairing students with individual faculty, or chief residents, could increase interest in a surgical career.

Does cigarette smoke exposure inhibit extracellular MMP-2 ( gelatinase A ) activity in human lung fibroblasts? Exposure to cigarette smoke is considered a major risk factor for the development of lung diseases, since its causative role has been assessed in the induction and maintenance of an inflamed state in the airways. Lung fibroblasts can contribute to these processes, due to their ability to produce proinflammatory chemotactic molecules and extracellular matrix remodelling proteinases. Among proteolytic enzymes, gelatinases A and B have been studied for their role in tissue breakdown and mobilisation of matrix-derived signalling molecules. Multiple reports linked gelatinase deregulation and overexpression to the development of inflammatory chronic lung diseases such as COPD. In this study we aimed to determine variations in the gelatinolytic pattern of human lung fibroblasts (HFL-1 cell line) exposed to cigarette smoke extract (CSE). Gelatinolytic activity levels were determined by using gelatin zymography for the in-gel detection of the enzymes (proenzyme and activated forms), and the subsequent semi-quantitative densitometric evaluation of lytic bands. Expression of gelatinases was evaluated also by RT-PCR, zymography of the cell lysates and by western blotting. CSE exposure at the doses used (1-10%) did not exert any significant cytotoxic effects on fibroblasts. Zymographic analysis showed that CSE exposure resulted in a linear decrease of the activity of gelatinase A. Control experiments allowed excluding a direct inhibitory effect of CSE on gelatinases. Zymography of cell lysates confirmed the expression of MMP-2 in all conditions. Semi-quantitative evaluation of mRNA expression allowed assessing a reduced transcription of the enzyme, as well as an increase in the expression of TIMP-2. Statistical analyses showed that the decrease of MMP-2 activity in conditioned media reached the statistical significance (p = 0.0031 for 24 h and p = 0.0012 for 48 h), while correlation analysis showed that this result was independent from CSE cytotoxicity (p = 0.7833 for both exposures).

Present work describes for the first time that, apart well characterized proinflammatory responses, human lung fibroblasts may react to CSE with a significant reduction of extracellular MMP-2 lytic activity. Therefore, fibroblasts may actively participate to the alteration of the proteolysis/antiproteolysis balance, which reflects the defective repair of the extracellular matrix. Such event should provide a further contribution to the maintenance of the inflamed state in the lungs.

Does integrin-associated protein association with SRC homology 2 domain containing tyrosine phosphatase substrate 1 regulate igf-I signaling in vivo? Smooth muscle cell (SMC) maintained in medium containing normal levels of glucose do not proliferate in response to IGF-I, whereas cells maintained in medium containing 25 mmol/l glucose can respond. The aim of this study was to determine whether signaling events that have been shown to be required for stimulation of SMC growth were regulated by glucose concentrations in vivo. We compared IGF-I-stimulated signaling events and growth in the aortic smooth muscle cells from normal and hyperglycemic mice. We determined that, in mice, hyperglycemia was associated with an increase in formation of the integrin-associated protein (IAP)/Src homology 2 domaine containing tyrosine phosphatase substrate 1 (SHPS-1) complex. There was a corresponding increase in Shc recruitment to SHPS-1 and Shc phosphorylation in response to IGF-I. There was also an increase in mitogen-activated protein kinase activation and SMC proliferation. The increase in IAP association with SHPS-1 in hyperglycemia appeared to be due to the protection of IAP from cleavage that occurred during exposure to normal glucose. In addition, we demonstrated that the protease responsible for IAP cleavage was matrix metalloprotease-2. An anti-IAP antibody that disrupted the IAP-SHPS-1 association resulted in complete inhibition of IGF-I-stimulated proliferation.

Taken together, our results support a model in which hyperglycemia is associated with a reduction in IAP cleavage, thus allowing the formation of the IAP-SHPS-1 signaling complex that is required for IGF-I-stimulated proliferation of SMC.

Does uncoupling protein-2 negatively regulate polymorphonuclear leukocytes chemotaxis via modulating [ Ca2+ ] influx? Previous studies demonstrated that uncoupling protein 2 (UCP2) plays a negative role in modulating leukocyte inflammatory responses. The mechanism underneath the role of UCP2 in modulating leukocyte inflammatory responses, however, is incompletely understood. Here, we investigated the effect of UCP2 in polymorphonuclear leukocyte (PMN) chemotaxis. First, we assessed PMN chemotaxis in zymosan-induced murine peritonitis and found that UCP2(-/-) mice had significantly more migrated PMN in peritoneal lavage compared to their wild-type littermates. In vitro transmigration assays using isolated PMN also showed that PMN from UCP2(-/-) mice migrated faster than those from wild-type mice in response to N-formyl-methionyl-leucyl-phenylalanine (fMLP). Second, in supporting an inhibitory role of UCP2 in PMN transmigration, migrated PMN had a decreased UCP2 expression compared to nonmigrated PMN. In contrast, in streptozotocin-induced diabetic mice in which UCP2 expression was enhanced, PMN chemotaxis was reduced. Third, comparing to UCP2(+/+) PMN, UCP2(-/-) PMN had a stronger upregulation of fMLP-induced surface CD11b/CD18 and CD11a/CD18. Finally, UCP2(-/-) PMN showed a quicker and larger fMLP-triggered intracellular calcium mobilization compared to UCP2(+/+) PMN.

Our study demonstrates that UCP2 serves as a brake in controlling PMN chemotaxis and that the effect of UCP2 on PMN chemotaxis may be through modulating calcium influx.

Does lactobacillus suntoryeus inhibit pro-inflammatory cytokine expression and TLR-4-linked NF-kappaB activation in experimental colitis? Lactic acid bacteria (LAB) can improve disturbances of indigenous microflora as well as inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease. We examined the anticolitic effect of Lactobacillus suntoryeus HY7801, which inhibited toll-like receptor (TLR)-4-linked NF-kappaB activation in human embryonic kidney (HEK) cells, in 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitic mice. We measured the ability of commercial and intestinal LAB to inhibit lipopolysaccharide (LPS)-stimulated, TLR-4-linked NF-kappaB activation in HEK cells, as well as to inhibit colitis outcomes in TNBS-induced colitic mice. We also measured levels of the inflammatory markers, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, and IL-6, and their transcription factor, NF-kappaB, in intestinal mucosa by enzyme-linked immunosorbent assay and immunoblotting.

LAB inhibited TLR-4-linked NF-kappaB activation, and L. suntoryeus HY7801 was the most potent inhibitor. Intrarectal treatment of TNBS in mice caused colon shortening and also increased colonic expression of IL-1beta, IL-6, and TNF-alpha expression. However, oral administration of Lactobacillus HY7801 (100 mg/kg) inhibited colon shortening (p < 0.001) and myeloperoxidase activity in TNBS-induced colitic mice (p < 0.0002) and also decreased colonic expression of IL - 1beta (p < 0.003), IL-6 (p < 0.0001), and TNF-alpha (p < 0.0001). Lactobacillus HY7801 inhibited the NF-kappaB activation and TLR-4 expression induced by TNBS, as well as the expression of cyclooxygenase 2. Lactobacillus HY7801 also reduced the activity of intestinal bacterial glycosaminoglycan degradation and beta-glucuronidase induced by TNBS.

Do short-term magnetic field exposures ( 60 Hz ) induce protection against ultraviolet radiation damage? To investigate the ability of electromagnetic (EM) field pre-exposures to induce protection in chick embryos against subsequent ultraviolet (UV) light exposure. Chick embryos in the 4th day of gestation were exposed for 20 minutes (short term) or 96 hours (long term) to 60 Hz, 8 microT magnetic or sham fields (controls) followed by 30 minutes rest. They were then exposed to UV radiation of either low (30J/m2) or high (45J/m2) intensity (long term was exposed only to 30J/m2) for 75 minutes. Mortality measurements were made every 30 minutes following UV exposure. At both UV intensities, short-term, EM field-exposed embryos showed significantly higher post-UV survival (p<0.05) at each time point as compared to controls. Long-term EM field exposures, however, offered no protection against low intensity UV light, in fact, 96 hour-EM field-exposed embryos were significantly less protected than non-EM field-exposed controls (p<0.05).

Results of the present study demonstrate that EM field exposures of appropriate duration induce protection against damage from UV light exposure. Because EM field exposures have been reported to activate stress protein response pathways and protect against anoxia/re-oxygenation damage, stress proteins are thought to play a role in the observed UV protection.

Does dexamethasone inhibit the Nox-dependent ROS production via suppression of MKP-1-dependent MAPK pathways in activated microglia? Nox-2 (also known as gp91phox), a subunit component of NADPH oxidases, generates reactive oxygen species (ROS). Nox-dependent ROS generation and nitric oxide (NO) release by microglia have been implicated in a variety of diseases in the central nervous system. Dexamethasone (Dex) has been shown to suppress the ROS production, NO release and inflammatory reaction of activated microglial cells. However, the underlying mechanisms remain unclear. The present study showed that the increased ROS production and NO release in activated BV-2 microglial cells by LPS were associated with increased expression of Nox-2 and iNOS. Dex suppressed the upregulation of Nox-2 and iNOS, as well as the subsequent ROS production and NO synthesis in activated BV-2 cells. This inhibition caused by Dex appeared to be mediated by upregulation of MAPK phosphatase-1 (MKP-1), which antagonizes the activity of mitogen-activated protein kinases (MAPKs). Dex induced-suppression of Nox-2 and -upregulation of MKP-1 was also evident in the activated microglia from corpus callosum of postnatal rat brains. The overexpression of MKP-1 or inhibition of MAPKs (by specific inhibitors of JNK and p38 MAPKs), were found to downregulate the expression of Nox-2 and iNOS and thereby inhibit the synthesis of ROS and NO in activated BV-2 cells. Moreover, Dex was unable to suppress the LPS-induced synthesis of ROS and NO in BV-2 cells transfected with MKP-1 siRNA. On the other hand, knockdown of Nox-2 in BV-2 cells suppressed the LPS-induced ROS production and NO release.

In conclusion, it is suggested that downregulation of Nox-2 and overexpression of MKP-1 that regulate ROS and NO may form the potential therapeutic strategy for the treatment of neuroinflammation in neurodegenerative diseases.

Do relationship between systemic bone mineral density and local bone quality as effectors of dental implant survival? This study aimed to assess (1) the relationship of systemic bone mineral density (BMD) and osteoporotic status with the surgeon's subjective assessment of local jawbone quality, and (2) whether the surgeon's subjective assessment of local jawbone quality is a predictor of implant failure. A retrospective analysis of 2,867 dental implants placed in 645 patients was accomplished. The surgeon's assessment of bone quality at the time of dental implant placement was recorded. Of those, 208 patients with 701 implants had BMD data available within 3 years. Statistical analyses were conducted to determine relationships between BMD, osteoporotic status, and local jawbone quality and to determine the relationship between local jawbone quality and implant survival. There was no association between systemic BMD and the surgeon's assessment of bone quality (p =.52) nor between osteoporotic status and the surgeon's assessment of local jawbone quality (Spearman rank correlation coefficient=0.08). Additional retrospective analysis revealed implants placed in moderate- (hazard ratio=1.67; p=.043) or poor-quality (HR=3.45, p< .001) bone (surgeon's assessment) were significantly more likely to fail than implants placed in good-quality bone.

Systemic BMD and osteoporotic status are not associated with local jawbone quality. Implants placed in good-quality bone, as assessed subjectively by the surgeon at the time of implant placement, have significantly better survival characteristics than implants placed in moderate-/poor-quality bone.

Does angiotensin II promote leptin production in cultured human fat cells by an ERK1/2-dependent pathway? The fat cell hormone leptin is known to be implicated in the pathogenesis of hypertension and cardiovascular disease. Here we tested whether angiotensin (Ang) II is involved in the control of leptin release from human adipocytes. Leptin secretion was assessed from in vitro differentiated human adipocytes by radioimmunoassay. Western blot experiments were used to test for the signaling pathway activated by Ang II. Ang II increased leptin secretion into the culture medium in a dose- and time-dependent fashion. At 10(-5) M Ang II, the leptin concentration in the medium was increased at 24 hours by 500+/-222% compared with control cultures (p<0.05). This effect was also seen at the mRNA level. Similar effects were seen after exposure of fat cells to Ang III and Ang IV. Preincubation of fat cells with candesartan, an angiotensin II type 1 receptor antagonist, or the extracellular-signal-regulated kinases 1 and 2 inhibitor UO126 completely abolished the effect of Ang II on leptin production. The peroxisome proliferator-activated receptor-gamma agonist troglitazone modestly attenuated leptin release.

In conclusion, Ang II and its metabolites stimulated leptin production in human adipocytes. This effect is mediated through an extracellular-signal-regulated kinases 1 and 2-dependent pathway and includes the angiotensin II type 1 receptor subtype.

Is antiviral response sustained after cessation of lamivudine treatment in chronic hepatitis B patients : A 10-year follow-up study? Although the ideal end point for antiviral treatment in patients with chronic hepatitis B (CHB) is loss of HBsAg, the typical clinical end points are HBeAg seroconversion in HBeAg-positive patients and long-term DNA suppression in HBeAg-negative patients. We evaluated the long-term antiviral response after cessation of lamivudine treatment in CHB patients. A total of 157 patients who had discontinued lamivudine between 1997 and 2014 were enrolled (97 HBeAg-positive and 60 HBeAg-negative CHB patients). The long-term durability of the antiviral response (viralogical relapse; HBV DNA ≥ 10 In HBeAg-positive patients, the mean follow-up period after discontinuation was 72.3 months. The cumulative probabilities of virological relapse at 1, 12, 24, 48, 60, 96, and 120 months were 10.3%, 40.2%, 55.6%, 62.8%, 65.9%, 67.0%, and 67.0%, respectively. In HBeAg-negative patients, the cumulative probabilities of a virological relapse at 1, 12, 24, 48, 60, 96, and 120 months were 25.0%, 35.0%, 41.7%, 43.3%, 43.3%, 46.7%, and 48.3%, respectively. Younger age [HR 1.732, 95% CI: 1.058-2.835, p = 0.02] was predictive of non-virological relapse in HBeAg-positive patients. And achievement of undetectable HBV DNA level within 3 months of treatment discontinuation was associated with decreased rate of virological relapse [HR 0.159, 95% CI: 0.069-0.367 p < 0.01] in HBeAg-negative patients.

