Is raised breath hydrogen related to the pathogenesis of pneumatosis coli?
Clinical and physiological studies were carried out in five patients with pneumatosis coli in order to investigate the origin of the high fasting breath hydrogen concentration in this condition and to determine its possible significance in the pathogenesis of the disease. All five patients excreted abnormally high fasting concentrations of hydrogen in their breath (69 +/- 9 ppm, mean +/- SEM). Moreover, analysis of the contents of the gas filled cysts revealed between 2% and 8% of hydrogen gas. Colonic washout significantly reduced breath hydrogen concentrations to 9 +/- 6 ppm, but did not abolish the cysts. Conversely, deflation of the cysts was achieved with oxygen or antibiotics, though this only reduced breath hydrogen concentrations to about 66% of their original value. After feeding a radiolabelled meal, breath hydrogen concentrations rose before the meal appeared to reach the colon, suggesting overgrowth of anaerobic bacteria in the small intestine. Despite this, 14C glycocholate breath tests were within normal limits. An alternative possibility is that the high levels of hydrogen excreted in the breath may be produced in the intestinal lumen possibly from the fermentation of copious amounts of colonic mucus. Finally, measurement of whole gut transit time and stool weight suggested that patients were constipated despite passing mucus and blood. The relevance of our observations to the pathogenesis of submucosal cysts is unclear, but the data favour the hypothesis that these are produced by invasion of the colonic submucosa with anaerobic bacteria.


Impact of the New American Hypertension Guidelines on the Prevalence of Postpartum Hypertension.
Cardiovascular disease (CVD) is the leading cause of death and disability among women, with more than half occurring in individuals with hypertension. New blood pressure criteria for the diagnosis of hypertension from the American College of Cardiology/American Heart Association recognize that there is no specific blood pressure threshold that is associated with vascular disease. We performed a secondary analysis of two published postpartum databases (the Pre-Eclampsia New Emerging Team [PE-NET] cohort and the Maternal Health Clinic [MHC] cohort) to determine the impact of the change in blood pressure criteria on the diagnosis of hypertension. The prevalence of hypertension in women with uncomplicated pregnancies (PE-NET control) was 22% compared with 56.4% in those who have had a pregnancy complicated by preeclampsia (PE, PE-NET patient) and 67.2% in those referred to the MHC due to a pregnancy complicated by any of the hypertensive disorders of pregnancy. It is well established that certain complications in pregnancy can reliably identify women with risk factors for future CVD. Thus, pregnancy and the postpartum afford a new opportunity for cardiovascular risk screening that could lead to lifestyle modification and therapeutic intervention. Applying the new guideline criteria at least doubles the prevalence of women with hypertension postpartum.


Poultry trading behaviours in Vietnamese live bird markets as risk factors for avian influenza infection in chickens.
Vietnamese poultry are host to co-circulating subtypes of avian influenza viruses, including H5N1 and H9N2, which pose a great risk to poultry productivity and to human health. AIVs circulate throughout the poultry trade network in Vietnam, with live bird markets being an integral component to this network. Traders at LBMs exhibit a variety of trading practices, which may influence the transmission of AIVs. We identified trading practices that impacted on AIV prevalence in chickens marketed in northern Vietnamese LBMs. We generated sequencing data for 31 H9N2 and two H5N6 viruses. Viruses isolated in the same LBM or from chickens sourced from the same province were genetically closer than viruses isolated in different LBMs or from chickens sourced in different provinces. The position of a vendor in the trading network impacted on their odds of having AIV-infected chickens. Being a retailer and purchasing chickens from middlemen was associated with increased odds of infection, whereas odds decreased if vendors purchased chickens directly from large farms. Odds of infection were also higher for vendors having a greater volume of ducks unsold per day. These results indicate how the spread of AIVs is influenced by the structure of the live poultry trading network.


Permeable guidance channels containing microfilament scaffolds enhance axon growth and maturation.
Successful peripheral nerve regeneration is still limited in artificial conduits, especially for long lesion gaps. In this study, porous poly(L-lactide-co-DL-lactide, 75:25) (PLA) conduits were manufactured with 16 poly(L-lactide) (PLLA) microfilaments aligned inside the lumen. Fourteen and 18 mm lesion gaps were created in a rat sciatic nerve lesion model. To evaluate the combined effect of permeable PLA conduits and microfilament bundles on axon growth, four types of implants were tested for each lesion gap: PLA conduits with 16 filaments; PLA conduits without filaments; silicone conduits with 16 filaments; and silicone conduits without filaments. Ten weeks following implantation, regeneration within the distal nerve was compared between corresponding groups. Antibodies against the markers S100, calcitonin gene related peptide (CGRP), RMDO95, and P0 were used to identify Schwann cells, unmyelinated axons, myelinated axons, and myelin, respectively. Results demonstrated that the filament scaffold enhanced tissue cable formation and Schwann cell migration in all groups. The filament scaffold enhanced axonal regeneration toward the distal stump, especially across long lesion gaps, but significance was only achieved with PLA conduits. When compared to corresponding silicone conduits, permeable PLA conduits enhanced myelinated axon regeneration across both lesion gaps and achieved significance only in combination with filament scaffolds. Myelin staining indicated PLA conduits supported axon myelination with better myelin quantity and quality when compared to silicone conduits.


Diagnostic accuracy of fine-needle aspiration of solid pancreatic lesions guided by endoscopic ultrasound elastography.
Real-time elastography (RTE) may increase the diagnostic accuracy of fine-needle aspiration guided by endoscopic ultrasound. The aim of this study was to establish the diagnostic accuracy, sensitivity, and specificity of this combined methodological approach in a cohort of patients with solid pancreatic masses. We reviewed data from 54 patients with solid pancreatic lesions referred to our institution between January 2014 and June 2015. RTE, assessed in terms of strain ratio, was performed both qualitatively and semi-quantitatively, and a 25G needle was inserted into the most suspicious part of the lesion. Sensitivity, specificity, diagnostic accuracy, positive and negative predictive values were calculated. The median lesion size was 35 mm (interquartile range: 25-43 mm). A diagnosis of adenocarcinoma was confirmed in 85.1% of cases. RTE, with a strain ratio cutoff of 4.21, showed a sensitivity of 86.9%, a specificity of 75%, and diagnostic accuracy of 85.1%. The diagnostic accuracy, sensitivity, and specificity of the combined methodology were 94.4%, 93.4%, and 100%, respectively. The positive predictive value was 100%, the negative predictive value 72.7% and the negative likelihood ratio 6.5. No severe adverse events were registered. The combination of RTE with endoscopic ultrasound-guided fine-needle aspiration appears to be an efficient and safe technique for the characterization of solid pancreatic masses.


Measurement error in the Hawksley random zero sphygmomanometer: what damage has been done and what can we learn?
The Hawksley random zero sphygmomanometer is used in all aspects of blood pressure research, from clinical trials to evaluation of new blood pressure recorders. It is designed to reduce observer bias in blood pressure measurement. The problem is that it also underestimates blood pressure. Furthermore, this was first reported more than two decades ago. In this paper Rónán Conroy and colleagues explore the consequences of using an inaccurate instrument for important research and why prestigious organisations like the World Health Organisation continue to use it.


Dispensing Practice of Prescribed Medicines in the Private Pharmacies in Urban Areas of Tanzania.
A descriptive cross-sectional study was conducted to assess quality of dispensing and knowledge of dispensers in 206 private retail pharmacies. The study was conducted in Dar es Salaam, Tanzania between September 2011 and April 2012. Patient simulation (mystery shopper) approach was used to assess dispensing skills of drug dispensers for prescription only medicines. In assessing dispensing skills, a 7-days course of metronidazole tablets was bought from each pharmacy. The knowledge of drug dispenser's regarding dispensing of prescription only medicines was assessed through focus group discussions and interviews. Majority (70.4%) of drug dispensers were not trained pharmaceutical personnel. The level of dispensing skills ranged from low (25.7%) to medium (70.4%). Majority of drug dispensers had low (11.4%) to medium (83.2%) levels of knowledge about dispensing of 'prescription only' medicines. From these findings, it is recommended that the national Pharmacy Council should ensure that prescription only medicines are dispensed by trained pharmaceutical personnel. On job training and continuing professional development should also be emphasized to build capacity of drug dispensers.


Reassessment of feline leukaemia virus (FeLV) vaccines with novel sensitive molecular assays.
We previously described antigen negative, provirus positive cats. Subsequently, we hypothesized that efficacious FeLV vaccines cannot prevent minimal viral replication. Thus, we vaccinated cats with either a canarypox-vectored live or a killed virus vaccine and analyzed the challenge outcome with quantitative PCR and a newly established real-time RT-PCR. When judged by conventional parameters (antigenaemia, virus isolation), most of the vaccinated cats were, as expected, protected from persistent viraemia. However, all cats were found to be plasma viral RNA positive. The loads were significantly associated with the infection outcome. Thus, commonly used FeLV vaccines understood to be successful model antiretroviral vaccines protecting against FeLV-related diseases do not confer sterilizing immunity.


Neuropsychiatric performance and treatment of hepatitis C with direct-acting antivirals: a prospective study.
Since direct-acting antivirals (DAAs) have been approved for the treatment of hepatitis C virus (HCV) infection, a small series of patients with new-onset neuropsychiatric alterations have been referred to us. We therefore set out to study neuropsychiatric function in relation to DAAs prospectively. Ten patients with cirrhosis and 12 post-liver transplant (post-LT) patients were enrolled. All underwent wake electroencephalography (EEG) and a neuropsychological evaluation (paper and pencil battery, simple/choice reaction times, working memory task) at baseline, at the end of treatment with DAAs and after 6 months. At the same time points, full blood count, liver/kidney function tests, quantitative HCV RNA, ammonia and immunosuppressant drug levels were obtained, as appropriate. Patients with cirrhosis were significantly older than post-LT patients (65±12 vs 55±7 years; P<0.05). Neuropsychological performance and wake EEG were comparable in the two groups at baseline. At the end of a course of treatment with DAAs, a significant slowing in choice reaction times and in the EEG (increased relative delta power) was observed in patients with cirrhosis, which resolved after 6 months. In contrast, no significant changes over time were observed in the neuropsychiatric performance of post-LT patients. No significant associations were observed between neuropsychiatric performance and stand-alone/combined laboratory variables. Some degree of neuropsychiatric impairment was observed in relation to treatment with DAAs in patients with cirrhosis, but not in post-LT patients, suggesting that the former may be sensitive to mild DAA neurotoxicity.


Organization of carbamoyl-phosphate synthase genes in Neisseria gonorrhoeae includes a large, variable intergenic sequence which is also present in other Neisseria species.
The carbamoyl-phosphate synthase (CPS) enzyme in prokaryotes is a heterodimer, encoded by genes commonly called carA and carB. In most prokaryotes examined, these genes are separated by up to 24 bp and are cotranscribed. In Pseudomonas aeruginosa, carA and carB are also co-transcribed, but are separated by 682 bp. We have determined the complete DNA sequence of the carA and carB genes of Neisseria gonorrhoeae strain CH811. carA (1125 bp) and carB (3237 bp) are similar in size and sequence to other prokaryotic CPS genes, however they are separated by an intervening sequence of 3290 bp which has no similarity to the intervening sequence between other CPS genes; furthermore, putative transcription terminators are found downstream of both carA and carB. Several neisserial repetitive sequences were identified within the 9 kb sequenced, as well as novel 120 and 150 bp repeats (designated RS6 and RS7, respectively) which were found within the intervening sequence between carA and carB. To determine whether the intervening sequence observed in N. gonorrhoeae CH811 was not unusual, the sequence between carA and carB was amplified by PCR from 30 isolates of N. gonorrhoeae. The intervening sequence was found to vary in size, from approximately 2.2 to 3.7 kb, although the carA and carB genes themselves did not vary in size in isolates with functional CPS enzyme. A similar large, variably sized intervening sequence was also found between the carA and carB genes of 12 isolates of N. meningitidis and 18 commensal Neisseria isolates comprising nine species. This unexpected organization of the CPS genes in N. gonorrhoeae is therefore widespread throughout the genus Neisseria.


Arterial pulse pressure and postoperative morbidity in high-risk surgical patients.
Systemic arterial pulse pressure (systolic minus diastolic pressure) ≤53 mm Hg in patients with cardiac failure is correlated with reduced stroke volume and is independently associated with accelerated morbidity and mortality. Given that deconditioned surgical and heart failure patients share similar cardiopulmonary physiology, we examined whether lower pulse pressure is associated with excess morbidity after major surgery. This was a prospective observational cohort study of patients deemed by their preoperative assessors to be at higher risk of postoperative morbidity. Preoperative pulse pressure was calculated before cardiopulmonary exercise testing. The primary outcome was any morbidity (PostOperative Morbidity Survey) occurring within 5 days of surgery, stratified by pulse pressure threshold ≤53 mm Hg. The relationship between pulse pressure, postoperative morbidity, and oxygen pulse (a robust surrogate for left ventricular stroke volume) was examined using logistic regression analysis (accounting for age, sex, BMI, cardiometabolic co-morbidity, and operation type). The primary outcome occurred in 578/660 (87.6%) patients, but postoperative morbidity was more common in 243/ 660 patients with preoperative pulse pressure ≤53 mm Hg{odds ratio (OR): 2.24 [95% confidence interval (CI): 1.29-3.38]; P<0.001). Pulse pressure ≤53 mm Hg [OR:1.23 (95% CI: 1.03-1.46); P=0.02] and type of surgery were independently associated with all-cause postoperative morbidity (multivariate analysis). Oxygen pulse <90% of population-predicted normal values was associated with pulse pressure ≤ 53 mm Hg [OR: 1.93 (95% CI: 1.32-2.84); P=0.007]. In deconditioned surgical patients, lower preoperative systemic arterial pulse pressure is associated with excess morbidity. These data are strikingly similar to meta-analyses identifying low pulse pressure as an independent risk factor for adverse outcomes in cardiac failure. Low preoperative pulse pressure is a readily available measure, indicating that detailed physiological assessment may be warranted. ISRCT registry, ISRCTN88456378.


[Effectiveness of anti-stigma interventions regarding severe mental illness: a systematic literature review].
Stigma is one of the greatest challenges facing people with severe mental illness (smi) and can have profound psychological, social and professional consequences.
 AIM: To systematically review the evidence of effectiveness of anti-stigma interventions (anti-stigma campaigns and specific interventions to reduce public stigma and self-stigma) for people with smi and to make recommendations for clinical practice.
 METHOD: A systematic literature search for individual studies and reviews concerning the efficacy of interventions that reduce stigma for people with smi.
 RESULTS: Anti-stigma interventions have small-to-medium effects. Although head-to-head comparisons do not show a clear advantage for educational or contact interventions, results suggest that the elements of contact, recovery and continuity (for public stigma) and psycho-education (for self-stigma) may yield the greatest effects. Due to the short follow-up period of most studies, there is limited evidence on the long-term effectiveness of these interventions. More specifically, it remains unknown whether these interventions lead to changes in actual behavior.
 CONCLUSION: Anti-stigma interventions have limited effects on knowledge, attitudes and behavior. Several methodological shortcomings, as well as short follow-up periods in most studies, preclude making firm conclusions.


Increased mortality after dronedarone therapy for severe heart failure.
Dronedarone is a novel antiarrhythmic drug with electrophysiological properties that are similar to those of amiodarone, but it does not contain iodine and thus does not cause iodine-related adverse reactions. Therefore, it may be of value in the treatment of patients with heart failure. In a multicenter study with a double-blind design, we planned to randomly assign 1000 patients who were hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction to receive 400 mg of dronedarone twice a day or placebo. The primary end point was the composite of death from any cause or hospitalization for heart failure. After inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group), the trial was prematurely terminated for safety reasons, at the recommendation of the data and safety monitoring board, in accordance with the board's predefined rules for termination of the study. During a median follow-up of 2 months, 25 patients in the dronedarone group (8.1%) and 12 patients in the placebo group (3.8%) died (hazard ratio in the dronedarone group, 2.13; 95% confidence interval [CI], 1.07 to 4.25; P=0.03). The excess mortality was predominantly related to worsening of heart failure--10 deaths in the dronedarone group and 2 in the placebo group. The primary end point did not differ significantly between the two groups; there were 53 events in the dronedarone group (17.1%) and 40 events in the placebo group (12.6%) (hazard ratio, 1.38; 95% CI, 0.92 to 2.09; P=0.12). More increases in the creatinine concentration were reported as serious adverse events in the dronedarone group than in the placebo group. In patients with severe heart failure and left ventricular systolic dysfunction, treatment with dronedarone was associated with increased early mortality related to the worsening of heart failure. (ClinicalTrials.gov number, NCT00543699.)