Despite meeting the requirements for treatment discontinuation, approximately half of the CHB patients treated with lamivudine relapsed. Thus, the antiviral response is not reliably sustained after lamivudine treatment cessation. This article is protected by copyright. All rights reserved.

Is mortality after acute myocardial infarction lower in metropolitan regions than in non-metropolitan regions? To compare in-hospital mortality for acute myocardial infarction (AMI) between metropolitan and non-metropolitan hospitals after adjustment for patients' severity; to examine the role of the use of effective cardiac medications in the possible mortality difference between these types of hospital. Retrospective cohort study. 47 acute public hospitals in metropolitan and non-metropolitan areas of New South Wales, Australia, taking part in the Acute Cardiac Care Project based on medical record review. 1665 patients with principal discharge diagnosis of AMI from February to June 1996. There was no difference in crude mortality rate (assessed as seven day mortality) between metropolitan and non-metropolitan hospitals (11.0% compared with 10.7% respectively, p=0.893). After adjustment for severity in a logistic regression model, the odds of death in non-metropolitan hospitals was significantly higher than in metropolitan hospitals (odds ratio = 1. 90; 95% CI 1.21, 3.23). The addition of the use of effective cardiac medications to the model resulted in the difference between hospital type becoming non-significant (odds ratio=1.09; 95% CI 0.57, 2.07).

In-hospital mortality in non-metropolitan hospitals was higher than that in metropolitan hospitals, after adjustment for patients' severity. This might partly be explained by the difference in use of effective cardiac medications between hospital type.

Does body mass interact with fat quality to determine the postprandial lipoprotein response in healthy young adults? Postprandial lipemia predicts the evolution of cardiovascular disease. Obesity is associated with an increase in the magnitude of postprandial lipemia. Our objective was to evaluate the influence of body mass index (BMI) on the effects of acute ingestion of different types of fat on the postprandial lipemic response. Twenty-one healthy men followed a 4-week baseline diet and then consumed three fat-loaded meals that included 1g fat/kg body wt (65%fat) according to a randomized crossover design. The compositions of the three meals were olive oil meal (22% saturated fatty acids (SFA), 38% monounsaturated fatty acids (MUFA), 4% polyunsaturated fatty acids (PUFA)); butter meal (35% SFA, 22% MUFA, 4% PUFA); walnuts meal (20% SFA, 24% MUFA, 16% PUFA, and 4% α-linolenic acid). Higher-weight (HW) subjects (BMI greater than the median 26.18 kg/m(2), n = 11) presented higher incremental area under the curve (iAUC) for triglycerides (TG), both in large- and small-TG rich lipoproteins (TRL) than lower-weight (LW) subjects (BMI<26.18 kg/m(2), n = 10) (p<0.05), and a similar trend for plasma TG (p = 0.084). Moreover, HW subjects presented higher concentrations for small TRL-cholesterol and small TRL-TG in different timepoints of the postprandial lipemia after the intake of enriched walnuts or butter meals compared with the olive oil-enriched meal (p < 0.05) No significant differences were observed between the three types of meals in the postprandial response of LW subjects.

HW subjects present a greater postprandial response than LW subjects, and they benefit from the consumption of monounsaturated fatty acids from olive oil, to lower their levels of TRL particles during the postprandial state.

Does nucleosome Assembly Protein 1-Like 1 ( Nap1l1 ) regulate the Proliferation of Murine Induced Pluripotent Stem Cells? To investigate whether nucleosome assembly protein 1-like 1 (Nap1l1) regulates the proliferation of induced pluripotent stem cells (iPSC) and the potential mechanisms. Nap1l1-knockdown-iPSC and Nap1l1-overexpression-iPSC were constructed by transfection of lentiviral particles. The proliferation of iPSC was detected by MTT analysis, and cell cycle was analyzed by flow cytometry. Nap1l1 overexpression promoted iPSC proliferation and induced G2/M transition compared to their control iPSC while Nap1l1-knockdown-iPSC dramatically displayed the reduced proliferation and accumulated G2/M phase cells. Further analysis showed that Nap1l1 overexpression in iPSC increased the expression of cyclin B1, downregulated the expression of p21 and p27, while knockdown of Nap1l1 showed the opposite effects. In addition, overexpression of Nap1l1 promoted the phosphorylation of AKT and ERK in iPSC, while knockdown of Nap1l1 inhibited the effects. However, these effects displayed in Nap1l1-overexpression-iPSC were greatly suppressed by the inhibition of AKT or ERK signaling.

The results indicate that Nap1l1 promotes the proliferation of iPSC attributable to G2/M transition caused by downregulation of p27 and p21, and upregulation of cyclin B1, the activation of AKT or ERK is involved in the process. The present study has revealed a novel molecular mechanism involved in the proliferation of iPSC.

Does the chemical compound PTC124 affect cellular electrophysiology of cardiac ventricular myocytes? Nonsense mutations that create premature termination codons (PTC) leading to disease by a mechanism of haploinsufficiency are relatively common in the SCN5A gene encoding the major sodium channel in heart. PTCs in SCN5A are associated with isolated conduction disease and Brugada syndrome (BrS). Pharmacological therapy does not exist for these disorders, but would be highly beneficial. Recently, an orally bio-available drug capable of suppressing premature termination, PTC124, has been identified that selectively induces ribosomal read-through of premature but not normal termination codons. In this study, we tested the acute and long-term effects of PTC124 on action potential characteristics of rabbit ventricular cardiomyocytes. The effects of PTC124 on action potentials of isolated adult rabbit ventricular cardiomyocytes were studied using the perforated patch-clamp methodology. Acute effects of PTC124 were measured in freshly isolated cardiomyocytes, while long term effects were measured after 48 h in cultured cardiomyocytes. Resting membrane potential, maximum upstroke velocity, action potential amplitude and action potential duration at 20, 50 and 90% of repolarization were not affected by application of PTC124, neither acute nor after 48 h.

PTC124 has no acute or long-term effects on rabbit ventricular action potentials. These experiments form the basis for future studies evaluating the use of this therapy in preventing potentially lethal arrhythmias in patients with BrS and/or conduction disease.

Do osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells? Prostate cancer metastasizes to the skeleton to form osteoblastic lesions. Androgen ablation is the current treatment for metastatic prostate cancer. This therapy is palliative, and the disease will return in an androgen-independent form that is preceded by a rising titer of prostate-specific antigen (PSA). Here, we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen-independent prostate cancer. Primary cultures of human osteoblasts were used as a source of conditioned medium (OCM). Proliferation, expression of androgen-regulated genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were measured, and its contribution to proliferation and expression of PSA were investigated by neutralization studies with anti IL-6 antibodies. OCM increased the proliferation and expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)- and pARR(3)-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH(2)-terminal domain of the AR. The effect of OCM on transcriptional activity of the AR was inhibited by an antiandrogen. Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM.

Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer.

Do structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation? Many studies have separately reported abnormalities of frontal and temporal lobe structures in schizophrenia, but little is known of structural fronto-temporal associations in this condition. We investigated whether male patients with chronic schizophrenia would show abnormal patterns of correlation between regional brain volumes. Structural magnetic resonance images of the brain in 42 patients were compared with 43 matched unaffected controls. We explored the pattern of association between regional brain volumes by correlational analyses, and non-parametrically tested for significance of between-group differences by randomization. The schizophrenics demonstrated significant volume deficits in several brain regions (left temporal lobe and hippocampus, right dorsolateral prefrontal cortex), and significant volume increases in the ventricular system (third ventricle and left temporal horn of the lateral ventricle). Controls demonstrated large positive correlations (r > 0.4) between prefrontal and temporal lobe regions. By contrast, inter-regional correlations significantly reduced in schizophrenics included those between prefrontal, anterior cingulate and temporal regions, and between posterior cingulate and hippocampus (P < 0.05). The most salient abnormality in patients was a dissociation between prefrontal and superior temporal gyrus volumes (P < 0.01).

These results support the existence of a relative 'fronto-temporal dissociation' in schizophrenia which we suggest may be due to lack of mutually trophic influences during frontal and temporal lobe development.

Does the aqueous phase of Alzheimer 's disease brain contain assemblies built from ∼4 and ∼7 kDa Aβ species? Much knowledge about amyloid β (Aβ) aggregation and toxicity has been acquired using synthetic peptides and mouse models, whereas less is known about soluble Aβ in human brain. We analyzed aqueous extracts from multiple AD brains using an array of techniques. Brains can contain at least four different Aβ assembly forms including: (i) monomers, (ii) a ∼7 kDa Aβ species, and larger species (iii) from ∼30-150 kDa, and (iv) >160 kDa. High molecular weight species are by far the most prevalent and appear to be built from ∼7 kDa Aβ species. The ∼7 kDa Aβ species resist denaturation by chaotropic agents and have a higher Aβ42/Aβ40 ratio than monomers, and are unreactive with antibodies to Asp1 of Ab or APP residues N-terminal of Asp1.

Further analysis of brain-derived ∼7 kDa Aβ species, the mechanism by which they assemble and the structures they form should reveal therapeutic and diagnostic opportunities.

Is female gender a risk factor for drug-induced long QT and cardiac arrhythmias in an in vivo rabbit model? Clinical observations and in vitro experimental data indicate that females have a longer QT interval than males, which is associated with a higher risk of drug-induced cardiac arrhythmias. Little is known about this gender difference in anesthetized animals, which may affect the outcome of in vivo drug tests. We evaluated potential gender differences in ventricular repolarization (QT, QTc, JT, and JTc interval) and its dispersion, as well as in its response to dofetilide, an IKr blocker, in anesthetized rabbits challenged with the alpha1-adrenoceptor agonist methoxamine. A 12-lead ECG was recorded during the experiments. At baseline, there were no significant gender differences in ventricular repolarization values in male and female rabbits under anesthesia. Dofetilide (0.04 mg/kg/min IV for 60 min; n = 10 per gender) produced marked prolongation of the ventricular repolarization time and its dispersion, associated with a high incidence of polymorphic ventricular tachycardia (PVT; 100% in females vs 80% in males) and ventricular fibrillation (VF; 80% in females vs 50% in males; P > 0.05). QT and JT interval at 2 minutes as well as QT and JT dispersion at 10 and 30 minutes during dofetilide infusion were significantly higher in female than in male rabbits. After 30 minutes of dofetilide infusion, 10 of 10 female rabbits had severe cardiac arrhythmias (complete AV block, PVT, or VF), so ECG parameters were impossible to assess (vs 3/10 males with severe cardiac arrhythmias; P < 0.05). During dofetilide infusion, female rabbits developed complete AV block, PVT, or VF at doses about 50% lower than those given to males.

The present study indicates that female rabbits are more susceptible to drug-induced long QT and cardiac arrhythmias than are male rabbits; therefore, female rabbits are more appropriate for testing drug-induced cardiac arrhythmias.

Is breastfeeding status at age 3 months associated with adiposity and cardiometabolic markers at age 4 years in Mexican children? The effect of breastfeeding (BF) on cardiometabolic risk factors is not well characterized. The objective was to assess the association of BF status at 3 mo and duration with adiposity and cardiometabolic markers at 4 y. We studied 727 children with prospectively collected BF information and anthropometric measurements at 4 y, of whom 524 provided a nonfasting blood sample. BF status at 3 mo was classified as exclusive or predominant (EBF-PreBF), partial (PaBF), or nonbreastfeeding (NBF). Total duration of any BF was classified as <3 mo, 3- 6 mo, >6 to 12 mo, and >12 mo. We modeled associations of BF with body mass index (BMI; in kg/m(2)), serum total cholesterol and low-density lipoprotein (LDL) cholesterol, triglycerides (TGs), and insulin at 4 y. Children who were NBF or PaBF at 3 mo had higher BMI [0.46 (95% CI: 0.16, 0.76) and 0.31 (95% CI: 0.07, 0.54), respectively] than the EBF-PreBF group (P < 0.01). NBF children had higher total cholesterol (8.02 mg/dL; 95% CI: 1.39, 14.64; P = 0.02) than children who were EBF-PreBF. LDL cholesterol (5.04 mg/dL; 95% CI: -0.72, 10.81) and TGs (12% change; 95% CI: -0.01, 0.24) showed similar patterns. An inverse association between EBF-PreBF and insulin, mediated through abdominal circumference, was documented (P < 0.05). Children breastfed <3 mo had higher BMI (0.44; 95% CI: 0.11, 0.77) at 4 y than children breastfed for >12 mo.

EBF and PreBF at 3 mo were associated with lower adiposity and serum total cholesterol in children at 4 y. In addition, BF >12 mo was associated with lower adiposity. These data confirm the importance of exclusive BF and prolonged BF for later cardiometabolic health.

Does pelvic arterial occlusive disease affect the RhoA/Rho-kinase pathway in bladder smooth muscle? We investigated the effect of pelvic arterial occlusive disease on the RhoA/Rho-kinase pathway in a rat model of chronic bladder ischemia. Male adult Sprague Dawley® rats at age 16 weeks were divided into arterial endothelial injury and control groups. The injury group underwent balloon endothelial injury of the bilateral iliac arteries and received a 2% cholesterol diet to induce pelvic arterial occlusive disease. The control group received a regular diet. At 8 weeks cystometrograms were performed. Bladder tissue was harvested for pharmacological studies and Western blot. Cystometrograms showed significantly lower bladder capacity in the arterial endothelial injury group than in controls. Organ bath studies revealed significantly decreased phasic contractions induced by carbachol in bladder strips from the injury group than from controls. In controls bladder strip tonic contractions induced by carbachol were significantly decreased compared with phasic contractions. However, no significant difference was observed between phasic and tonic contractions in the injury group. The Rho-kinase inhibitor Y-27632 produced a concentration dependent decrease in tonic contractions, which was more pronounced in the injury group. Western blot showed significantly increased RhoA and Rho-kinase β expression in the injury group.

Our results suggest that pelvic arterial occlusive disease can affect the RhoA/Rho-kinase pathway in the bladder. This pathway might possibly be involved in the maintenance of tonic contraction and contribute to the bladder hyperactivity caused by pelvic arterial occlusive disease.