A stable rhodium single-site catalyst encapsulated within dendritic mesoporous nanochannels.
Catalysis plays an essential role in the modern chemical industry. However, it still remains a great challenge to improve the efficiency of many heterogeneous catalysts based on a per metal atom basis. Single-site catalysts (SsCs) with isolated metal atoms/ions anchored to the supports are thus highly desirable, providing an innovative solution towards highly efficient usage of precious metal atoms in heterogeneous catalysts. Creating SsCs with high metal loading proves to be challenging because, without robust anchoring, atoms tend to diffuse to form large aggregates during catalytic reactions. We report a facile ligand exchange method to anchor a single-site Rh catalyst inside the individual channels of three-dimensional dendritic mesoporous silica nanospheres (MSNSs). The short porous channels inside MSNSs provide an easy access of reactants and the strong binding of the ligand prevents the aggregation of catalyst sites. The as-synthesized Rh1@MSNS-NH2 catalyst shows excellent activity, stability and reusability in the reduction of 4-nitrophenol. The same catalyst shows high regioselectivity in the hydrosilylation of terminal alkynes to yield α-vinylsilanes through the Markovnikov addition.


Publication Pressure versus Ethics, in Research and Publication.
Research is undertaken to increase scientific knowledge. Knowledge enters the domain of science after it is presented to others. Publishing research, contributes to medical community's knowledge. Research publications earn mileage to the researcher in carrier. Presently, a lot of pressure has built up on medical fraternity to publish in terms of quantity, thereby compromising the quality of papers as official bodies governing the medical professionals have linked the quantity of publications with career growth. These rules are to promote research but they create stress among medical teachers, lowering the quality of research and publications. Hence, It is the responsibility of authors to strictly follow guidelines while doing and publishing research. To promote academic research and deter plagiarism, educational institutions are to establish Academic Misconduct Panel to investigate the allegations, and report to Plagiarism Disciplinary authority which can impose penalties as conduct and publishing of research is a serious issue.


The long-term outcome of Maudsley depressives.
Eighty-nine consecutive admissions with primary depressive illness were prospectively ascertained and diagnosed in 1965-66 by R. E. Kendell, who also allocated each a position on a neurotic-psychotic continuum on the basis of previous discriminant function analysis. In 1983-84, 94% of the survivors were personally interviewed by a psychiatrist blind to index admission data. Operational outcome criteria were employed and longitudinal data were established for 98% of the series. Mortality risk was doubled overall, and increased sevenfold for women under 40 years at index admission. Less than one-fifth of the survivors had remained well, and over one-third of the series suffered unnatural death or severe chronic distress and handicap. Patients whose index episode marked their first psychiatric contact had a 50% chance of readmission within their lifetime, but those with previous admissions had a 50% chance of readmission within three years. Readmissions occurred even after 12 years of being symptom-free, and conversely patients recovered after as long as 15 years of illness. There was a high incidence of other disorders (schizoaffective disorder, alcoholism, schizophrenia), and only four patients showed pure recurrent unipolar histories. Patients at the psychotic end of the continuum were more likely to be readmitted and to have very poor outcomes.


Differential control of adrenal and renal sympathetic nerve activity during hemorrhagic hypotension in rats.
The reflex mechanisms that produce the neurocirculatory adjustments to hemorrhagic hypotension are incompletely understood. The goal of this study was to determine if hemorrhagic hypotension in rats produces differential effects on sympathetic outflow to the adrenal gland and kidney and if the two sympathetic nerve responses are governed by different reflex mechanisms. We performed simultaneous multifiber recordings of adrenal and renal sympathetic nerve activity (SNA) during 8 minutes of sustained hemorrhagic hypotension to a mean arterial pressure of 50 mm Hg in chloralose-anesthetized Sprague-Dawley rats with a) baroreceptors intact, b) cervical vagotomy, c) sinoaortic baroreceptor denervation, and d) combined vagotomy plus sinoaortic denervation. During hemorrhagic hypotension in rats with intact baroreceptors, renal SNA decreased by 31 +/- 10% (mean +/- SEM, p less than 0.05 vs. control) and heart rate decreased from 384 +/- 13 to 365 +/- 16 beats per minute (p less than 0.05), but adrenal SNA increased by 69 +/- 10% over control (p less than 0.05). The decreases in renal SNA and heart rate were reversed by cervical vagotomy but not by atropine, which indicates vagal afferent mediation. In contrast, the increases in adrenal SNA during hemorrhage were not affected by vagotomy alone or by sinoaortic denervation alone but were markedly attenuated by combined sinoaortic denervation and vagotomy, which indicates redundancy in the baroreflex control of adrenal SNA.(ABSTRACT TRUNCATED AT 250 WORDS)


Dynamic Fgf signaling couples morphogenesis and migration in the zebrafish lateral line primordium.
The collective migration of cells in the form of cohesive tissues is a hallmark of both morphogenesis and repair. The extrinsic cues that direct these complex migrations usually act by regulating the dynamics of a specific subset of cells, those at the leading edge. Given that normally the function of tissue migration is to lay down multicellular structures, such as branched epithelial networks or sensory organs, it is surprising how little is known about the mechanisms that organize cells behind the leading edge. Cells of the zebrafish lateral line primordium switch from mesenchyme-like leader cells to epithelial rosettes that develop into mechanosensory organs. Here, we show that this transition is regulated by an Fgf signaling circuit that is active within the migrating primordium. Point sources of Fgf ligand drive surrounding cells towards a ;non-leader' fate by increasing their epithelial character, a prerequisite for rosette formation. We demonstrate that the dynamic expression of Fgf ligands determines the spatiotemporal pattern of epithelialization underlying sensory organ formation in the lateral line. Furthermore, this work uncovers a surprising link between internal tissue organization and collective migration.


Publication bias in clinical trials due to statistical significance or direction of trial results.
The tendency for authors to submit, and of journals to accept, manuscripts for publication based on the direction or strength of the study findings has been termed publication bias. To assess the extent to which publication of a cohort of clinical trials is influenced by the statistical significance, perceived importance, or direction of their results. We searched the Cochrane Methodology Register (The Cochrane Library [Online] Issue 2, 2007), MEDLINE (1950 to March Week 2 2007), EMBASE (1980 to Week 11 2007) and Ovid MEDLINE In-Process & Other Non-Indexed Citations (March 21 2007). We also searched the Science Citation Index (April 2007), checked reference lists of relevant articles and contacted researchers to identify additional studies. Studies containing analyses of the association between publication and the statistical significance or direction of the results (trial findings), for a cohort of registered clinical trials. Two authors independently extracted data. We classified findings as either positive (defined as results classified by the investigators as statistically significant (P < 0.05), or perceived as striking or important, or showing a positive direction of effect) or negative (findings that were not statistically significant (P >/= 0.05), or perceived as unimportant, or showing a negative or null direction in effect). We extracted information on other potential risk factors for failure to publish, when these data were available. Five studies were included. Trials with positive findings were more likely to be published than trials with negative or null findings (odds ratio 3.90; 95% confidence interval 2.68 to 5.68). This corresponds to a risk ratio of 1.78 (95% CI 1.58 to 1.95), assuming that 41% of negative trials are published (the median among the included studies, range = 11% to 85%). In absolute terms, this means that if 41% of negative trials are published, we would expect that 73% of positive trials would be published.Two studies assessed time to publication and showed that trials with positive findings tended to be published after four to five years compared to those with negative findings, which were published after six to eight years. Three studies found no statistically significant association between sample size and publication. One study found no significant association between either funding mechanism, investigator rank, or sex and publication. Trials with positive findings are published more often, and more quickly, than trials with negative findings.


Non-equidistant scanning approach for millimetre-sized SPM measurements.
Long-range scanning probe microscope (SPM) measurements are usually extremely time consuming as many data need to be collected, and the microscope probe speed is limited. In this article, we present an adaptive measurement method for a large-area SPM. In contrast to the typically used line by line scanning with constant pixel spacing, we use an algorithm based on several levels of local refinement in order to minimize the amount of information that would be useless in the data processing phase. The data obtained from the measurement are in general formed by xyz data sets that are triangulated back with a desired local resolution. This enables storing more relevant information from a single measurement as the data are interpolated and regularized in the data processing phase instead of during the measurement. In this article, we also discuss the influence of thermal drifts on the measured data and compare the presented algorithm to the standard matrix-based measuring approach.