Do mexican American children have differential elevation of metabolic biomarkers proportional to obesity status? There is a health disparity for obesity among Mexican Americans compared with other racial/ethnic groups. In particular, Mexican American children who are obese are likely to become obese adults. The purpose of this study was to examine traditional and nontraditional risk factors in a subset of Mexican American children before their participation in a larger clinical weight loss study. Venous blood samples were collected from self-identified Mexican American children (12-14 years old) who were assigned to 1 of 3 weight groups based on their standardized body mass index; normal weight (N = 66), overweight (N = 23), or obese (N = 39). Serum was analyzed for interleukin-6, tumor necrosis factor-α, C-peptide, ghrelin, glucagon-like protein, gastric inhibitory polypeptide-1, glucagon, insulin, leptin, macrophage chemoattractant protein 1, and pancreatic polypeptide using a Luminex MagPix-based assay. Total cholesterol, high-density lipoprotein-cholesterol, triglycerides, and glucose were analyzed using enzymatic assays. Data were analyzed for significance using separate analysis of variance tests, with significance set at P < 0.05. Relative to normal weight and overweight children, obese children had significantly elevated C-peptide (P < 0.0001), insulin (P < 0.0001), leptin (P < 0.0001), macrophage chemoattractant protein 1 (P = 0.005), and tumor necrosis factor-α (P = 0.006).

We observed that Mexican American children as a function of body weight had elevated serum concentrations of several biomarkers that have been linked to chronic disease development in adults. More research is needed to understand how these differences affect disease risk in adulthood.

Does kSR1 protect from interleukin-10 deficiency-induced colitis in mice by suppressing T-lymphocyte interferon-γ production? Immunological disorders of the gastrointestinal tract such as inflammatory bowel disease often result in recurrent and persistently elevated levels of proinflammatory cytokines. Kinase suppressor of Ras 1 (KSR1) is involved in tumor necrosis factor-mediated colon epithelial cell survival, yet its role in chronic inflammation has not been defined. In this study, we tested the hypothesis that KSR1 is protective against spontaneous experimental colitis. KSR1(-/-)Interleukin-10 (Il10)(-/-) mice were generated and histolopathologic parameters of intestinal inflammation were scored. Bone marrow transplants performed on wild-type and KSR1(-/-)Il10(-/-) mice determined the contribution of KSR1 in hematopoietic lineages. Mucosal T helper (Th) 1 and Th17 cytokine were also examined. In vitro Th1 and Th17 polarization assays were conducted and interleukin (IL)-17A and interferon-γ (IFN-γ) production analyzed by flow cytometry. Neutralizing antibodies against IgG, IL-17A, or IFN-γ were administered to 3-week-old KSR1(-/-)Il10(-/-) mice for 3 weeks and scored for colitis. KSR1(-/-)Il10(-/-) mice developed accelerated and severe spontaneous colitis by 4 weeks of age. KSR1 expression in hematopoietic lineages was protective against colitis. Both IFN-γ and IL-17A transcripts were elevated in colons of KSR1(-/-) and KSR1(-/-)Il10(-/-) mice. IFN-γ production was increased in lamina propria T cells isolated from KSR1(-/-) and KSR1(-/-)Il10(-/-) mice. Additionally, in vitro Th1 polarization was increased while Th17 polarization was impaired in KSR1-deficient naïve T cells. Finally, administration of IFN-γ neutralizing antibodies attenuated colitis in KSR1(-/-)Il10(-/-) mice.

Mice lacking both KSR1 and IL-10 develop exacerbated colitis due to dysregulated IFN-γ production in T lymphocytes.

Does amlodipine inhibit doxorubicin-induced apoptosis in neonatal rat cardiac myocytes? We examined whether amlodipine, a calcium channel antagonist with potent antioxidant activity, inhibits doxorubicin-induced apoptosis in cultured neonatal rat cardiac myocytes. Recent studies have shown that doxorubicin induces apoptosis as well as necrosis in myocytes through generation of reactive oxygen species. The effects of amlodipine and several other antioxidants on doxorubicin-induced oxidative stress and mitochondria-mediated apoptosis were examined. Treatment of myocytes with doxorubicin (10(-6) mol/l) for 14 h increased the number of cells with elevated peroxides, as histochemically estimated by 2',7'-dichlorofluorescin (DCF) diacetate, and the percentage of apoptotic myocytes, as estimated by Hoechst 33258 nuclear staining, compared with control myocytes (25.0 +/- 1.6% vs. 5.2 +/- 1.2%). Moreover, doxorubicin-induced myocyte apoptosis was also confirmed by annexin V-fluorescein isothiocyanate binding assay. Doxorubicin induced a reduction in myocyte adenosine 5'-triphosphate content, a loss of mitochondrial membrane potential, cytochrome c release from the mitochondria into the cytosol, and caspase-3 activation to 1.9-fold of control. Amlodipine significantly attenuated increased DCF fluorescence, inhibited the mitochondria-mediated apoptotic responses described earlier, and decreased apoptosis in the doxorubicin-treated myocytes in a dose-dependent fashion. Amlodipine at 10(-6) mol/l significantly decreased apoptosis to 15.4 +/- 0.7%, and this antiapoptotic action was more effective than that seen with other antioxidants, including probucol, ascorbic acid, and alpha-tocopherol. In contrast, the calcium channel antagonist nifedipine (10(-6) mol/l) did not inhibit apoptosis. Catalase, glutathione, and N-acetylcysteine, but not mannitol or superoxide dismutase, significantly decreased DCF fluorescence and attenuated myocyte apoptosis induced by doxorubicin to 18.7 +/- 1.2%, 19.1 +/- 1.7%, and 18.7 +/- 0.6%, respectively.

Amlodipine significantly inhibits doxorubicin-induced myocyte apoptosis by suppressing the mitochondrial apoptotic pathway. This effect is attributed to the antioxidant properties of amlodipine, affecting mainly hydrogen peroxide.

Are plasma lipoprotein ( a ) levels associated with mild renal impairment in type 2 diabetics independent of albuminuria? CKD, an independent risk factor for CV disease, increases mortality in T2DM. Treating modifiable CV risk factors decreases mortality in diabetics with microalbuminuria, but the role of early CV prevention in diabetics with mild CKD by GFR criteria alone remains unclear. The purpose of this study was to probe whether T2DM patients with mild GFR impairment have atherogenic lipid profiles compared to diabetic counterparts with normal renal function. In the Penn Diabetes Heart Study (PDHS), a single-center observational cohort of T2DM patients without clinical CVD, cross-sectional analyses were performed for directly measured lipid fractions in 1852 subjects with eGFR>60 mL/min/1.73 m² determined by the CKD-EPI equation (n = 1852). Unadjusted and multivariable analyses of eGFR association with log-transformed lipid parameters in incremental linear and logistic regression models (with eGFR 90 mL/min/1.73 m² as a cut-point) were performed. Mild GFR impairment (eGFR 60-90 mL/min/1.73 m², median urinary ACR 5.25 mg/g) was associated with higher log-transformed Lp(a) values (OR 1.17, p = 0.005) and with clinically atherogenic Lp(a) levels above 30 mg/dL (OR 1.35, p = 0.013) even after full adjustment for demographics, medications, metabolic parameters, and albuminuria. Logistic regression demonstrated a trend towards significance between worse kidney function and apoB (p = 0.17) as well as apoC-III (p = 0.067) in the fully adjusted model.

Elevated Lp(a) levels have a robust association with mild GFR impairment in type 2 diabetics independent of race, insulin resistance, and albuminuria.

Do acid and weakly acidic solutions impair mucosal integrity of distal exposed and proximal non-exposed human oesophagus? Oesophageal mucosa dilated intercellular spaces (DIS) may be important for symptom perception in non-erosive reflux disease (NERD). Patients with NERD might have DIS even in the proximal oesophagus. We aimed to assess the effect of oesophageal perfusions with acid and weakly acidic solutions on 'exposed' and 'non-exposed' oesophageal mucosa and its relationship to symptoms in healthy subjects. 14 healthy volunteers underwent upper gastrointestinal endoscopy with biopsies at 3 and 13 cm proximal to the oesophagogastric junction (OGJ). In following sessions, subjects received 30 min perfusions with neutral, weakly acidic, acidic and acidic-bile acid solutions at 5 cm above the EGJ (separated 4 weeks). Biopsies were taken 20 min after perfusions. Electron microscopy was used to measure DIS. Subjects scored heartburn during perfusions using a visual analogue scale. (1) Oesophageal perfusion with acid solutions, with or without bile acids, provoked DIS in the 'exposed' oesophageal mucosa; (2) oesophageal perfusion with weakly acidic solutions provoked identical changes to those observed after perfusion with acid solutions; (3) distal oesophageal perfusions not only provoked changes in the 'exposed' but also in the more proximal 'non-exposed' mucosa; and (4) in spite of the presence of perfusion-induced DIS, most healthy subjects did not perceive heartburn during the experiments.

The human oesophageal mucosa is very sensitive to continuous exposure with acidic and weakly acidic solutions. In spite of the presence of intraluminal acid and DIS, healthy subjects did not experience heartburn, suggesting that NERD patients should have other critical factors underlying their symptoms.

Is a leptin serum concentration less than 10 ng/ml a predictive marker of outcome in patients with moderate to severe secondary peritonitis? Leptin is involved in the sepsis syndrome. A possible relationship exists between low leptin levels and peritonitis severity and a poorer prognosis. We aimed to corroborate the relationship between low leptin serum levels and death in patients with peritonitis and to explore the associations between leptin and interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-13 (IL-13), tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP). In 230 adult patients with surgically confirmed secondary peritonitis, the Mannheim Peritonitis Index and the serum concentrations of leptin, IL-6, IL-10, IL-13, TNF-alpha and CRP were determined. Two cohorts were established (leptin < or = 10 ng/ml and > 10 ng/ml). Death or survival was followed through 30 days. The relationship between leptin (< or = 10 ng/ml) and death was evaluated using the accumulated incidence ratio (AIR). The association of leptin (dependent variable) with IL-6, IL-10, IL-13, TNF-alpha and CRP (independent variables) was studied by regression analysis. The general mortality rate was 7.8% and the death AIR was 3.15 (p nonsignificant). A subsample of patients with a Mannheim Peritonitis Index > or = 21 was studied, showing a significant AIR of 4.26 (p = 0.017). Regression analysis determined an association only between leptin and IL-6 (p < 0.001), IL-10 (p < 0.047) and CRP (p < 0.001).

A serum leptin below the threshold of 10 ng/ml is an adverse prognostic marker in patients with moderate to severe secondary peritonitis. The results of the regression analysis suggest that the mechanisms involved are opposing, in that leptin associated with IL-6 has a proinflammatory effect and, through IL-10 and CRP production, restrains the inflammatory response.

Is dNAH5 associated with total lung capacity in chronic obstructive pulmonary disease? Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD. We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <0.7 and FEV1 < 80% predicted on post-bronchodilator spirometry. TLC was calculated by using volumetric computed tomography scans at full inspiration (TLCCT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLCCT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis. Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, β = 0.42L, P = 4.66 × 10-8).

In COPD, TLCCT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.

Does tiotropium ameliorate symptoms in patients with chronic airway mucus hypersecretion which is resistant to macrolide therapy? Low-dose, long-term macrolide therapy has been shown to be effective for the treatment of diffuse panbronchiolitis (DPB) and similar disorders in terms of the presence of airway mucus hypersecretion such as bronchiectasis, chronic bronchitis and sinobronchial syndrome. However, there are some patients, especially advanced cases, whose volume of sputum does not decrease sufficiently with macrolide therapy. These patients suffer from copious expectoration. There is currently no effective treatment, and an effective therapy is therefore urgently required. The aim of this study was to clarify whether or not the inhalation of tiotropium improves the symptoms in these cases. Tiotropium (18 microg/day) was administered to patients with DPB and similar disorders with airway mucus hypersecretion who did not respond to macrolide. The symptoms were evaluated by a visual analog scale (VAS) prior to and at 1 and 3 months after tiotropium administration. Radiological and pulmonary function tests were also performed to evaluate the effects of tiotropium. Thirteen patients (DPB 5, sinobronchial syndrome 5, bronchiectasis 3) were enrolled. The VAS scores were dramatically improved after the introduction of tiotropium. FEV(1) was significantly improved after 3 months of treatment with tiotropium. In contrast, the radiological findings remained unchanged.

Tiotropium improved the symptoms of cough, sputum and breathlessness in the macrolide-resistant cases of DPB or similar disorders. These beneficial effects might be due to the suppression of airway secretion through the anticholinergic effect of tiotropium on the submucosal gland, however, the long-term efficiency of this treatment still needs to be further assessed.

Is iSL1 common variant rs1017 associated with susceptibility to congenital heart disease in a Chinese population? ISL1, as a member of the LIM homeodomain transcription factor family, is expressed in a distinct population of undifferentiated cardiac progenitors and plays a pivotal role in cardiogenesis. Lacking ISL1 expression results in growth arrest or displays profound defects in heart development, including atria, ventricle, and the inflow and outflow tracts, which constitute a major form of congenital heart disease (CHD). Recently, an important study by Stevens et al. found that genetic variation in ISL1 is associated with risk of CHD in white and black/African American populations; this observation led us to hypothesize that ISL1 common variants might influence susceptibility to sporadic CHD in our Chinese population. We conducted a case-control study of CHD in Chinese to test our hypothesis by genotyping ISL1 common variant rs1017 in 1003 CHD cases and 1012 non-CHD controls. We found that rs1017 was not associated with the risk of CHD (p=0.213). When we performed stratified analyses according to subjects' age, sex, and CHD classifications, we found no overall heterogeneity of risk in different subgroups.

This is the first study which indicates that ISL1 common variant rs1017 may not play a role in sporadic CHD susceptibility in the Chinese population.

Do muscle composition measured by CT scan is a measurable predictor of overall survival in advanced ovarian cancer? To assess the impact of muscle composition and sarcopenia on overall survival in advanced epithelial ovarian cancer (EOC) after primary debulking surgery (PDS). Women with stage IIIC/IV EOC who underwent PDS with curative intent between 1/1/2006 and 12/31/2012 were included. Patient variables and vital status were abstracted. Body composition was evaluated in a semi-automated process using Slice-O-Matic software v4.3 (TomoVision). Skeletal muscle area and mean skeletal muscle attenuation were recorded. Associations with overall survival were evaluated using Cox proportional hazards models and recursive partitioning. We identified 296 patients and 132 (44.6%) were classified as sarcopenic. The average mean skeletal muscle attenuation of the entire cohort was 33.4 Hounsfield units (HU). A multivariate model of overall risk of death included histology, residual disease, and mean skeletal attenuation. Among patients without residual disease, overall survival, but not progression free survival was significantly different between patients with low versus high mean skeletal attenuation (median survival, 2.8 vs. 3.3years). Among patients with residual disease, overall survival was significantly different between patients with low versus high mean skeletal attenuation ≥36.40 vs. <36.40 HU (median survival, 2.0 vs. 3.3years).