The effect of metformin on glucose homeostasis during moderate exercise.
We investigated the role of metformin on glucose kinetics during moderate exercise. Before, during, and after a 45-min bout of exercise at 60% VO2max, glucose kinetics were determined by isotope tracer technique in patients with type 2 diabetes mellitus with metformin treatment (DM2+Met) or without metformin treatment (DM2) and in healthy control subjects (CON) matched for BMI and age. Glucoregulatory hormones and metabolites were measured throughout the study. Plasma glucose concentration was unchanged during exercise in CON but decreased in DM2. No significant change was found in DM2+Met. Hormones and metabolites showed no differences among the groups except for elevated exercise-induced concentrations of lactate in DM2 (area under the curve [AUC] 31 ± 1% vs. CON) and glucagon in DM2 (AUC 5 ± 1% vs. DM2+Met). Free fatty acid levels were lower in DM2+Met than in DM2 (AUC -14 ± 1%). Absolute values of the baseline glucose rate of appearance (Ra) were elevated in DM2 and DM2+Met, but the increase in glucose Ra relative to baseline was blunted in DM2 (19 ± 1%) and DM2+Met (18 ± 4%) compared with CON (46 ± 4%). Glucose rate of disappearance relative to baseline increased more in CON (31 ± 3%) than in DM2 (6 ± 1%) and DM2+Met (21 ± 2%), showing a small increase caused by metformin. Glucose metabolic clearance rate relative to baseline was similar during exercise in DM2 (33 ± 1%) and CON (35 ± 3%) but was improved in DM2+Met (37 ± 3%) compared with DM2. Metformin has a positive effect on glucose homeostasis during exercise.


Evaluation of Smear Layer Removal Using Different Irrigation Methods In Root Canals.
This study evaluated different irrigation methods in smear layer removal from the root canal walls using maleic acid (MA). Maxillary anterior teeth (N=30, n=10 per group) were decoronated, canals were enlarged with Protaper (size F4) and allocated to three groups: EndoUltra: 2.5 ml of 7% MA was irrigated for 30 s, followed by EndoUltra activation for 30 s; EndoSafe: EndoSafe irrigation system was used for 1 minute using 5 ml of 7% MA; Side-vented needle: 30 gauge needle irrigation was performed for 1 min using 5 ml of 7% MA. After SEM analysis, the inter-examiner reliability was verified using Kendall's Co-efficient and data were analyzed using Pearson Chi-Square test. No statistical significant differences were found between the two examiners (p⟩0.05). In intra-group comparison, needle and EndoSafe irrigation demonstrated significantly better smear layer removal at middle third of the root canal system (p⟨0.05) when compared to apical third. In inter-group comparison, smear layer was minimally removed with needle irrigation. In the apical third, EndoUltra group removed smear layer more effectively. Endosafe needle irrigation in combination with 7% MA removed the smear layer in the root canal at best, while the EndoUltra performed the best at the apical third of the root.


A systematic review of surgical biopsy for LCIS found at core needle biopsy - do we have the answer yet?
The natural history of lobular carcinoma in-situ (LCIS) suggests that women are at increased risk of subsequent invasive breast cancer. Questions of effective management for women with this lesion have led to the need for evidence-based guidance and, in particular, guidance regarding management after LCIS is found at core needle biopsy (CNB). A systematic review was conducted to determine the most appropriate management for women with LCIS found at CNB. A comprehensive search of the scientific literature was conducted to identify the literature pertaining to this population. Critical appraisal of the literature, data extraction and a narrative synthesis of the results were conducted. The outcome of interest was upgrade of diagnosis to invasive breast cancer or ductal carcinoma in-situ (DCIS). Sparse data, with limited generalisability and considerable uncertainty, are available for women with LCIS at CNB. Nine studies were identified that met pre-specified inclusion criteria. The reported estimates of upgrade of diagnosis from LCIS to invasive breast cancer or DCIS ranged from 2% to 25%. The body of evidence was limited by its retrospective nature, risk of selection bias and poor generalisability to all women with LCIS at CNB. Further, higher quality research is required to determine the best approach for women with LCIS at CNB with any certainty.


Worldwide never-smoking youth susceptibility to smoking.
To estimate susceptibility to smoking among never-smoking youth globally and identify factors associated with such behavior. Cross-sectional data for 168 countries were obtained from the Global Youth Tobacco Survey. Simple and multiple logistic regression analyses were conducted. Frequencies and proportions for descriptive statistics, and adjusted odds ratios with 95% confidence intervals for logistic regression models were reported. Approximately 12.5% of never-smoking youth worldwide were susceptible to smoking worldwide, of which 7.2% were males and 5.3% were females. Compared with youth in the Americas, those in other WHO regions were associated with decreased susceptibility to smoking. Regardless of gender, exposure to parental or peer smoking, secondhand smoke inside or outside home, and tobacco industry promotion was associated with increased smoking susceptibility. In contrast, support for smoke-free policies and school antismoking education was associated with decreased susceptibility to smoking among females. Moreover, exposure to antismoking media messages was associated with increased susceptibility to smoking among never-smoking youth. Approximately 1 in 8 never-smoking youth worldwide was found to be susceptible to smoking. A comprehensive approach involving parental and peer education, smoke-free policies, ban on tobacco advertising and promotions, and antismoking education in schools should be developed by policy makers and public health professionals to protect never-smoking youth from being susceptible to smoking and transforming into future regular smokers.


Exploratory Research on Key Technology of Human-Computer Interactive 2.5-Minute Fast Digital Early Warning for Mild Cognitive Impairment.
As the preclinical stage of Alzheimer's disease (AD), Mild Cognitive Impairment (MCI) is characterized by hidden onset, which is difficult to detect early. Traditional neuropsychological scales are main tools used for assessing MCI. However, due to its strong subjectivity and the influence of many factors such as subjects' educational background, language and hearing ability, and time cost, its accuracy as the standard of early screening is low. Therefore, the purpose of this paper is to propose a new key technology of fast digital early warning for MCI based on eye movement objective data analysis. Methodology. Firstly, four exploratory indexes (test durations, correlation degree, lengths of gaze trajectory, and drift rate) of MCI early warning are determined based on the relevant literature research and semistructured expert interview; secondly, the eye movement state is captured based on the eye tracker to realize the data extraction of four exploratory indexes. On this basis, the human-computer interactive 2.5-minute fast digital early warning paradigm for MCI is designed; thirdly, the rationality of the four early warning indexes proposed in this paper and their early warning effectiveness on MCI are verified. Through the small sample test of human-computer interactive 2.5 fast digital early warning paradigm for MCI conducted by 32 elderly people aged 70-90 in a medical institution in Hangzhou, the two indexes of "correlation degree" and "drift rate" with statistical differences are selected. The experiment results show that AUC of this MCI early warning paradigm is 0.824. The key technology of human-computer interactive 2.5 fast digital early warning for MCI proposed in this paper overcomes the limitations of the existing MCI early warning tools, such as low objectification level, high dependence on professional doctors, long test time, requiring high educational level, and so on. The experiment results show that the early warning technology, as a new generation of objective and effective digital early warning tool, can realize 2.5-minute fast and high-precision preliminary screening and early warning for MCI in the elderly.


T lymphocytes and iron overload: novel correlations of possible significance to the biology of the immunological system.
This paper is written in the context of our changing perception of the immunological system as a system with possible biological roles exceeding the prevailing view of a system concerned principally with the defense against external pathogens. The view discussed here relates the immunological system inextricably to the metabolism of iron, the circulation of the blood and the resolution of the evolutionary paradox created by oxygen and iron. Indirect evidence for this inextricable relationship between the two systems can be derived from the discrepancy between the theoretical quasi-impossibility of the existence of an iron deficiency state in the adult and the reality of the WHO numbers of people in the world with iron deficiency anemia. With the mounting evidence that TNF, IL-1, and T lymphocyte cytokines affect hemopoiesis and iron metabolism it is possible that the reported discrepancy is a reflection of that inextricable interdependence between the two systems in the face of infection. Further direct evidence for a relationship between T cell subset numbers and iron metabolism is presented from the results of a study of T cell populations in patients with hereditary hemochromatosis. The recent finding of a correlation between low CD8+ lymphocyte numbers, liver damage associated with HCV positivity and severity of iron overload in beta-thalassemia major patients (unpublished data of RW Grady, P. Giardina, M. Hilgartner) concludes this review.