Sarcopenia and low mean skeletal muscle attenuation are common in women undergoing PDS for advanced EOC. These factors are associated with poorer outcomes, and can be used in preoperative risk stratification and patient counseling. Further research into body composition and whether this risk factor can be altered via nutrition or fitness in this population is warranted.

Does a simple risk score predict poor quality of life and non-survival at 1 year follow-up in dialysis patients? Quality of life (QoL) in end-stage renal disease patients has become an important focus of attention in evaluating dialysis. We studied risk factors of poor QoL at 1 year follow-up. Of a baseline sample of 80 dialysis patients, we contacted 60 patients who were alive at 1 year follow-up. QoL data were obtained for 46 (76.7%) of these patients. QoL measured with the SF-36 [physical health component score (PCS) and mental health component score (MCS)] at 1 year-follow-up was predicted by means of multivariate regression analysis by data collected at baseline using INTERMED-an observer-rated method to assess biopsychosocial care needs-and several indicators for disease severity and comorbidity. The regression models explained 32% of the variance in PCS and 40% in MCS. INTERMED score (P < 0.01) was the only independent risk factor for low MCS, while for low PCS, diabetic comorbidity (P = 0.02) and age (P = 0.03) were independent risk factors. A simple risk score consisting of INTERMED > or =21, diabetic comorbidity and age > or =65 was significantly correlated with non-survival (P = 0.02) and with PCS (P < 0.01) and MCS (P < 0.01) in surviving patients, although not with hospital admissions during follow-up.

A simple risk score based on INTERMED, age (> or =65) and comorbid diabetes (yes/no) can be used to detect patients at risk of poor QoL and non-survival at an early stage of treatment.

Do extrasystolic beats affect transmural electrical dispersion during programmed electrical stimulation? Experimental studies suggest that the electrocardiographic Tpeak-Tend (TpTe) interval reflects transmural dispersion of repolarization (TDR). The genesis and role of the TpTe interval in a clinical setting have not been established. This study aimed to assess the clinical usefulness of the TpTe interval as an index of TDR and a pro-arrhythmic marker. Endocardial monophasic action potential (MAP) duration and electrocardiographic QTp, QTe and TpTe intervals were assessed in 13 patients undergoing an electrophysiological study. Surface electrocardiograms were recorded during right ventricular pacing (Basic Cycle Length = 600 ms) before and after single extrastimuli. Ventricular arrhythmia was induced in six patients. During ventricular pacing, MAP duration and QTp intervals shortened in response to extrastimuli applied at progressively shorter coupling intervals. In contrast, QTe intervals increased in response to premature stimulation and QTe dispersion increased at short coupling intervals. During sinus rhythm, the TpTe interval was greater in the inducible group in leads V3-V4. Premature stimulation increased the duration of TpTe intervals, suggesting an increase in TDR. The maximum TpTe interval was greater in the inducible than in the noninducible group, both during baseline ventricular drive pacing (163 +/- 22 vs. 130 +/- 27 ms, respectively, P < 0.03) and after application of shortly coupled extrastimuli (263 +/- 66 vs. 200 +/- 47 ms, respectively, P < 0.05).

The TpTe interval of surface ECG is likely to represent TDR. TDR is increased by premature ventricular stimulation and the magnitude of the maximum TpTe interval (i.e. maximum TDR) during ventricular pacing is greater in patients with inducible arrhythmias.

Does a classification based on peak systolic velocity and end diastolic velocity predict sildenafil citrate success? To attempt to predict the success rate of sildenafil citrate in erectile dysfunction patients using penile Doppler ultrasonography (PDU) measurements of peak arterial velocity and end diastolic velocity. A total of 212 patients (age range 27-76 years) with vascular pathologies were included in the study. Following a PDU test, the patients were divided into arterial insufficiency, veno-occlusive dysfunction and mixed vascular pathology groups. Subsequently, patients were given sildenafil citrate 50 mg and re-evaluated 1 month later to determine its efficacy. If it was ineffective, the dose was increased to 100 mg and patients were reassessed. Arterial insufficiency and veno-occlusive dysfunction patients were classified into mild, moderate and severe groups depending on peak systolic and end diastolic velocities. The overall response rate in patients with arterial insufficiency was 74.5%, regardless of the degree of arterial insufficiency or the dose of sildenafil. The severe arterial insufficiency group had a much better response to 100 mg compared to 50 mg doses of sildenafil. Although the 50 mg sildenafil dose was effective in patients with minimal veno-occlusive dysfunction, 100 mg was better than 50 mg to achieve adequate erection in the mild and severe veno-occlusive dysfunction groups.

Sildenafil was ineffective in patients with severe arterial and venous insufficiency. PDU and a simple classification of PDU velocity measurements can provide some important clues to the prognosis of treatment and avoid overtreatment and unnecessary office visits.

Do an iterative model for in vitro laboratory assessment of tamper deterrent formulations? In an effort to address the continuing problem of prescription opioid abuse, manufacturers are incorporating new technologies into formulations that are designed to deter product tampering and misuse. Standards for laboratory assessment of tamper deterrent properties of new formulations have not previously been developed. Experimental designs were developed for the in vitro laboratory assessment of the tamper deterrent properties of reformulated oxycodone. Given that an exhaustive study of all potential tampering methods was impractical; this model was developed to evaluate the product in an incremental fashion with iterative changes that were amenable to objective and replicable laboratory testing. A description of the model is provided along with pertinent examples involving assessment of reformulated oxycodone with comparisons to the original formulation. Physical and chemical procedures were developed that relate to "real-world" scenarios that may be applied to opioid formulations. Test results were interpreted in relation to the relative ease or difficulty of the manipulation as compared to control materials and the amount and purity of active drug that could be accessed. Results from some of the tests were designed to be useful in predicting whether specific tampering methods would facilitate or deter drug administration by different routes of administration.

This model, developed to assess the tamper deterrent properties of reformulated oxycodone, should have application in the assessment of other drug formulations designed to exhibit tamper deterrence properties.

Does a qualitative meta-analysis reveal consistent effects of atrazine on freshwater fish and amphibians? The biological effects of the herbicide atrazine on freshwater vertebrates are highly controversial. In an effort to resolve the controversy, we conducted a qualitative meta-analysis on the effects of ecologically relevant atrazine concentrations on amphibian and fish survival, behavior, metamorphic traits, infections, and immune, endocrine, and reproductive systems. We used published, peer-reviewed research and applied strict quality criteria for inclusion of studies in the meta-analysis. We found little evidence that atrazine consistently caused direct mortality of fish or amphibians, but we found evidence that it can have indirect and sublethal effects. The relationship between atrazine concentration and timing of amphibian metamorphosis was regularly nonmonotonic, indicating that atrazine can both accelerate and delay metamorphosis. Atrazine reduced size at or near metamorphosis in 15 of 17 studies and 14 of 14 species. Atrazine elevated amphibian and fish activity in 12 of 13 studies, reduced antipredator behaviors in 6 of 7 studies, and reduced olfactory abilities for fish but not for amphibians. Atrazine was associated with a reduction in 33 of 43 immune function end points and with an increase in 13 of 16 infection end points. Atrazine altered at least one aspect of gonadal morphology in 7 of 10 studies and consistently affected gonadal function, altering spermatogenesis in 2 of 2 studies and sex hormone concentrations in 6 of 7 studies. Atrazine did not affect vitellogenin in 5 studies and increased aromatase in only 1 of 6 studies. Effects of atrazine on fish and amphibian reproductive success, sex ratios, gene frequencies, populations, and communities remain uncertain.

Although there is much left to learn about the effects of atrazine, we identified several consistent effects of atrazine that must be weighed against any of its benefits and the costs and benefits of alternatives to atrazine use.

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

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

Does morbidity associated with gastrostomy placement in children demand an ongoing integrated approach to care? To evaluate the short and long term morbidity of gastrostomy insertion, and to identify ongoing management requirements. A retrospective review was undertaken of the hospital casenotes of children aged up to fifteen years who had a gastrostomy placed in Christchurch over a six year period to March 1998. 42 children had a gastrostomy fashioned, 35 in the last three years of the period reviewed. The most common underlying diagnosis was neurological disease (48%), and the most common indication for tube placement was failure to feed orally. Complications were frequent but minor. Morbidity was related to local erythema and infection around the stoma (85 episodes in 23 children), persistent and major gastric fluid leakage (three episodes), and mechanical failure of the tube (21 episodes). Gastro-oesophageal reflux was seen in fourteen children, nine of whom had primary neurological disease. Complications were seen more after open gastrostomy than after percutaneous endoscopic placement (6.6:4.7). There was no mortality related directly to the gastrostomy tube or tube placement.

An increase in the frequency of gastrostomy placements has been seen over this period. As the number of children with a gastrostomy increases, so too have the demands on medical and nursing staff to care for and manage the devices. The frequency of minor ongoing problems necessitates ongoing support of the child and care of the gastrostomy. A close working relationship between outreach nursing staff, stoma therapists and medical staff is required if morbidity is to be minimised. Education, audit and review remain important additional aspects of care.

Does erythropoietin promote Neural Plasticity and Spatial Memory Recovery in Fimbria-Fornix-Lesioned Rats? Erythropoietin (EPO) upregulates the mitogen activated protein kinase (MAPK) cascade, a central signaling pathway in cellular plastic mechanisms, and is critical for normal brain development. We hypothesized that EPO could modulate the plasticity mechanisms supporting spatial memory recovery in fimbria-fornix-transected animals. Fimbria-fornix was transected in 3 groups of rats. Seven days later, EPO was injected daily for 4 consecutive days within 10 minutes after training on a water maze task. Our results show that EPO injections 10 minutes after training produced a substantial spatial memory recovery in fimbria-fornix-lesioned animals. In contrast, an EPO injection shortly after fimbria-fornix lesion surgery does not promote spatial-memory recovery. Neither does daily EPO injection 5 hours after the water maze performance. EPO, on the other hand, induced the expression of plasticity-related genes like arc and bdnf, but this effect was independent of training or lesion.

This finding supports our working hypothesis that EPO can modulate transient neuroplastic mechanisms triggered by training in lesioned animals. Consequently, we propose that EPO administration can be a useful trophic factor to promote neural restoration when given in combination with training.

Does end tidal CO2 in recreational rebreather divers on surfacing after decompression dive? Deep dives using rebreather devices result in oxygen exposures that carry a risk of cerebral oxygen toxicity. Elevation of arterial CO2 levels increases this risk. CO2 retention may occur during the deep working phases of dives, but it has not been investigated in 'real world' dives at the end of resting decompression when oxygen exposures are peaking, often to levels higher than recommended maxima. We conducted an observational field study to measure end tidal CO2 (Petco2) in divers surfacing after decompression. Sixteen rebreather divers conducted two dives and two completed one dive (a total of 34 dives) to depths ranging from 44-55 msw. Bottom times ranged from 35 to 56 min and time spent on decompression ranged from 40 to 92 min. The first breaths on reaching the surface after removing the rebreather mouthpiece were taken through a portable capnograph. The Petco2 was recorded for the first breath that produced a clean capnography trace. Petco2 measurement was repeated for each subject 2-3 h after diving to give paired observations. There were no differences between mean surfacing Petco2 [36.8 mmHg (SD 3.0)] and the mean Petco2 made later after diving [36.9 mmHg (SD 4.0)]. One subject on one dive returned a surfacing Petco2 higher than a nominal upper limit of 45 mmHg.

We found no general tendency to CO2 retention during decompression. It is plausible that breaching oxygen exposure limits during resting decompression is less hazardous than equivalent breaches when exercising at deep depths. Mitchell SJ, Mesley P, Hannam JA. End tidal CO2 in recreational rebreather divers on surfacing after decompression dives.

Does superoxide enhance tubuloglomerular feedback by constricting the afferent arteriole? Superoxide (O(2) (-)) has been shown to augment tubuloglomerular feedback (TGF) both in vivo and in vitro by scavenging nitric oxide (NO) in the macula densa (MD). We hypothesized that in addition to this mechanism O(2) (-) potentiates TGF by acting directly on the afferent arteriole (Af-Art). Microdissected Af-Arts and adherent tubular segments containing the MD were simultaneously microperfused in vitro, maintaining Af-Art pressure at 60 mm Hg. TGF response was determined by measuring changes in Af-Art diameter while increasing NaCl in the MD perfusate from 11/10 to 81/80 mmol/L Na/Cl. To determine whether O(2) (-) acts at the MD in the absence of MD NO, we inhibited MD nNOS with 7-nitroindazole (7-NI) and added Tempol to the lumen. When 7-NI was added to the MD lumen, it increased TGF from 2.3 +/- 0.2 to 4.2 +/- 0.2 microm (P < 0.01). When Tempol was added to the MD lumen in the presence of 7-NI, it had no effect on TGF. To investigate whether O(2) (-) has any effect via the Af-Art in the absence of MD NO, we inhibited MD nNOS with 7-NI and added Tempol to the bath to scavenge O(2) (-) in the Af-Art. Adding Tempol to the bath with 7-NI in the MD lumen reduced TGF from 3.9 +/- 0.3 to 2.8 +/- 0.5 microm (P < 0.05 vs. 7-NI). To see if this effect was due to O(2) (-) scavenging NO production by the endothelium, we repeated the experiment in Af-Arts with damaged endothelium and found that adding Tempol to the bath lowered TGF from 3.4 +/- 0.9 to 1.2 +/- 0.6 microm (P < 0.01). When catalase was added to the bath together with Tempol, TGF response was not modified.

We concluded that it is O(2) (-) rather than H(2)O(2) that enhances TGF response, both directly by constricting the Af-Art and indirectly by scavenging NO in the MD.

Do [ Summarized real clinical cases use to learn clinical aptitude ]? to evaluate clinical skills indicators (CSI) with summarized real clinical cases (SRCC) by two generations of pregraduates interns. with a descriptive survey design 430 SRCC were elaborated according to the CSI: risk factors, clinical diagnosis, laboratory and x-ray diagnosis, commission and omission iatrogenesis procedures, therapeutics, nosology and peer critical medical actions. An evaluation scale for the clinical cases included: a relationship with the clinical experience, and the CSI selected. The final evaluation was considered as adequate or inadequate and was performed independently by three medical social service students. except for family medicine, the SRCC were related to the clinical experience of the students. A 62 % of the total was considered as adequate. The CSI assessed were related to risk factors (18 %), clinical diagnosis (32 %), omission and commission iatrogenesis (9 %), laboratory and x-ray diagnosis resources (16 %), therapeutics (17 %), nosology (9 %) and a critical to peer medical actions (3 %).

the SRCC patients studied from different points of view by the interns included the CSI. Therefore, this action is advisable for the improvement of the patients' clinical approach.