The value of a family physician.
Most efforts to improve health care have been made without a full understanding of the value of a primary care approach. This article synthesizes the observations from the Direct Observation of Primary Care (DOPC) study. This multimethod study of 138 family physicians in 84 practices included direct observation of 4454 patients visits were used to describe aspects of family practice that may provide value for patients. Family physicians provide and coordinate care for a wide variety of patients problems, prioritizing these competing demands on the basis of relationships developed during multiple patient visits over time. They use acute and chronic illness visits as opportunities to integrate care for specific diseases, mental health, and preventive care in ways that are tailored to the specific needs of patients and families. Higher rates of delivery of core attributes of family practice are associated with patient satisfaction and preventive services delivery, and are diminished by forced discontinuity of care. Family physicians prioritize and deliver care according to a broad agenda based on patient needs. These needs are understood within ongoing relationships with the patient, family, larger health care system, and community. This integrative approach includes numerous avenues for affecting important patient outcomes that are unlikely to be optimally met by less integrated models of medical care. Expanding the value of family practice will require the development and application of new knowledge of the core structures, processes, and contexts of family practice, and their effects on patient outcomes.


Dopamine-assisted fixation of drug-loaded polymeric multilayers to osteoarticular implants for tuberculosis therapy.
Currently, the major issues in the treatment of osteoarticular tuberculosis (TB) after implant placement are low drug concentration at the infected focus and drug resistance resulting from the long-term chemotherapy. The application of drug-loaded polymeric multilayers on implantable devices offers a promising solution to the problems. Herein, a poly(ethylene glycol)-based hydrogel film embedded with isoniazid (INH)-loaded alginate microparticles was fixed to Ti implants via adhesive polydopamine, subsequently capped by poly(lactic-co-glycolic acid) membranes for the sustained and localized delivery of the anti-TB drug. The antibacterial efficacy of the released INH was confirmed by a 4.5 ± 0.8 cm inhibition zone formed in the fourth week after inoculation of Mycobacterium tuberculosis. The INH-loaded Ti implants showed no toxicity to the osteoblast cell and provided a consistent drug release for nearly one week in vitro. The release profile in vivo showed a high local concentration and low systemic exposure. The local INH concentration could be kept higher than its minimum inhibitory concentration over a period of 8 weeks, which proves that it is a promising strategy to improve the severe osteoarticular TB treatment.


Accelerated vaccine development against emerging infectious diseases.
Emerging and re-emerging infectious diseases represent a major challenge to vaccine development since it involves two seemingly contradictory requirements. Rapid and flexible vaccine generation while using technologies and processes that can facilitate accelerated regulatory review. Development in the "-omics" in combination with advances in vaccinology offer novel opportunities to meet these requirements. Here we describe how a consortium of five different organizations from academia and industry is addressing these challenges. This novel approach has the potential to become the new standard in vaccine development allowing timely deployment to avert potential pandemics.


Key rules of life and the fading cryosphere: Impacts in alpine lakes and streams.
Alpine regions are changing rapidly due to loss of snow and ice in response to ongoing climate change. While studies have documented ecological responses in alpine lakes and streams to these changes, our ability to predict such outcomes is limited. We propose that the application of fundamental rules of life can help develop necessary predictive frameworks. We focus on four key rules of life and their interactions: the temperature dependence of biotic processes from enzymes to evolution; the wavelength dependence of the effects of solar radiation on biological and ecological processes; the ramifications of the non-arbitrary elemental stoichiometry of life; and maximization of limiting resource use efficiency across scales. As the cryosphere melts and thaws, alpine lakes and streams will experience major changes in temperature regimes, absolute and relative inputs of solar radiation in ultraviolet and photosynthetically active radiation, and relative supplies of resources (e.g., carbon, nitrogen, and phosphorus), leading to nonlinear and interactive effects on particular biota, as well as on community and ecosystem properties. We propose that applying these key rules of life to cryosphere-influenced ecosystems will reduce uncertainties about the impacts of global change and help develop an integrated global view of rapidly changing alpine environments. However, doing so will require intensive interdisciplinary collaboration and international cooperation. More broadly, the alpine cryosphere is an example of a system where improving our understanding of mechanistic underpinnings of living systems might transform our ability to predict and mitigate the impacts of ongoing global change across the daunting scope of diversity in Earth's biota and environments.


An HDAC6-dependent surveillance mechanism suppresses tau-mediated neurodegeneration and cognitive decline.
Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.


A systematic review of clinical diagnostic systems used in the diagnosis of tuberculosis in children.
Background. Tuberculosis (TB) is difficult to diagnose in children due to lack of a gold standard, especially in resource-limited settings. Scoring systems and diagnostic criteria are often used to assist in diagnosis; however their validity, especially in areas with high HIV prevalence, remains unclear. Methods. We searched online bibliographic databases, including MEDLINE and EMBASE. We selected all studies involving scoring systems or diagnostic criteria used to aid in the diagnosis of tuberculosis in children and extracted data from these studies. Results. The search yielded 2261 titles, of which 40 met selection criteria. Eighteen studies used point-based scoring systems. Eighteen studies used diagnostic criteria. Validation of these scoring systems yielded varying sensitivities as gold standards used ranged widely. Four studies evaluated and compared multiple scoring criteria. Ten studies selected for pulmonary tuberculosis. Five studies specifically evaluated the use of scoring systems in HIV-positive children, generally finding the specificity to be lower. Conclusions. Though scoring systems and diagnostic criteria remain widely used in the diagnosis of tuberculosis in children, validation has been difficult due to lack of an established and accessible gold standard. Estimates of sensitivity and specificity vary widely, especially in populations with high HIV co-infection.


Quantifying tissue mechanical properties using photoplethysmography.
Photoplethysmography (PPG) is a non-invasive optical method that can be used to detect blood volume changes in the microvascular bed of tissue. The PPG signal comprises two components; a pulsatile waveform (AC) attributed to changes in the interrogated blood volume with each heartbeat, and a slowly varying baseline (DC) combining low frequency fluctuations mainly due to respiration and sympathetic nervous system activity. In this report, we investigate the AC pulsatile waveform of the PPG pulse for ultimate use in extracting information regarding the biomechanical properties of tissue and vasculature. By analyzing the rise time of the pulse in the diastole period, we show that PPG is capable of measuring changes in the Young's Modulus of tissue mimicking phantoms with a resolution of 4 KPa in the range of 12 to 61 KPa. In addition, the shape of the pulse can potentially be used to diagnose vascular complications by differentiating upstream from downstream complications. A Windkessel model was used to model changes in the biomechanical properties of the circulation and to test the proposed concept. The modeling data confirmed the response seen in vitro and showed the same trends in the PPG rise and fall times with changes in compliance and vascular resistance.


The effect of acute tryptophan depletion on the neural correlates of emotional processing in healthy volunteers.
The processing of affective material is known to be modulated by serotonin (5-HT), but few studies have used neurophysiological measures to characterize the effect of changes in 5-HT on neural responses to emotional stimuli. We used functional magnetic resonance imaging to investigate the effect of acute tryptophan depletion, which reduces central 5-HT synthesis, on neural responses to emotionally valenced verbal stimuli. Though no participants experienced significant mood change, emotional information processing was substantially modified following 5-HT depletion. A behavioral bias toward positive stimuli was attenuated following depletion, which was accompanied by increased hemodynamic responses during the processing of emotional words in several subcortical structures. Inter-individual differences in tryptophan depletion-elicited anxiety correlated positively with the caudate bias toward negative stimuli. These data suggest that 5-HT may play an important role in mediating automatic negative attentional biases in major depression, as well as resilience against negative distracting stimuli in never-depressed individuals.


Assessment of a bronchoscopy simulator.
The study objective was to validate a flexible bronchoscopy simulator by determining if it could differentiate between expert and novice bronchoscopists. A subsequent evaluation phase was then done to determine whether use of the simulator would improve the rate of bronchoscopy skill acquisition for new pulmonary fellows. A multicenter prospective cohort study was performed using a bronchoscopy simulator. Three cohorts were evaluated based on the number of bronchoscopies previously performed: "experts" (> 500, n = 9), "intermediates" (25 to 500, n = 8), and "novices" (none, n = 11). Each participant performed two simulated cases with performance measures being recorded by the simulator. Performance measures that distinguished between groups were then used to evaluate the learning curve for new fellows training on the simulator. A randomized-controlled trial was then conducted comparing the quality of bronchoscopy performance for new pulmonary fellows who were trained either with conventional methods or with the simulator. Expert bronchoscopists performed better on the simulator than intermediates who performed better than novices in terms of procedure time, percentage of segments visualized, time in red-out, and wall collisions. Training of new fellows demonstrated that after performing 20 bronchoscopic simulations, the skill level acquired with the simulator significantly improved in terms of speed, percentage of segments visualized, time in red-out, and collisions. Fellows trained on the simulator performed better than fellows trained using conventional methods during their first actual bronchoscopies as assessed by procedure time (815 versus 1,168 s, p = 0.001), a bronchoscopy nurse's subjective quality assessment score (7.7 +/- 0.3 versus 3.7 +/- 2.5, p = 0.05), and by a quantitative bronchoscopy quality score (percentage of segments correctly identified/procedure time, 0.119 +/- 0.015 versus 0.046 +/- 034, p = 0.03). In conclusion, the bronchoscopy simulator was able to accurately assess bronchoscopy experience level. Training new fellows on the bronchoscopy simulator leads to more rapid acquisition of bronchoscopy expertise compared with conventional training methods. This technology has the potential to facilitate bronchoscopy training and to improve objective evaluations of bronchoscopy skills.


Citric acid metabolism in the bovine rumen.
Rumen microorganisms rapidly metabolize citric acid to carbon dioxide and acetic acid. The rate of metabolism varied between 0.00008 and 0.76 mumoles per g per min, the rate becoming higher as the citric acid concentration increased. The addition of potassium chloride to rumen contents decreased the rate of utilization. The results indicate that dietary citric acid is unlikely to accumulate in the rumen to a sufficiently high level to be an important factor in hypomagnesemia, except where other factors such as very high potassium levels in the food influence its metabolism.


Glucose modulation of insulin mRNA levels is dependent on transcription factor PDX-1 and occurs independently of changes in intracellular Ca2+.
Glucose regulates insulin production in pancreatic beta-cells in the long term by stimulating insulin gene transcription. These effects are partially mediated through the activity of a homeodomain transcription factor, PDX-1, which binds to four sites within the human insulin gene promoter. The availability of a human beta-like cell line, NES2Y, which lacks PDX-1 but expresses the insulin gene, allowed us to determine whether PDX-1 was essential for the stimulatory effect of glucose on insulin mRNA levels. In NES2Y cells, glucose had no effect on the insulin gene promoter linked to a firefly luciferase reporter or on endogenous insulin mRNA levels. However, in NES2Y cells stably transfected with PDX-1 (NES-PDX-1), glucose exhibited a marked stimulatory effect on both the insulin promoter (5+/-0.2-fold, n = 6) and insulin mRNA levels (4.8+/-0.5-fold, n = 4). NES2Y cells were derived from a patient with persistent hyperinsulinemic hypoglycemia of infancy; the cells therefore lacked operational ATP-sensitive potassium channels, which results in the failure to control depolarization-dependent intracellular Ca2+ signaling. Despite the loss of control of Ca2+ channel activity, NES-PDX-1 cells maintained normal glucose-responsive insulin gene regulation. These results demonstrate that glucose modulation of insulin mRNA levels is dependent on the activity of PDX-1 and that these effects are independent of changes in intracellular Ca2+ concentrations.


Orthosis reduces breast pain and mechanical forces through natural and augmented breast tissue in women lying prone.
Breast implant displacement or rupture can cause aesthetic problems and serious medical complications. Activities with prone positioning and loading of the anterior chest wall, such as massage, chiropractic or osteopathic therapies may increase the risk of implant failure and can also cause discomfort in women with natural breast tissue. Here we test the effectiveness of a newly developed orthosis on pain, mechanical pressure and displacement of breast tissue in women with cosmetic augmentation, post-mastectomy reconstruction, lactating or natural breast tissue. Thirty-two females volunteers, aged 25-56 years with augmented, reconstructed, natural or lactating breast tissue and cup sizes B-F, participated in this open-label clinical trial. We measured pain perception, peak pressure, maximum force, and breast tissue displacement using different sizes of the orthosis compared to no orthosis. Different densities of the orthosis were also tested in a subgroup of women (n = 7). Pain perception was rated using a validated 11-point visual-analogue scale. Peak pressure and maximum force were assessed using a bilateral set of capacitance-pliance® sensor strips whilst participants were load bearing in a prone position, and breast displacement was measured by magnetic-resonance-imaging. The orthosis significantly reduced pain, breast displacement and mechanical pressures in women with natural and augmented breast tissue in prone position. Greater relief of pain and greater reduction in mechanical forces were found with increased size and density of the orthosis. Use of the orthosis improved overall comfort by 64-100%, lowered peak pressure by up to 85% and maximum force by up to 96%. Medio-lateral displacement of breast tissue was reduced by 16%, resulting in a 51% desirable increase of breast tissue height. Our study demonstrated that the newly developed orthosis significantly reduced pain, mechanical pressure and breast tissue displacement in women with augmented and natural breast tissue when lying prone. Our findings are of clinical significance, potentially reducing the risk of complication from prone activities in women with breast augmentation or reconstruction, as well as improving comfort whilst undergoing prone procedures. Australia and New Zealand Clinical Trials Register, ACTRN12613000541707.


Pretreatment determination of isohaemagglutinin titter values in patients with malignant lymphomas and metastatic solid tumors.
Isohaemagglutinin synthesis starts 2-4 months after birth, growing progressively and reaching adult values at the age of 5-10 years. Isohaemagglutinin concentration decreases with age. Isohaemagglutinins are mostly immunoglobulins belonging to the class IgM, but also IgA and IgG. Agglutination titter shows correlation with the total concentration of those three immunoglobulin isotypes. For the time being there are few data on the isohaemagglutinin titter level in various diseases. Purpose of this work is to determine whether there are any isohaemagglutinin titter alterations in patients with neoplasia. Isohaemagglutinin titter was investigated in 177 patients treated at the Institute of Oncology and Radiology and 340 blood donors. Out of 177 patients, 31 had Hodgkin's lymphoma (HL), 89 had non-Hodgkin Lymphoma (NHL) and 57 had metastatic solid tumors (MST). Statistical evaluation included Kruskal-Wallis and Mann-Whitney tests. In all groups of patients isohaemagglutinin titters were considerably lower as compared with the healthy population (p < 1 x 10e-5). There was a significant difference in titter values (p = 0.003) between O blood group patients with NHL where anti-A1 titter was significantly lower (Med = 8; range: 1-256) compared with anti-A1 titter in patients with O blood group suffering from MST (Med = 16; range: 2-64). Anti-B titter in the same groups of patients also showed lower values (p = 0.042); in NHL anti-B titter values was Med = 4, range: 1-32 vs Med = 8, range: 1-64 in MST. In the group of patients with HL, A blood group was far more frequent (17/31) compared with the group with MST (22/57) (p = 0.02). Pretherapy determination of isohaemagglutinin titter in patients with malignant diseases shows that it is significantly lower than the titter in healthy population. Abnormally low isohaemagglutinin titter value irrespective of the type and site of the malignant tumor, points to insufficiency of the IgM-related humoral immune response, to malignancy as a systemic disease, and places isohaemagglutinins among biological markers.


Comparison of label-free methods for quantifying human proteins by shotgun proteomics.
Measurements of mass spectral peak intensities and spectral counts are promising methods for quantifying protein abundance changes in shotgun proteomic analyses. We describe Serac, software developed to evaluate the ability of each method to quantify relative changes in protein abundance. Dynamic range and linearity using a three-dimensional ion trap were tested using standard proteins spiked into a complex sample. Linearity and good agreement between observed versus expected protein ratios were obtained after normalization and background subtraction of peak area intensity measurements and correction of spectral counts to eliminate discontinuity in ratio estimates. Peak intensity values useful for protein quantitation ranged from 10(7) to 10(11) counts with no obvious saturation effect, and proteins in replicate samples showed variations of less than 2-fold within the 95% range (+/-2sigma) when >or=3 peptides/protein were shared between samples. Protein ratios were determined with high confidence from spectral counts when maximum spectral counts were >or=4 spectra/protein, and replicates showed equivalent measurements well within 95% confidence limits. In further tests, complex samples were separated by gel exclusion chromatography, quantifying changes in protein abundance between different fractions. Linear behavior of peak area intensity measurements was obtained for peptides from proteins in different fractions. Protein ratios determined by spectral counting agreed well with those determined from peak area intensity measurements, and both agreed with independent measurements based on gel staining intensities. Overall spectral counting proved to be a more sensitive method for detecting proteins that undergo changes in abundance, whereas peak area intensity measurements yielded more accurate estimates of protein ratios. Finally these methods were used to analyze differential changes in protein expression in human erythroleukemia K562 cells stimulated under conditions that promote cell differentiation by mitogen-activated protein kinase pathway activation. Protein changes identified with p<0.1 showed good correlations with parallel measurements of changes in mRNA expression.