Is the parathyroid hormone-2 receptor expressed on human leukocytes and down-regulated in hyperparathyroidism? Parathyroid hormone (PTH) has specific effects on function, migration and proliferation of human leukocytes. These effects may contribute to accelerated atherosclerosis and impaired immune response observed in patients with renal insufficiency. Recently, a new G protein-coupled receptor with substantial implications for vascular function--the PTH2 receptor (PTH2-R)--has been identified, however, expression and distribution in humans and a possible regulation has not yet been studied. We therefore investigated the expression of the PTH2 receptor on human leukocytes in healthy subjects and in patients with hyperparathyroidism. PTH2 receptor expression was quantified by flow cytometry (FACS) analysis on monocytes, lymphocytes and granulocytes that were isolated from peripheral blood (hypotonic density gradient centrifugation) and by immunohistochemistry using a specific alpha-PTH2-R antibody produced in rabbit. Results of 22 patients with hyperparathyroidism (12 renal allograft recipients, 10 hemodialysis patients, mean age 43 +/- 8 years) were compared to 22 age and sex-matched healthy controls. Mean relative antigen density of the PTH2 receptor and percentage of positive cells in healthy subjects was 19 +/- 5 and 90 +/- 6% on granulocytes, 5 +/- 2 and 55 +/- 19% on monocytes, and 24 +/- 7 and 21 +/- 7% on lymphocytes. In patients with hyperparathyroidism, mean antigen density was significantly lower on granulocytes and monocytes (17 +/- 4% and 3 +/- 1%, p < 0.01, respectively). The percentage of positive cells and mean expression on lymphocytes was not significantly different. A significant and inverse correlation was found between plasma PTH concentrations and the mean PTH2 receptor expression on granulocytes (r = -0.41, p < 0.05).

The PTH2 receptor is expressed on human granulocytes and--to a lesser degree--on monocytes and lymphocytes. In patients with hyperparathyroidism the PTH2 receptor is down-regulated as function of plasma PTH levels.

Is charlson score a robust predictor of 30-day complications following spinal metastasis surgery? Retrospective chart review. To identify predictors of 30-day complications after the surgical treatment of spinal metastasis. Surgical treatment of spinal metastasis is considered palliative with the aim of reducing or delaying neurologic deficit. Postoperative complication rates as high as 39% have been reported in the literature. Complications may impact patient quality of life and increase costs; therefore, an understanding of which preoperative variables best predict 30-day complications will help risk-stratify patients and guide therapeutic decision making and informed consent. We retrospectively reviewed 200 cases of spinal metastasis surgically treated at Stanford Hospital between 1999 and 2009. Multiple logistic regression was performed to determine which preoperative variables were independent predictors of 30-day complications. Sixty-eight patients (34%) experienced one or more complications within 30 days of surgery. The most common complications were respiratory failure, venous thromboembolism, and pneumonia. On multivariate analysis, Charlson Comorbidity Index score was the most significant predictor of 30-day complications. Patients with a Charlson score of two or greater had over five times the odds of a 30-day complication as patients with a score of zero or one.

After adjusting for demographic, oncologic, neurologic, operative, and health factors, Charlson score was the most robust predictor of 30-day complications. A Charlson score of two or greater should be considered a surgical risk factor for 30-day complications, and should be used to risk-stratify surgical candidates. If complications are anticipated, medical staff can prepare in advance, for instance, scheduling aggressive ICU care to monitor for and treat complications. Finally, Charlson score should be controlled for in future spinal metastasis outcomes studies and compared to other comorbidity assessment tools.

Is increase in exhaled nitric oxide associated with bronchial hyperresponsiveness among apprentices? Airway inflammation is a hallmark of asthma. Several studies have validated the use of the fractional concentration of exhaled nitric oxide (Fe(NO)) as a surrogate marker of airway inflammation in asthma. We examined how the change in Fe(NO) levels, since the beginning of occupational exposure, could be associated with the incidence of bronchial hyperresponsiveness (BHR) among baker, pastry maker, and hairdresser apprentices during their 2-year training. A standardized questionnaire was administered; skin prick tests for common and specific occupational allergens were done; methacholine challenge and measurement of Fe(NO) were performed 6, 12, and 15 months after the first examination. Of 441 apprentices initially included, 351 completed the study. The increase in Fe(NO), since the beginning of exposure, was associated with the incidence of BHR (odds ratio, 2.00 [95% confidence interval, 1.21-3.32] per unit increase in log parts per billion) both in atopic and nonatopic subjects. The average increase in Fe(NO) was similar in atopic and nonatopic subjects and was unrelated to past or current smoking habits, sex, or training track. Atopy in bakers/pastry makers and sensitization to alkaline persulfates in hairdressers were also independently associated with the incidence of BHR. BHR occurred sooner among bakers/pastry makers than among hairdressers, but its incidence leveled off later.

Our results suggest that measurement of Fe(NO), a simple and reproducible test, could be useful in the screening of BHR in workers newly exposed to agents known to cause occupational asthma.

Do porphyromonas gingivalis-stimulated macrophage subsets exhibit differential induction and responsiveness to interleukin-10? Oral mucosal macrophages (Mϕs) determine immune responses; maintaining tolerance whilst retaining the capacity to activate defences against pathogens. Mϕ responses are determined by two distinct subsets; pro-inflammatory M1- and anti-inflammatory/regulatory M2-Mϕs. Tolerance induction is driven by M2 Mϕs, whereas M1-like Mϕs predominate in inflammation, such as that exhibited in chronic Porphyromonas gingivalis (PG) periodontal infection. Mϕ responses can be suppressed to benefit either the host or the pathogen. Chronic stimulation by pathogen associated molecular patterns (PAMPs), such as LPS, is well established to induce tolerance. The aim of this study was to investigate the P. gingivalis-driven induction of and responsiveness to the suppressive, anti-inflammatory cytokine, IL-10, by Mϕ subsets. M1- and M2-like Mϕs were generated in vitro from the THP-1 monocyte cell line by differentiation with PMA and Vitamin D PG-LPS differentially induced IL-10 secretion and endogenous IL-10 activity in M1- and M2-like subsets. In addition, these subsets exhibited differential sensitivity to IL-10-mediated suppression of TNFα, where M2 Mϕs where sensitive to IL-10 and M1 Mϕs were refractory to suppression. In addition, this differential responsiveness to IL-10 was independent of IL-10-binding and expression of the IL-10 receptor signal transducing subunit, IL-10Rβ, but was in fact dependent on activation of STAT-3.

P.gingivalis selectively tolerises regulatory M2 Mϕs with little effect on pro-inflammatory M1 Mϕs; differential suppression facilitating immunopathology at the expense of immunity.

Do [ Quality assessment of randomized controlled trials related to dental implant ]? To assess the quality of reporting by randomized controlled trial (RCT) related to dental implants in China during 2000 to 2012 by using the revised Jadad scale and consolidated standards of reporting trials (CONSORT) (2010) statement. The following electronic databases were searched: Chinese Biomedical Literature Database, Database for Chinese Technical Periodicals, China National Knowledge Infrastructure, PubMed, and EMBASE. A total of 19 journals of stomatology in China were also searched manually. The qualities of RCT with dental implant published between 2000 and 2012 were assessed using CONSORT (2010) statement and revised Jadad scale. Twenty-eight RCTs related to dental implants were identified. The quality of reporting in 28 articles was low. The mean revised Jadad score was 1.29 ± 0.71 and the CONSORT (2010) score was 9.75 ± 3.60.

The methodological qualities of the included studies on dental implants are generally low, and reporting quality remain unsatisfactory.

Is the role of dynamic flexion in spine injury altered by increasing dynamic load magnitude? Evidence indicates that loads and postures that an individual is exposed to alter their risk of reporting low back pain or incurring a spine injury. In vitro research indicates cyclic flexion under static compressive loads can lead to disc herniation, while repetitive compression in neutral or flexed postures leads to vertebral failure. However, no research has examined the likelihood of altering injury site (disc vs. bone) when dynamic load exposures are varied concurrently with cyclic flexion. Fifty porcine cervical spinal units were assigned to one of five groups based on peak normalized loads of 10%, 30%, 50%, 70% and 90% of the unit's predicted tolerance. Specimens underwent passive range of motion tests to determine individualized range of motion. Once individualized loads and angles were determined, specimens were cyclically compressed and flexed based on profiles obtained from a floor to waist height lift until failure occurred or 12h elapsed. After testing specimens were dissected to identify injury site, and cumulative exposures sustained to failure were calculated. Disc injury was not observed when peak loads exceeded 30% of the tolerance, while they comprised a higher percentage of the total injuries incurred when decreasing from the 30% to 10% groups. Those specimens exhibiting disc injury tolerated significantly greater: cycles to failure (9000 vs. 930, P<0.0001), cumulative compression (10872.7 vs. 1089.5MNs, P<0.001), shear (1822.1 vs. 150.6MNs, P<0.001) and angular excursion (130809.7 degrees vs. 12714.7 degrees , P<0.001).

If the spine is exposed to greater levels of load, in the presence of repetitive flexion, it is more likely to experience vertebral fracture. However, if the spine is exposed to many cycles of low peak loads, injury is more likely to occur to the intervertebral disc than to the vertebral bone or endplate.

Does ascorbate depletion increase growth and metastasis of melanoma cells in vitamin C deficient mice? Our main objective was to determine the effect of ascorbate supplementation in mice unable to synthesize ascorbic acid (gulo KO) when challenged with murine B16FO cancer cells. Gulo KO female mice 36-40 weeks of age were deprived of or maintained on ascorbate in food and water for 4 weeks prior to subcutaneous injection of 2.5×10(6) B16FO murine melanoma cells in the right flank of mice. A control group of wild type mice were also injected with the melanoma cells and maintained on a regular murine diet. Mice were continued on their respective diets for another 2 weeks after injection. The mice were then sacrificed, blood was drawn and their tumors were measured, excised and processed for histology. Mean weight of animals decreased significantly (30%, p < 0.0001) in the ascorbate-restricted group but increased slightly, but insignificantly, in the ascorbate-supplemented group. The mean tumor weight in ascorbate supplemented mice was significantly reduced (by 64%, p = 0.004) compared to tumor weight in ascorbate-deprived gulo mice. The mean tumor weight of wild type mice did not differ significantly from the ascorbate-supplemented mice. Gulo KO mice supplemented with ascorbate developed smaller tumors with more collagen encapsulation and fibrous capsule interdigitation, while gulo KO mice deprived of ascorbate hosted large tumors with poorly defined borders, showing more necrosis and mitosis. Ascorbate supplementation of gulo KO mice resulted in profoundly decreased serum inflammatory cytokine IL-6 (90% decrease, p = 0.04) and IL-1β (62% decrease) compared to the levels in gulo KO mice deprived of ascorbate.

Ascorbate supplementation modulated tumor growth and inflammatory cytokine secretion as well as enhanced encapsulation of tumors in scorbutic mice.

Does global gene expression analysis reveal reduced abundance of putative microRNA targets in human prostate tumours? Recently, microRNAs (miRNAs) have taken centre stage in the field of human molecular oncology. Several studies have shown that miRNA profiling analyses offer new possibilities in cancer classification, diagnosis and prognosis. However, the function of miRNAs that are dysregulated in tumours remains largely a mystery. Global analysis of miRNA-target gene expression has helped illuminate the role of miRNAs in developmental gene expression programs, but such an approach has not been reported in cancer transcriptomics. In this study, we globally analysed the expression patterns of miRNA target genes in prostate cancer by using several public microarray datasets. Intriguingly, we found that, in contrast to global mRNA transcript levels, putative miRNA targets showed a reduced abundance in prostate tumours relative to benign prostate tissue. Additionally, the down-regulation of these miRNA targets positively correlated with the number of types of miRNA target-sites in the 3' untranslated regions of these targets. Further investigation revealed that the globally low expression was mainly driven by the targets of 36 specific miRNAs that were reported to be up-regulated in prostate cancer by a miRNA expression profiling study. We also found that the transcript levels of miRNA targets were lower in androgen-independent prostate cancer than in androgen-dependent prostate cancer. Moreover, when the global analysis was extended to four other cancers, significant differences in transcript levels between miRNA targets and total mRNA backgrounds were found.

Global gene expression analysis, along with further investigation, suggests that miRNA targets have a significantly reduced transcript abundance in prostate cancer, when compared with the combined pool of all mRNAs. The abnormal expression pattern of miRNA targets in human cancer could be a common feature of the human cancer transcriptome. Our study may help to shed new light on the functional roles of miRNAs in cancer transcriptomics.

Does lentivirus-mediated angiopoietin-2 gene silencing decrease TNF-α induced apoptosis of alveolar epithelium cells? To investigate the role of angiopoietin-2 (Ang-2) in tumor necrosis factor-α (TNF-α) induced apoptosis of alveolar epithelium cells (AECs). TNF-α was used to induce human alveolar epithelial HPAEpiC cells, and Ang-2 siRNA vector was transfected to the HPAEpiC cells. RT-PCR and Western blot were used. TUNEL staining was applied to observe apoptosis, and annexin V-FITC-PI staining was used to calculate apoptosis rate. mRNA and protein expressions of Ang-2, activated Bax, and cleaved caspase-3 in HPAEpiC cells were up-regulated, but the expression level of Bcl-2 decreased (P < 0.05). After transfection of Ang-2 siRNA, mRNA and protein expressions of Ang-2, activated Bax, and cleaved caspase-3 in HPAEpiC cells were down-regulated, but the expression level of Bcl-2 increased (P < 0.05). The number of apoptotic cells increased after TNF-α treatment; however, the number decreased after Ang-2 siRNA transfection. Annexin V-FITC-PI staining verified that the total number of apoptotic cells was elevated with TNF-α treatment, but declined after transfection of Ang-2 siRNA.

The expression level of Ang-2 increased during TNF-α-induced apoptosis. Inhibiting Ang-2 expression may suppress the early stages of cell apoptosis and the degree of TNF-α-induced apoptosis.

Are glomerulosclerosis and body growth mediated by different portions of bovine growth hormone . Studies in transgenic mice? Mice transgenic for bovine growth hormone (bGH) gene have increased body weight and severe glomerulosclerosis leading to death in uremia. The aim of this study was to determine if body growth and glomerulosclerosis were mediated by different bGH regions. Amino acid substitutions in the bGH alpha-helix III were generated, and lines of transgenic mice that expressed these products were developed. Female transgenic mice carrying the native bGH gene (bGH mice), a mutated bGH gene that encodes a destabilized alpha-helix III (bGH-L121P, E126G; bGH-m11 mice), or a mutated bGH gene that encodes a perfect amphiphilic alpha-helix III (bGH-E117L, G119R, A122D; bGH-m8 mice) were examined at 2-3 months and 6-9 months of age. Body, kidney, and heart weights were measured. Urinary glucose, albumin, creatinine, and serum glucose were measured in all mice. Serum levels of insulin-like growth factor I (IGF-I) were measured in the 2-3 month group. Whole blood hemoglobin A1 was measured in some mice of the 6-9 month group. Kidney sections were examined by light and immunofluorescence microscopy. Glomerular volume was measured and related to body weight by allometry. The bGH-m11 mice developed glomerulosclerosis indistinguishable from that seen in bGH transgenic mice, even though they had normal body size. Glomerular growth exceeded body growth by allometry in both bGH and bGH-m11 strains. bGH-m8 mice had glomeruli of appropriate size and normal histologic appearance; however, they were dwarfs. IGF-I was increased in bGH mice; they also had an increased albumin/creatinine ratio at 6-9 months. None of the mice were hyperglycemic.

These data indicated that development of glomerulosclerosis and body growth promotion were mediated by different regions of the growth hormone molecule. The glomerular response to bGH was unique and consisted of increased size and glomerulosclerosis.

Do urine markers predict biopsy findings or presence of bladder ulcers in interstitial cystitis/painful bladder syndrome? We tested for associations between urine markers, bladder biopsy features and bladder ulcers in interstitial cystitis/painful bladder syndrome. Subjects were 72 patients with interstitial cystitis/painful bladder syndrome undergoing bladder distention and biopsy. Urine was collected before the procedure. Urine marker levels were correlated with biopsy and cystoscopic findings. Patients with no previous interstitial cystitis/painful bladder syndrome treatments (47) were analyzed separately from previously treated patients (25). For untreated patients urine interleukin-6 and cyclic guanosine monophosphate were associated with urothelial epidermal growth factor receptor staining (for interleukin-6 r = 0.29; 95% CI 0.07, 0.51; p = 0.01 and for cyclic guanosine monophosphate r = 0.34; 95% CI 0.13, 0.55; p = 0.002). Urine interleukin-8 was negatively associated with urothelial heparin-binding epidermal growth factor-like growth factor staining (r = -0.34; 95% CI -0.55, -0.12; p = 0.002) and positively associated with lamina propria mast cell count (r = 0.29; 95% CI 0.06, 0.52; p = 0.01). The latter association also was seen in treated patients (r = 0.46; 95% CI 0.20, 0.73; p <0.001). None of the urine markers was significantly different for ulcer vs nonulcer groups. All of the patients with ulcer had extensive inflammation on bladder biopsy including severe mononuclear cell infiltration, moderate or strong interleukin-6 staining in the urothelium and lamina propria, and leukocyte common antigen staining in more than 10% of the lamina propria. However, these features also were seen in 24% to 76% of the patients without ulcer.

Overall urine markers did not associate robustly with biopsy findings. The strongest association was a positive association between urine interleukin-8 levels and bladder mast cell count. Patients with ulcer consistently had bladder inflammation but the cystoscopic finding of ulcers was not a sensitive indicator of inflammation on bladder biopsy.

Are reference intervals for TSH and thyroid hormones mainly affected by age , body mass index and number of blood leucocytes , but hardly by gender and thyroid autoantibodies during the first decades of life? The purpose of our study was to establish reference intervals for thyroid function tests in children and adolescents and to identify factors that may influence the limits of these intervals. TSH, FT3, FT4, T3, T4, t-uptake, TPO-antibody (TPO-Ab) and TG-antibody (TG-Ab) levels were determined in blood of 1004 infants, children and adolescents by the Elecsys system (Roche). A distinct overall age-dependent decrease of analyte levels was found for all parameters investigated. Puberty was accompanied by an increase of TSH, FT3 and T3 levels. Results of T4 and t-uptake were significantly higher in girls compared to boys. The exclusion of children with increased TPO-Ab and TG-Ab had no significant effect on the limits of the reference interval. We found that besides age, BMI-SDS but also white blood cells count and gender played a role in the prediction of analyte variation.

Covariates like BMI-SDS and white blood cell count should be taken into consideration when interpreting TSH and thyroid hormone measurements as well whereas gender and TPO-Ab or TG-Ab play a minor role.

Is age-related macular degeneration associated with incident myocardial infarction among elderly Americans? To investigate whether age-related macular degeneration (AMD) is associated with the development of myocardial infarction (MI) among elderly Americans. Population-based cross-sectional and cohort study. Five percent random sample of 2000 to 2003 Medicare enrollees. The cross-sectional study included the first 2-year (2000 and 2001) enrollees who were aged > or =65 years (n = 1,519,086). The cohort study included only baseline MI-free enrollees (n = 1445677). Chronic conditions (AMD and type, history of MI, hypertension, and diabetes) were defined based on any occurrence of relevant International Classification of Diseases 9 codes in relevant diagnosis fields of the baseline Medicare claim files. A total of 56611 incident MI cases were identified from the follow-up data (2002 and 2003). Baseline mean age was 76 years, with 60% women and 88% whites. The prevalence of neovascular AMD was 2.2% (2.3% in women vs. 1.7% in men and 2.3% in whites vs. 1.2% in blacks; P<0.01 for both gender and race differences). The prevalence of nonneovascular AMD was 8.8% (9.9% in women vs. 7.3% in men and 9.5% in whites vs. 4.3% in blacks; P<0.01 for both gender and race differences). Baseline age-, gender-, and race-adjusted prevalences of hypertension, diabetes, and history of MI were 75%, 33%, and 5.00%, respectively, in the neovascular AMD group. In contrast, they were 73%, 27%, and 4.68% in the nonneovascular AMD group, and 65%, 25%, and 4.54% in the non-AMD group (P<0.01 for comparing the prevalence in neovascular and nonneovascular AMD vs. non-AMD groups). Prospectively, baseline age-, gender-, race-, hypertension-, and diabetes-adjusted 2-year incident odds ratios and 95% confidence intervals of MI associated with AMD are 1.19 (1.16-1.22) for all persons with AMD, 1.26 (1.20-1.33) for neovascular AMD, and 1.18 (1.14-1.21) for nonneovascular AMD.

AMD is associated with older age, female gender, being white, and having a history of MI, hypertension, and diabetes. Furthermore, presence of AMD, especially neovascular AMD, is prospectively associated with a higher risk of incident MI. These findings, if confirmed by other studies that control for smoking and other lifestyle covariables, suggest the possibility of shared common antecedents between MI and AMD.

Do apoptotic and proliferative defects characterize ocular development in a microphthalmic BMP model? Vision is critically dependent on ocular size, which is regulated by environmental and genetic factors. Mutation of human Growth and Differentiation Factor 6 (GDF6) or zebrafish gdf6a results in a spectrum of small eye phenotypes (microphthalmia, anophthalmia, and coloboma). However, current models do not explain their etiology fully. As such, analyses of apoptosis and cell cycle regulation were undertaken in a zebrafish gdf6a mutant. Microarray analysis was performed at 2 days after fertilization to uncover novel gdf6a-dependent cell cycle regulators. Altered expression of Gdf6a targets was confirmed by in situ hybridization, and resulting changes in cell proliferation were assessed by phosphohistone H3 immunohistochemistry. Analysis of apoptosis was evaluated through activated Caspase 3 immunohistochemistry and chemical inhibitors of cell death. Reduced numbers of retinal progenitor cells are observed at 24 hours post fertilization (hpf), resulting in microphthalmic eyes in gdf6a(-/-) embryos. At 28 hpf, a wave of apoptosis occurs; however, apoptosis inhibition does not rescue eye size, indicating a limited contribution. Mutants display altered proliferation and expression levels of cell cycle regulators, including members of the forkhead box i (foxi) transcription factor family expressed in the ciliary marginal zone. Notably, inhibition of foxi2 in gdf6a(-/-) embryos further reduces eye size.

These data support a model whereby the gdf6a(-/-)-induced microphthalmia is based on early regulation of retinal progenitor cell number, and later by regulation of proliferation in the ciliary marginal zone. Foxi genes represent downstream effectors of Gdf6a function in the CMZ required for eye size determination.

Do methylation status in healthy subjects with normal and high serum folate concentration? We assessed the impact of high serum folate concentration on erythrocyte S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) concentrations, SAM/SAH ratio, CpG methylation levels across the promoter region of the extracellular superoxide dismutase (ec-SOD) gene, and ec-SOD activity in healthy men. Serum folate levels were measured in 111 subjects who were categorized in quintiles according to their folate status. Subjects located at the lowest, middle, and upper quintiles were selected for assessment of SAM and SAH by high-performance liquid chromatography, C677T genotype of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, ec-SOD methylation of CpG sites in lymphocytes genomic DNA by bisulfate treatment, and ec-SOD activity by a chemical assay. Sixteen subjects were in the lowest serum folate quintile (<23.6 nmol/L), 17 in the middle (>34-<42 nmol/L), and 14 in the highest (>45nmol/L). SAM concentration was higher in the upper than in the middle and lowest quintiles (5.57 +/- 1.58, 2.52 +/- 0.97, 2.29 +/- 1.2 micromol/L; P < 0.0001). SAH concentration was higher in the upper compared with the lowest quintile (0.76 +/- 0.24 versus 0.52 +/- 0.23 micromol/L, P < 0.001). There were no differences in the SAM/SAH ratio, ec-SOD activity, methylation status of CpG sites of the ec-SOD gene, and TMTHFR C677T genotype between groups.

Serum folate concentrations in the highest quintile among healthy humans are associated with increased erythrocyte SAM and SAH concentrations, but not with SAM/SAH ratio or with methylation levels of CpG sites across the promoter region of the ec-SOD gene. Further research is required to determine if these findings are beneficial or harmful.

Are stunting , poor iron status and parasite infection significant risk factors for lower cognitive performance in Cambodian school-aged children? Nutrition is one of many factors affecting the cognitive development of children. In Cambodia, 55% of children <5 y were anemic and 40% stunted in 2010. Currently, no data exists on the nutritional status of Cambodian school-aged children, or on how malnutrition potentially affects their cognitive development. To assess the anthropometric and micronutrient status (iron, vitamin A, zinc, iodine) of Cambodian schoolchildren and their associations with cognitive performance. School children aged 6-16 y (n = 2443) from 20 primary schools in Cambodia were recruited. Anthropometry, hemoglobin, serum ferritin, transferrin receptors, retinol-binding protein and zinc concentrations, inflammation status, urinary iodine concentration and parasite infection were measured. Socio-economic data were collected in a sub-group of children (n = 616). Cognitive performance was assessed using Raven's Colored Progressive Matrices (RCPM) and block design and picture completion, two standardized tests from the Wechsler Intelligence Scale for Children (WISC-III). The prevalence of anemia, iron, zinc, iodine and vitamin A deficiency were 15.7%; 51.2%, 92.8%, 17.3% and 0.7% respectively. The prevalence of stunting was 40.0%, including 10.9% of severe stunting. Stunted children scored significantly lower than non-stunted children on all tests. In RCPM test, boys with iron-deficiency anemia had lower scores than boys with normal iron status (-1.46, p<0.05). In picture completion test, children with normal iron status tended to score higher than iron-deficient children with anemia (-0.81; p = 0.067) or without anemia (-0.49; p = 0.064). Parasite infection was associated with an increase in risk of scoring below the median value in block design test (OR = 1.62; p<0.05), and with lower scores in other tests, for girls only (both p<0.05).

Poor cognitive performance of Cambodian school-children was multifactorial and significantly associated with long-term (stunting) and current nutritional status indicators (iron status), as well as parasite infection. A life-cycle approach with programs to improve nutrition in early life and at school-age could contribute to optimal cognitive performance.

Do elevated circulating endothelial progenitor marker CD133 messenger RNA levels predict colon cancer recurrence? CD133 is a specific surface marker for bone marrow-derived circulating endothelial progenitors, which are vital in postnatal physiologic and pathologic (eg, tumor) angiogenesis. In this study, the authors examined whether increased levels of expression of CD133 messenger RNA (mRNA) in peripheral blood predicted disease recurrence in patients with colon cancer. Semiquantitative real-time reverse transcriptase-polymerase chain reaction analysis was used to quantify CD133 mRNA levels in peripheral blood mononuclear cells from patients with colon cancer. The assay was developed first and tested at laboratory A (n = 34) and then was validated independently at laboratory B (n = 66). All patients were enrolled between February 2002 and December 2003. A central statistician performed the analysis. At laboratory A, the median CD133 mRNA level was elevated in patients with recurrent disease (4.2; range, 0.017-106.9) compared with patients without recurrence (0.0017; range, 0.0-9.51; P < .001), leading to a 14.6 odds ratio of recurrence (95% confidence interval [95% CI], 1.7-126; P = .004). At laboratory B, it was confirmed that elevated CD133 mRNA levels at a cutoff point >or=4.79 versus <4.79 were associated with an odds ratio of 22.6 for recurrence (95% CI, 1.7-291.2; P = .02). By comparison, the odds ratio for recurrence was 17.2 (95% CI, 1.8-164; P = .01) for patients with stage III-IV disease versus stage I-II disease according to the Tumor, Lymph Node, Metastasis (TNM) classification. An association also was observed between elevated carcinoma embryonic antigen levels (P = .03; 1-sided) and decreased survival (P = .035; 1-sided) with a CD133 mRNA cutoff level of >or=4.79.

Elevated CD133 mRNA levels at >or=4.79 predicted colon cancer recurrence independent of TNM stage IV disease. Larger prospective studies comparing the current assay with standardized methodology are warranted.