Antioxidant and Cytotoxic Effects and Identification of Ophiocordyceps sinensis Bioactive Proteins Using Shotgun Proteomic Analysis.
Ophiocordyceps sinensis, a highly valued medicinal fungus, is close to extinction due to overexploitation. Successful cultivation of O. sinensis fruiting body (OCS02®) shows that the cultivar has a promising nutritional value and numerous bioactive compounds. Antioxidant and antiproliferative properties and biologically active proteins of the OCS02® are investigated for possible development into nutraceuticals. The chemical composition of the OCS02® cold water extract was determined, and the antioxidant activities were examined using ferric reducing, DPPH• and O2 •- scavenging assays. Tetrazolium dye (MTT) cytotoxic assay was performed to assess the antiproliferative activity of the extract. Bioactive proteins in the active fraction of the extract were identified using liquid chromatography (LC) and tandem-mass spectrometry (MS/MS). The OCS02® extract exhibited strong O2 •- scavenging (expressed as Trolox equivalents (18.4±1.1) mol/g) and potent cytotoxic activities against adenocarcinomic human alveolar basal epithelial (A549) cells (IC50=(58.2±6.8) µg/mL). High molecular mass polysaccharides, proteins and protein-polysaccharide complexes could have contributed to the antioxidant and cytotoxic selectivity of the OCS02®. LC-MS/MS analysis identified several potential cytotoxic proteases and an oxalate decarboxylase protein which may exhibit protection effects on kidneys. The findings demonstrate the potential of OCS02® to be developed into functional food due to its promising superoxide anion radical scavenging capacity, cytotoxic effect and presence of biopharmaceutically active proteins.


Ribosome processing in HeLa cells. Studies on structural aspects of precursor and mature ribosomes.
Mature ribosomes, their subunits, and their ribonucleoprotein precursors were extracted from HeLa cells and prepared for electron microscopy by a method based on adsorption of nucleic acid to a charged grid. Images so obtained revealed the presence of two types of ribonuclease-sensitive fibrils of consistent morphology. One of these types of fibril is present on the 80S and 55S nucleolar ribonucleoprotein precursors and the mature 60S subunit. The other type is restricted to the 80S precursor. The morphology of the fibrils and their distribution in the various preparations suggest identification with known secondary structural features of isolated pre-rRNA.


Atypical testicular pain.
Testicular tuberculosis (TB) is rare, and, because of this, the lack of pathognomonic clinical features and its tendency to mimic other commoner conditions, the diagnosis is frequently delayed or may be missed. In this case, the initial clinical presentation was typical for bacterial epididymo-orchitis in a 38-year-old man. When the patient failed to improve with standard treatment including broadening of antibiotics, the diagnosis was re-considered because some unusual signs suggested testicular malignancy or lymphoma. Further, history-taking and subsequent cross-sectional imaging with CT/MRI identified co-existent pulmonary nodularity, thoracic and abdominal lymphadenopathy and bony changes that, together, raised the suspicion of TB. Mycobacterium tuberculosis was confirmed on DNA-based testing of the hydrocele fluid, although standard acid-fast bacilli culture was negative. This case prompted a review of the literature to explore the optimal steps in the investigation and diagnosis of this rare disease.


Outbreak of mass sociogenic illness in a school feeding program in northwest Bangladesh, 2010.
In 2010, an acute illness outbreak was reported in school students eating high-energy biscuits supplied by the school feeding programme in northwest Bangladesh. We investigated this outbreak to describe the illness in terms of person, place and time, develop the timeline of events, and determine the cause and community perceptions regarding the outbreak. We defined case-patients as students from affected schools reporting any two symptoms including abdominal pain, heartburn, bitter taste, and headache after eating biscuits on the day of illness. We conducted in-depth interviews and group discussions with students, teachers, parents and community members to explore symptoms, exposures, and community perceptions. We conducted a questionnaire survey among case-patients to determine the symptoms and ascertain food items eaten 12 hours before illness onset, and microbiological and environmental investigations. Among 142 students seeking hospital care, 44 students from four schools qualified as case-patients. Of these, we surveyed 30 who had a mean age of 9 years; 70% (21/30) were females. Predominant symptoms included abdominal pain (93%), heartburn (90%), and bitter taste (57%). All students recovered within a few hours. No pathogenic Vibrio cholerae, Shigella or Salmonella spp. were isolated from collected stool samples. We found no rancid biscuits in schools and storage sites. The female index case perceived the unusually darker packet label as a "devil's deed" that made the biscuits poisonous. Many students, parents and community members reported concerns about rumors of students dying from biscuit poisoning. Rapid onset, followed by rapid recovery of symptoms; female preponderance; inconsistent physical, microbiological and environmental findings suggested mass sociogenic illness rather than a foodborne or toxic cause. Rumours of student deaths heightening community anxiety apparently propagated this outbreak. Sharing investigation results and reassuring students and parents through health communication campaigns could limit similar future outbreaks and help retain beneficiaries' trust on nutrition supplementation initiatives.


An interview with Juergen Knoblich.
Juergen Knoblich is a senior scientist and deputy scientific director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna. We met Juergen at the 56(th) Annual Drosophila Research Conference, where we asked him about his work in this model system and, more recently, on human cerebral organoids, and about his thoughts on recent technological developments and the funding situation.


Pharmacokinetics and biodistribution of Erufosine in nude mice--implications for combination with radiotherapy.
Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice. NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity. Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (<10%) in a dose dependent manner. Subcutaneous injections of high-dose Erufosine caused local reactions at the injection site. Therefore, this regimen at 40 mg/kg body weight Erufosine was stopped after 14 days. No gross changes were observed in organ weight, clinical chemistry and white blood cell count in treated compared to untreated controls except for a moderate increase in lactate dehydrogenase and aspartate-aminotransferase after intensive treatment. Repeated Erufosine injections resulted in drug-accumulation in different organs with maximum concentrations of about 1000 nmol/g in spleen, kidney and lungs. Erufosine was well tolerated and organ-concentrations surpassed the cytotoxic drug concentrations in vitro. Our investigations establish the basis for a future efficacy testing of Erufosine in xenograft tumor models in nude mice alone and in combination with chemo- or radiotherapy.


Kyo-Green improves sexual dysfunction in men and women.
Serendipitously, we discovered the effects of Kyo-Green, a green powdered nutritional supplement, on improving sexual dysfunctions in both men and women. In this paper, we presented two case reports and an open-labeled pilot study involving 40 subjects for a period of three months to determine the effects of Kyo-Green on sexual dysfunctions. Twenty-five men and 15 women were enrolled into this study. All the male subjects had suffered erectile dysfunction (ED). All the female subjects reported lack of libido. Subjects took one teaspoonful of Kyo-Green two times a day. Subjects completed a questionnaire at the beginning, and at the end of one, two, and three months while taking Kyo-Green. The analysis of data was based on the four questionnaires completed by the subjects. Increase of energy was reported by all the subjects. Sixteen males and 12 females reported satisfaction with their sex life after taking Kyo-Green for three months. Twenty of the 25 male subjects reported significant improvement in erectile dysfunction, and ability to initiate and maintain sexual activity with satisfaction. All the subjects experienced an increase of energy levels within a few weeks after taking this supplement. Eighty percent of the male subjects with ED regained erections while taking this supplement. The study suggests that Kyo-Green, particularly when used in conjunction with a lifestyle modification approach, may be useful in the management of sexual dysfunction in men and women who prefer a non-drug approach.


Coalescent histories for caterpillar-like families.
A coalescent history is an assignment of branches of a gene tree to branches of a species tree on which coalescences in the gene tree occur. The number of coalescent histories for a pair consisting of a labeled gene tree topology and a labeled species tree topology is important in gene tree probability computations, and more generally, in studying evolutionary possibilities for gene trees on species trees. Defining the Tr-caterpillar-like family as a sequence of n-taxon trees constructed by replacing the r-taxon subtree of n-taxon caterpillars by a specific r-taxon labeled topology Tr, we examine the number of coalescent histories for caterpillar-like families with matching gene tree and species tree labeled topologies. For each Tr with size r≤8, we compute the number of coalescent histories for n-taxon trees in the Tr-caterpillar-like family. Next, as n→∞, we find that the limiting ratio of the numbers of coalescent histories for the Tr family and caterpillars themselves is correlated with the number of labeled histories for Tr. The results support a view that large numbers of coalescent histories occur when a tree has both a relatively balanced subtree and a high tree depth, contributing to deeper understanding of the combinatorics of gene trees and species trees.