Does tadalafil prevent acute heart failure with reduced ejection fraction in mice? Phosphodiesterase-5 (PDE5) inhibitors were shown to exert powerful protection in various animal models of cardiomyopathy. Tadalafil is a long-acting and highly specific PDE5 inhibitor, which makes it the most attractive in its class for long-term management of patients with heart failure. We studied the effects of tadalafil in attenuating ischemic cardiomyopathy in mice. Adult male mice underwent myocardial infarction (MI) by permanent left coronary artery ligation and were treated daily with tadalafil (1 mg/kg; ip) or volume-matched 10% DMSO for 4 weeks. Twenty four hours after coronary ligation, infarct size, measured by TTC staining, was reduced from 70.1 ± 3.1% in DMSO-treated group to 49.3 ± 2.6% with tadalafil (P < 0.05). Similarly, tadalafil treatment yielded a smaller fibrotic area (8.8 ± 2.8% of LV), assessed by Masson's trichrome staining, as compared to DMSO group (21.9 ± 3.9%, P < 0.05). Apoptosis, measured by TUNEL assay, also declined with tadalafil (2.1 ± 0.2%) as compared to DMSO (6.7 ± 0.4%, P < 0.05) at 28 days post MI. Tadalafil also attenuated the increase in cardiac hypertrophy and pulmonary edema following infarction. These parameters reflect diminished left ventricular (LV) adverse remodeling and preserved fractional shortening with tadalafil at 7 and 28 days post infarction.

Tadalafil attenuates ischemic cardiomyopathy in mice and preserves LV function.

Does perioperative very low-dose ketamine infusion actually increase the incidence of postoperative remifentanil-induced shivering-double-blind randomized trial? Low-dose ketamine infusion (blood concentration around 100 ng/mL) during surgery reduces the incidence of postoperative shivering after remifentanil-based anesthesia. We hypothesized that perioperative infusion of very low-dose ketamine (blood concentration around 40 ng/mL) during remifentanil-based anesthesia may also prevent the development of remifentanil-induced shivering during the 2-hour period after the end of anesthesia. Fifty female patients scheduled to undergo laparoscopic cystectomy or oophorectomy were assigned to one of two groups: (1) ketamine group, in which the patients received ketamine infusion (0.1 mg/kg/hour) from induction of anesthesia to emergence from anesthesia; and (2) control group, in which the patients received saline infusion from induction up till emergence from anesthesia. Anesthesia was induced and maintained by target-controlled infusion of propofol (estimated blood concentration: 2-4 μg/mL) and infusion of remifentanil, at 0.2-0.3 μg/kg/minute. Patients were observed for shivering from the end of anesthesia to 120 minutes after anesthesia. The time point at which the patient began to shiver was recorded and assigned to one of four time periods: at emergence, from emergence to 30 minutes after anesthesia, from 30 minutes to 60 minutes after anesthesia, and >60 minutes after anesthesia. During the 120-minute observation period, the number of patients who shivered was higher in the ketamine group than the in control group (18 vs. 8, ketamine group vs. control group, p = 0.01). The time period during which patients began to shiver was different between the two groups (1 patient, 4 patients, and 13 patients vs. 3 patients, 2 patients, and 3 patients at emergence, from emergence to 30 minutes, and from 30 minutes to 60 minutes after anesthesia, respectively; ketamine group vs. control group, p = 0.007).

Intraoperative infusion of very low-dose ketamine during remifentanil-based anesthesia may increase the incidence of postoperative shivering.

Is esophageal acid-clearance physiology altered after Nissen-Collis gastroplasty? Nissen-Collis gastroplasty (NCG) is an effective treatment for short esophagus, but it sometimes is associated with abnormal postoperative esophageal acid exposure. This study was designed to test the hypothesis that NCG prevents gastric reflux and that pathologic distal esophagus acid exposure is due to prolonged acid clearance in the "neoesophagus." The study enrolled 11 normal healthy subjects (ten patients status post--laparoscopic Nissen fundoplication and nine patients status post-NCG). All the participants were age and gender matched, and all were studied via manometry, acid-clearance test, and 24-h pH analysis. The clearance test was performed according to an established protocol. A 15-ml acid bolus (pH 1.2) was rapidly infused (×4) using a nasogastric tube 15 cm proximal to the lower esophageal sphincter, followed by dry swallows every 30 s until the esophageal pH rose above 4. All the subjects had normal esophageal peristalsis and distal amplitudes. The acid-clearance time was significantly higher with NCG (P < 0.001 vs Nissen and normal subjects). Pathologic esophageal acid exposure occurred in one of ten Nissen patients (10 %) and in two of nine NCG patients (22 %) (nonsignificant difference [NS]). The median distal esophageal acid exposure time during the 24-h pH study was similar in the two groups (NCG, 1.2 %; Nissen, 2.5 %; NS).

The findings showed that NCG is an adequate antireflux procedure but that it is characterized by a delayed esophageal acid clearance.

Do serotonin 5-HT2A receptors in the CA1 field of the hippocampus mediate head movements in the rabbit? Motor movements (head bobs) in the rabbit have been shown to be elicited by LSD-like hallucinogenic drugs through actions at central serotonin 5-HT(2A) receptors, though their central locus remains unknown. Serotonergic innervation of the hippocampus has been suggested to play an important role in motor programming including movements of the head. We examined whether intrahippocampal injections of a 5-HT(2A) receptor agonist would elicit head bobs and whether elicitation of head bobs would be modified by increases in hippocampal 5-HT(2A) receptor density. Animals received bilateral injections of DOI or its vehicle into the dorsal hippocampus either before or after chronic administration of MDL 11,939 or its vehicle. The number of head bobs was counted continuously for 60 min and reported in blocks of 10 min and this was compared with the density of 5-HT(2A) receptors in dorsal hippocampus. Infusion of DOI into the CA1 region of the dorsal hippocampus elicited head bobs that were blocked by prior intrahippocampal injection of the 5-HT(2A) receptor antagonist ketanserin. Receptor autoradiography revealed that chronic administration of MDL 11,939 produced a 2.5-fold up-regulation of 5-HT(2A) receptors in the CA1 field and dentate gyrus of the hippocampus. This 5-HT(2A) receptor up-regulation was associated with a nearly 2-fold increase in head bobs elicited by infusion of DOI into the CA1 field.

These results indicate that 5-HT(2A) receptors located in the CA1 field of the hippocampus mediate a motor movement, head bobs, and that this mediation is functionally related to receptor density.

Is intake of wholegrain products associated with dietary , lifestyle , anthropometric and socio-economic factors in Denmark? To evaluate the association between wholegrain products intake and other dietary, lifestyle, anthropometric and socio-economic factors. Cross-sectional study, with data on diet, lifestyle and socio-economic factors obtained from questionnaires. Anthropometric measurements were collected by trained professionals. Multiple linear and principal components regression analyses were used in statistical analyses. Part of the Diet, Cancer and Health study, a prospective cohort study to evaluate the aetiological role of diet on cancer risk, conducted in the greater Copenhagen and Aarhus area, Denmark. Men and women (n 54,720) aged 50-64 years. In multiple linear regression analyses focusing on individual dietary factors, intake of wholegrain products was associated with intake of all dietary factors studied (fish, red meat, poultry, processed meat, dairy products, fruits, vegetables, cakes and refined-grain products). The strongest positive associations were seen for intake of vegetables and processed meat, whereas the strongest negative associations were seen for intake of red meat and refined-grain products. Regression analyses on dietary patterns identified by principal components analysis yielded similar results. Also, wholegrain products intake was positively associated with cycling, taking dietary supplements and high school education, and negatively associated with intake of alcohol, BMI and smoking.

Intake of wholegrain products is associated with other dietary factors, healthier lifestyle habits and higher socio-economic status. Therefore future studies need to account for the possible confounding by other dietary and lifestyle-related parameters when investigating relationships between wholegrain products intake and disease risk.

Does cyclosporine enhance the development of accelerated coronary artery disease : experimental study in a rat cardiac transplant model? Among other factors, cyclosporine (CsA) is linked with the development of accelerated coronary artery disease (ACAD) after transplantation. The objective of this study was to assess the influence of different CsA regimens on ACAD after rat heart transplantation. After heterotopic cardiac transplantation (Lewis to Fisher), animals were treated with 3 or 12 mg/kg per day of CsA, administered subcutaneously. The control group received no therapy. CsA blood levels were determined every 10 days. Twenty and 80 days after grafting, the incidence of ACAD was determined and the extent of ACAD was assessed as mean vessel occlusion (mvo). In the 12-mg group, CsA levels were nearly 10-fold higher than in the 3-mg group. Only in the 12-mg CsA group was the incidence of ACAD significantly reduced at Days 20 and 80 when compared with controls. Continuous therapy with 3 mg and 12 mg of CsA significantly reduced the mvo at Days 20 and 80 when compared with control animals (p <.05). However, comparing the two dosages, there were no significant differences. When the 20-day-limited course of CsA application was used we did not observe significant differences in mvo at Day 80 upon comparison of 3-mg and 12-mg CsA treatment versus untreated animals.

Despite the excessive increase in CsA blood levels we observed neither a further reduction nor an increase of ACAD in the high-dose group compared with the low-dose group. Therefore, CsA did not enhance the development of chronic rejection in this experiment.

Are porcine CYP2A19 , CYP2E1 and CYP1A2 forms responsible for skatole biotransformation in the reconstituted system? To study the contribution of individual purified porcine CYP1A2, 2E1 and 2A19 enzymes to the biotransformation of skatole. Individual porcine and human enzymes (CYP1A2, 2E1 or 2A6/19) were used to study their potential involvement in skatole metabolism. Furthermore, the inhibition experiments using specific inhibitors of CYP1A2, 2E1 or 2A6/19, were performed. For determination of skatole biotransformation by individual CYP forms in reconstituted systems, HPLC method with UV detection was used. The data presented in this paper show that porcine and human CYPs are responsible for the formation of indole-3-carbinol and 3-methyloxindole. Whereas in pig CYP2A19 and CYP1A2 seem to be the most important for metabolism of skatole, in man CYP1A2 and CYP2E1 forms are mainly responsible for the production of the metabolites mentioned above.

The porcine and human CYP1A2, 2E1, 2A6/19 forms contribute to formation of 3-methyloxindole and indole-3-carbinol.

Does 374 Modeling the Effects of Current Steering With Directional lead? Directional deep brain stimulation (DBS) leads designed to preferentially stimulate structures radially about the DBS lead are currently under development. Recent publications have demonstrated the ability of these leads to obtain directional effects during acute testing in patients. Here we will use computational modeling to demonstrate that combining directional leads with Multiple Independent Current Control (MICC) will offer additional control over the shape of the Volume of Tissue Activated (VTA). A finite element model (FEM) for DBS using example directional lead geometry was developed (COMSOL) and used to calculate potentials in the space surrounding the lead. These potentials were then used to evaluate neural activation by using axon cable models (NEURON) following the methods of McIntyre et al. Further analysis was performed in MATLAB to visualize and characterize the effects of stimulation. Modeled threshold fields iso-surfaced at relevant stimulation levels demonstrates the ability of MICC to enable selection and shaping of field profiles that are not possible when using single source systems.

Modeling results suggest additional clinical benefit may be achieved when coupling directional leads with MICC designs. These additional fields may result in clinical benefits for some patients, and further study will be needed to evaluate their effects.

Is the cholinergic response increased in isolated ileum from gastroschisis rat model? Babies with gastroschisis (G) have high morbidity rate and long hospital stay due to bowel hypomotility caused by chronic exposure of the bowel to the amniotic fluid. Our aim was to evaluate the reactivity of isolated ileum in fetal rats selected for experimental gastroschisis. G was surgically created at 18.5 days of gestation (term = 22 days). Concentration-dependent curve to the muscarinic agonist methacholine (1-30 μM) and contractions induced by electrical field stimulation (EFS, 1-16 Hz, 50 V, 1 ms) were carried out in isolated ileum of groups control (C), sham (S) and gastroschisis (G) (n = 30). Protein expression for M(3) was assessed by western blot analysis. The frequency and amplitude of spontaneous contractions were decreased in G (p < 0.001). Methacholine produced concentration-dependent contractions being the maximal response values higher in G (p < 0.01). EFS-induced frequency-dependent contractions showed 1.8 times higher in G as well as an increase of M(3) expression.

The frequency and the amplitude of rhythmic contractions were reduced along with an increase in the contraction induced by mucarinic agonist and by EFS in G. These results suggest the occurrence of an adaptative supersensitivity to cholinergic response via increases in the protein expression for M(3) receptor.

Does evolution of outer retinal fold occurring after vitrectomy for retinal detachment repair? To assess the evolution of outer retinal folds (ORFs) occurring after repair of rhegmatogenous retinal detachment (RRD) using spectral domain-optical coherence tomography (sd-OCT) and fundus autofluorescence (FAF), and to discuss their pathogenesis. Twenty patients were operated on with 25-gauge pars plana vitrectomy and 20% sulfur hexafluoride gas injection for primary macula-off RRD repair and were followed prospectively. Sd-OCT and FAF images were recorded at 1, 3 and 6 months postoperatively. ORFs appeared on sd-OCT as hyperreflective lesions consisting of folded inner segment/outer segment of photoreceptors band and external limiting membrane band. Corresponding lines of increased or decreased autofluorescence were observed on FAF. Over the follow-up, the thick hypoautofluorescent lines progressively evolved to thick hyperautofluorescent lines and to thin hyperautofluorescent lines and eventually disappeared. Concomitantly, OCT scans revealed that the corresponding hyperreflective lesions decreased in number, height, and size. In six cases FAF assessment at month 6 was precluded by cataract development.

ORFS tend to resolve spontaneously within a few months from operation leaving no or subtle abnormalities at the level of the outer retinal layers. OCT is superior to FAF to follow the evolution of orfs in phakic eyes. The following factors might be involved in ORFS pathogenesis: structural changes occurring in the detached retina, residual pockets of subretinal fluid after retinal reattachment, intravitreal gas, unintentional retinal translocation, and intraoperative or perioperative hypotony.

Is pathological but not physiological retinal neovascularization altered in TNF-Rp55-receptor-deficient mice? Tumor necrosis factor (TNF)-alpha is one of the major cytokines in inflammation and apoptosis. It has been demonstrated that inhibition of TNFalpha can reduce leukocyte adhesion, vascular leakage, and apoptotic endothelial cell death in diabetes. This study was conducted to investigate the effect of TNF-Rp55 and TNF-Rp75 on retinal development in oxygen-induced retinopathy. TNF-Rp55- and TNF-Rp75-deficient mice, as well as their respective wild-type controls, were exposed to 75% oxygen from postnatal day P7 to P12. Retinal vascularization was investigated in flatmount preparations after concanavalin A labeling of endothelial cells on days P6, P14, P17, and P20. Retinal mRNA expression of VEGF, angiopoietin-1 and -2, and PDGF was examined at days P14 and P20. TNF-Rp55- and TNF-Rp75-deficient mice demonstrated similar retinal development and vascularization under normoxic conditions. In comparison to wild-type mice, the vascularized area remained stable during the observation time, although the gene expression of VEGF, angiopoietin (ang)-1 and -2, and PDGFb changed. Compared with that in the wild type mice, the relative expression of VEGF, ang-1, ang-2, and PDGFb changed 5.14-, 1.7-, 0.39-, and 0.36-fold in Rp55(-/-) mice and 4.1-, 9.5 x 10(-5)-, 0.12-, and 2975-fold in Rp75(-/-) mice, respectively. Treatment with oxygen resulted in a significantly reduced vascularization in Rp55(-/-) but not Rp75(-/-) mice on postnatal day (P)20.

Inhibition of TNFalpha via TNF-Rp55 can alter retinal development and angiogenesis in a model of oxygen-induced retinopathy. The data underscore the potential effectiveness of TNF-inhibitory treatments as modulators in oxygen-induced retinopathy.

Does potassium sorbate reduce gastric colonization in patients receiving mechanical ventilation? Tube feeding might increase gastric burden of pathogenic bacteria and predispose patients to ventilator-associated pneumonia. We sought to determine whether a tube feeding formula acidified using potassium sorbate could reduce gastric burden of potentially pathogenic bacteria. Prospective, randomized, double-blind trial. RML Specialty Hospital, a facility with expertise in weaning patients from prolonged mechanical ventilation. Thirty patients recovering from prolonged mechanical ventilation. Patients were randomized to receive either a standard tube feeding formula (n=14) or a formula acidified using potassium sorbate to a pH of 4.25 (n=16). Weekly quantitative cultures of gastric aspirates. The number of colony-forming units (CFUs) per patient was higher in the control than in the treatment group (53%+/-11% vs 9%+/-3.4%, threshold of >or=100,000 CFU/mL fluid, P=.003). The number of organisms isolated in each patient per week was higher among patients receiving standard tube feeding formula than among patients receiving acidified formula (0.91 +/- 0.20 vs 0.13 +/- 0.05 organisms per patient per week, threshold of >or=100,000 CFU/mL fluid, P=.0014). There was no difference in the incidence of gastrointestinal bleeding or ventilator-associated pneumonia between study groups.

Tube feeding formula acidified using potassium sorbate was well tolerated and reduced gastric bacterial burden in patients recovering from prolonged mechanical ventilation.

Are serum adiponectin concentrations related to glycosylated hemoglobin levels ( HbA1c ) in obese diabetic and non-diabetic caucasians? Although circulating adiponectin has been inversely correlated with obesity, type 2 diabetes and serum glycosylated hemoglobin (HbA1c) in humans, contradictory reports on that subject exist. In this study, serum concentrations of adiponectin in obese non-diabetic and diabetic humans were measured to examine whether they were associated with levels of HbA1c. The WHO definitions of obesity and diabetes were used. One hundred and five obese euglycemic subjects and 49 obese diabetics (aged 51+/-6.9, and 52+/-6.7 years, respectively) were studied. Their BMI, HbA1c and % of body fat were measured. Adiponectin was determined by an enzyme-linked immunosorbent assay. Although the serum adiponectin concentrations differed between diabetics and non-diabetics ( P<0.01), they were not correlated with HbA1c (r=-0.0814; P=0.5823, and r=-0.1861; P=0.1099, for diabetics and non-diabetics, respectively). Both diabetics and non-diabetics were segregated into tertiles according to their HbA1c levels. Plasma adiponectin did not differ significantly between the high (H), intermediate (I), and low (L) HbA1c tertiles.

Concentrations of adiponectin were not correlated with levels of glycosylated hemoglobin in the diabetic and non-diabetic subjects examined.

Does variability in CNR1 locus influence protein intake and smoking status in the Central-European population? The endocannabinoid receptor 1 (CB1) is encoded by the CNR1 gene and has been recently recognized to play an important role in the regulation of satiety and feeding behaviour with a huge potential of modulating metabolic response and feeding control. The aim of the study was to investigate the potential of three selected single nucleotide polymorphisms (SNPs) in the CNR1 locus on native dietary composition in the Central-European Caucasian population. A total of 258 unrelated individuals originating from the Central-European Caucasian population were enrolled into the study and rs1049353, rs12720071, and rs806368 polymorphisms in CNR1 locus were examined in these individuals using PCR-based methodology. Body composition was assessed using a bioimpedance method, various anthropometric parameters were investigated (waist and hip circumference, skin folds), and native dietary composition was analysed using 7-day food records as well as a food frequency questionnaire. Allelic variations and common haplotypes in the CNR1 gene were associated with the daily intake of proteins, fluids, and fibre, regardless of the physical activity of the individuals. The common haplotype in the CNR1 gene was associated with self-reported smoking (number of cigarettes per day, smoking years).

Our results indicate that specific genetic variations in the CNR1 gene may act as susceptibility markers for specific dietary composition in the Central-European population.

Do patients with irritable bowel syndrome have altered emotional modulation of neural responses to visceral stimuli? In patients with irritable bowel syndrome (IBS), pain amplification and hypervigilance might result from altered affective-motivational modulation of the pain response. We investigated the effects of emotional context on the behavioral and neural response to visceral stimuli in IBS patients. We used functional magnetic resonance imaging (fMRI) to assess the blood oxygen level-dependent response to nonpainful and painful rectal distensions in 15 female IBS patients and 12 healthy women. Distensions were delivered during psychologic stress or relaxation; data were compared with those in a neutral condition (control). Group and context-dependent differences in the processing of visceral stimulation were assessed at behavioral and the neuronal levels. Secondary analyses of group differences were performed using anxiety scores as a covariate because of higher anxiety symptoms among patients with IBS. During rectal stimulation, IBS patients demonstrated more pronounced stress-induced modulation of neural activation in multiple brain regions, including the insula, midcingulate cortex, and ventrolateral prefrontal cortex. In response to relaxation, IBS patients demonstrated reduced modulation of distension-induced activation in the insula. During relaxation, the difference observed between groups could be accounted for by higher anxiety symptoms in patients with IBS; differential effects of stress in the insula and prefrontal regions were not attributable to anxiety.

IBS patients appear to have disrupted emotional modulation of neural responses to visceral stimuli, possibly reflecting the neural basis for altered visceral interoception by stress and negative emotions.

Does siRNA Targeting of MDR1 reverse Multidrug Resistance in a Nude Mouse Model of Doxorubicin-resistant Human Hepatocellular Carcinoma? To investigate the effects of vector-based small interfering RNA (siRNA) targeting MDR1 on the reversal of multidrug resistance in a mouse model of doxorubicin (DOX)-resistant human hepatocellular carcinoma. Three siRNAs plasmid vectors (MDR1 siRNA1, MDR1 siRNA2 and MDR1 siRNA3) targeting MDR1 were constructed and transfected into DOX-resistant human hepatocellular carcinoma Bel-7402/ADM cells. The expression of MDR1 mRNA and P-glycoprotein (P-gp) was detected with RT-PCR and western blotting, respectively. A nude mouse model of DOX-resistance was established with untransfected Bel-7402/ADM or Bel-7402/ADM transfected with MDR1 siRNA (Bel-7402/ADMsi). The nude mice with tumors from untransfected Bel-7402/ADM cells were treated with either saline (Group 1); intravenous DOX (Group 2); or the combination of intra-tumoral MDR1 siRNA and intravenous DOX (Group 3). The nude mice with tumors from Bel-7402/ADMsi cells were treated with intravenous DOX (Group 4). DOX and MDR1 siRNA were administered twice a week at 20 mg/kg/dose and 9.8 mg/kg/dose, respectively. Tumor growth was measured to assess reversal of multidrug resistance by MDR1 siRNA. MDRl mRNA and P-gp expression of Bel-7402/ADM cells was reduced by transfection of three siRNAs with different silencing efficiency (p<0.05). DOX treatment (Group 4) resulted in significant reduction in tumor size in the Bel-7402/ADMsi tumor model (p<0.05), indicating reversal of multidrug resistance in tumor by MDR1 siRNA. However, the combination treatment of intratumoral MDR1 siRNA and DOX (Group 3) showed no significant anti-tumor efficacy in the untransfected Bel-7402/ADM (p>0.05) tumor model, suggesting poor in vivo transfection efficiency of MDR1 siRNA. Analysis of the tumor samples showed the reduced expression level of MDR1 mRNA and P-gp was due to efficacy of MDR1 siRNA.

In vitro transfection of siRNAs' vectors targeting the MDR1 gene can effectively silence MDR1 mRNA and P-gp expression in DOX-resistant human hepatocellular carcinoma Bel-7402/ADM cells that resulted in reversal of multidrug resistance to DOX in the xenograft tumor model.

Does microRNA-21 in pancreatic ductal adenocarcinoma tumor-associated fibroblasts promote metastasis? Pancreatic ductal adenocarcinoma (PDAC) is projected to rise to the second leading cause of U.S. cancer-related deaths by 2020. Novel therapeutic targets are desperately needed. MicroRNAs (miRs) are small noncoding RNAs that function by suppressing gene expression and are dysregulated in cancer. miR-21 is overexpressed in PDAC tumor cells (TC) and is associated with decreased survival, chemoresistance and invasion. Dysregulation of miR regulatory networks in PDAC tumor-associated fibroblasts (TAFs) have not been previously described. In this study, we show that miR-21 expression in TAFs promotes TC invasion. In-situ hybridization for miR-21 was performed on the 153 PDAC patient UCLA tissue microarray and 23 patient-matched lymph node metastases. Stromal and TC histoscores were correlated with clinicopathologic parameters by univariate and multivariate Cox regression. miR-21 positive cells were further characterized by immunofluorescence for mesenchymal/epithelial markers. For in vitro studies, TAFs were isolated from freshly resected human PDAC tumors by the outgrowth method. miR-21 was overexpressed/inhibited in fibroblasts and then co-cultured with GFP-MiaPaCa TCs to assess TC invasion in modified Boyden chambers. miR-21 was upregulated in TAFs of 78% of tumors, and high miR-21 significantly correlated with decreased overall survival (P = 0.04). Stromal miR-21 expression was also significantly associated with lymph node invasion (P = 0.004), suggesting that it is driving TC spread. Co-immunofluorescence revealed that miR-21 colocalized with peritumoral fibroblasts expressing α-smooth muscle actin. Moreover, expression of miR-21 in primary TAFs correlated with miR-21 in TAFs from patient-matched LN metastases; evidence that PDAC tumor cells induce TAFs to express miR-21. miR-21 expression in TAFs and TCs promotes invasion of TCs and is inhibited with anti-miR-21.

miR-21 expression in PDAC TAFs is associated with decreased overall survival and promotes TC invasion. Anti-miR-21 may represent a novel therapeutic strategy for dual targeting of both tumor and stroma in PDAC.

Is daily treatment with esomeprazole superior to that taken on-demand for maintenance of healed erosive oesophagitis? On-demand therapy with esomeprazole is effective for long-term treatment of non-erosive gastro-oesophageal reflux disease, but it has not been evaluated in erosive gastro-oesophageal reflux disease. To compare endoscopic and symptomatic remission over a 6-month period when patients with healed erosive gastro-oesophageal reflux disease are treated with esomeprazole 20 mg, either once daily or on-demand. Patients with verified erosive reflux oesophagitis of Los Angeles grades A-D were enrolled. Following 4-8 weeks treatment with esomeprazole 40 mg daily, those who were endoscopically healed and had symptom control during the last week were randomized to maintenance therapy for 6 months with esomeprazole 20 mg, taken either once daily or on-demand. Of 539 enrolled patients, 494 (91%) were healed at 8 weeks and 477 were randomized to maintenance therapy with esomeprazole 20 mg, 243 once daily and 234 on-demand. After once daily treatment, 81% of patients were still in remission at 6 months, compared with only 58% who took on-demand treatment (P < 0.0001). A difference in remission was found irrespective of baseline grade of oesophagitis, but it was more pronounced for the more severe grades. There was no difference in overall symptomatic remission between the two treatments, although heartburn was significantly more prevalent in the on-demand group.

Once daily esomeprazole 20 mg was better than that taken on-demand for maintaining healed erosive oesophagitis, regardless of baseline Los Angeles grade.

Do many LINE1 elements contribute to the transcriptome of human somatic cells? While LINE1 (L1) retroelements comprise nearly 20% of the human genome, the majority are thought to have been rendered transcriptionally inactive, due to either mutation or epigenetic suppression. How many L1 elements 'escape' these forms of repression and contribute to the transcriptome of human somatic cells? We have cloned out expressed sequence tags corresponding to the 5' and 3' flanks of L1 elements in order to characterize the population of elements that are being actively transcribed. We also examined expression of a select number of elements in different individuals. We isolated expressed sequence tags from human lymphoblastoid cell lines corresponding to 692 distinct L1 element sites, including 410 full-length elements. Four of the expression tagged sites corresponding to full-length elements from the human specific L1Hs subfamily were examined in European-American individuals and found to be differentially expressed in different family members.

A large number of different L1 element sites are expressed in human somatic tissues, and this expression varies among different individuals. Paradoxically, few elements were tagged at high frequency, indicating that the majority of expressed L1s are transcribed at low levels. Based on our preliminary expression studies of a limited number of elements in a single family, we predict a significant degree of inter-individual transcript-level polymorphism in this class of sequence.

Are pancreatic juice prostaglandin e2 concentrations elevated in chronic pancreatitis and improve detection of early disease? Chronic pancreatitis (CP) may be difficult to diagnose in early stages. We aimed to measure pancreatic juice (PJ) prostaglandin E2 (PGE2) concentrations to determine whether they are elevated in CP and improve diagnosis of early disease. We measured PJ PGE2 in 10 patients with established CP, 25 patients who met criteria for "minimal change" chronic pancreatitis (MCCP), and 10 normal control participants. Median PJ PGE2 was elevated in CP (307 pg/ml, IQR (249-362)) and MCCP (568 pg/ml, (418-854)) compared with normal controls (104 pg/ml, (68-206)) (P≤ 0.001). Area under receiving operator curve (AUROC) for diagnosis of CP and MCCP was 0.9 and 0.62, respectively, for PJ bicarbonate concentration alone; AUROC was 1.0 and 0.94 for the combination of PJ bicarbonate and PGE2 concentrations.

PJ PGE2 appears to be a biomarker for CP and is elevated in both established and "minimal change" chronic pancreatitis.