Differential item functioning (DIF) analyses of health-related quality of life instruments using logistic regression.
Differential item functioning (DIF) methods can be used to determine whether different subgroups respond differently to particular items within a health-related quality of life (HRQoL) subscale, after allowing for overall subgroup differences in that scale. This article reviews issues that arise when testing for DIF in HRQoL instruments. We focus on logistic regression methods, which are often used because of their efficiency, simplicity and ease of application. A review of logistic regression DIF analyses in HRQoL was undertaken. Methodological articles from other fields and using other DIF methods were also included if considered relevant. There are many competing approaches for the conduct of DIF analyses and many criteria for determining what constitutes significant DIF. DIF in short scales, as commonly found in HRQL instruments, may be more difficult to interpret. Qualitative methods may aid interpretation of such DIF analyses. A number of methodological choices must be made when applying logistic regression for DIF analyses, and many of these affect the results. We provide recommendations based on reviewing the current evidence. Although the focus is on logistic regression, many of our results should be applicable to DIF analyses in general. There is a need for more empirical and theoretical work in this area.


Involvement of the vacuolar proton-translocating ATPase in multiple steps of the endo-lysosomal system and in the contractile vacuole system of Dictyostelium discoideum.
We have investigated the effects of Concanamycin A (CMA), a specific inhibitor of vacuolar type H(+)-ATPases, on acidification and function of the endo-lysosomal and contractile vacuole (CV) systems of D. discoideum. This drug inhibited acidification and increased the pH of endo-lysosomal vesicles both in vivo and in vitro in a dose dependent manner. Treatment also inhibited endocytosis and exocytosis of fluid phase, and phagocytosis of latex beads. This report also confirms our previous conclusions (Cardelli et al. (1989) J. Biol. Chem. 264, 3454-3463) that maintenance of acidic pH in lumenal compartments is required for efficient processing and targeting of a lysosomal enzyme, alpha-mannosidase. CMA treatment compromised the function of the contractile vacuole complex as amoebae exposed to a hypo-osmotic environment in the presence of CMA, swelled rapidly and ruptured. Fluorescence microscopy revealed that CMA treatment induced gross morphological changes in D. discoideum cells, characterized by the formation of large intracellular vacuoles containing fluid phase. The reticular membranes of the CV system were also no longer as apparent in drug treated cells. Finally, this is the first report describing cells that can adapt in the presence of CMA; in nutrient medium, D. discoideum overcame the effects of CMA after one hour of drug treatment even in the absence of protein synthesis. Upon adaptation to CMA, normal sized endo-lysosomal vesicles reappeared, endo-lysosomal pH decreased, and the rate of endocytosis, exocytosis and phagocytosis returned to normal. This study demonstrates that the V-H(+)-ATPase plays an important role in maintaining the integrity and function of the endo-lysosomal and CV systems and that D. discoideum can compensate for the loss of a functional V-H(+)-ATPase.


Dietary, physiological, genetic and pathological influences on postprandial lipid metabolism.
Most of diurnal time is spent in a postprandial state due to successive meal intakes during the day. As long as the meals contain enough fat, a transient increase in triacylglycerolaemia and a change in lipoprotein pattern occurs. The extent and kinetics of such postprandial changes are highly variable and are modulated by numerous factors. This review focuses on factors affecting postprandial lipoprotein metabolism and genes, their variability and their relationship with intermediate phenotypes and risk of CHD. Postprandial lipoprotein metabolism is modulated by background dietary pattern as well as meal composition (fat amount and type, carbohydrate, protein, fibre, alcohol) and several lifestyle conditions (physical activity, tobacco use), physiological factors (age, gender, menopausal status) and pathological conditions (obesity, insulin resistance, diabetes mellitus). The roles of many genes have been explored in order to establish the possible implications of their variability in lipid metabolism and CHD risk. The postprandial lipid response has been shown to be modified by polymorphisms within the genes for apo A-I, A-IV, A-V, E, B, C-I and C-III, lipoprotein lipase, hepatic lipase, fatty acid binding and transport proteins, microsomal triglyceride transfer protein and scavenger receptor class B type I. Overall, the variability in postprandial response is important and complex, and the interactions between nutrients or dietary or meal compositions and gene variants need further investigation. The extent of present knowledge and needs for future studies are discussed in light of ongoing developments in nutrigenetics.


Kinetic distribution of 14C-metsulfuron-methyl residues in paddy soils under different moisture conditions.
Rice paddy soils undergo several cycles of drying and wetting during a growing season. A laboratory study was conducted to determine the effect of soil moisture conditions on the distribution and kinetics of extractable and bound residues of 14C-metsulfuron-methyl in six Chinese paddy soils during 84 d of incubation at 15 degrees C with moisture contents varying from 20 to 50% of the field water-holding capacity. The amount of extractable residues consistently increased and bound residues decreased with increasing soil moisture content. At the end of the incubation experiments, extractable residues and bound residues accounted for 34.5 to 84.4% and 11.6 to 53.3% of applied radioactivity in soils, respectively. Soil pH and soil microbial biomass carbon were the most predominant factors affecting the formation and relative distribution of herbicide residues between extractable and bound residue forms. In high-pH soils, bound residues decreased and extractable residues increased, suggesting an increased leaching risk for metsulfuron-methyl in alkaline soils. High precipitation rates, along with the common practice of liming in southeastern China, may lead to enhanced herbicide leaching as well as phytotoxicity to rotation plants and should be considered in overall pest management practices.


Blood pressure and dietary polyunsaturated and saturated fats: a controlled trial.
Fifty-four healthy, omnivore normotensive volunteers aged 20-59 years were randomly allocated either to a control group eating a low polyunsaturated to saturated fat ratio (P/S ratio) diet (0.3) throughout, or to one of two experimental groups eating a high P/S ratio diet (1.0) for one of two 6-week experimental periods. Changes in other components were avoided. Twenty-four hour diet records showed substantial changes in the P/S ratio for experimental groups when on the high P/S ratio diet (0.3 to 1.0). There were significant increases in relative concentrations of linoleic acid in plasma phospholipids when on the high P/S ratio diet. There was no consistent effect of dietary P/S ratio elevation from 0.3 to 1.0 on group mean systolic and diastolic blood pressures. Adjustment of blood pressure changes for changes in electrolytes, other dietary components, plasma lipids, weight and other lifestyle variables did not alter this result. It was concluded that the blood pressure lowering effect of a vegetarian diet reported previously was unlikely to have been due to changes in dietary P/S ratio.


Optimized flash light-emitting diode spectra for mobile phone cameras.
Flash light-emitting diodes (LEDs) of modern mobile phones lack red and cyan spectral parts, however, the color gamut of their respective displays has increased in recent years. The influence of this discrepancy on the color reproduction of smart phones is investigated in this paper. Based on the CIECAM02 color appearance model, a metric is introduced to judge color reproduction of mobile phones under flash LED illumination. An evaluation method is established to compare the visual appearance of a scene under various surrounding illuminations with the reproduction of that scene. To facilitate a comparison with measurements, the evaluation method is based on the raw data of two test cameras and a Digital ColorChecker SG. To reduce the color shift between perception and reproduction, optimized flash LED spectra are presented. A single-LED and a double-LED concept with adjustable color temperature are derived from these results. Additionally, the common characteristics of flash LED spectra giving good results is investigated, identifying the spectral parts with the most influence on camera color reproduction and showing the spectral parts not contributing or even resulting in poor color reproduction. Finally the efficiency of optimized flash LED spectra is compared to standard flash LEDs.


Intermediate filament proteins in choroid plexus and ependyma and their tumors.
The intermediate filament protein types of normal choroid plexus and ependymal tissue and their putative tumors were investigated. In normal human choroid plexus tissue, but not in ependyma, keratin could be demonstrated immunohistochemically. By immunoblotting, keratins 8, 18, and 19 were found, but glial fibrillary acidic protein (GFAP) was absent. In mouse and rat, choroid plexus epithelium and ependymal lining cells were keratin-positive. In addition, many ependymal cells were vimentin-positive. Keratin was immunohistochemically found in three of four choroid plexus papillomas, two of two choroid plexus carcinomas, and the lining cells of three neuroepithelial cysts. GFAP-positive cells were present in some choroid plexus tumors. In contrast, none of the eight ependymomas contained keratin, but all were strongly positive for GFAP. The results show that choroid plexus lining cells and choroid plexus tumors have true epithelial characteristics in their cytoskeleton, in contrast to ependymomas, which do not show keratin positivity but show glial filaments, as would be seen in astrocytic tumors.


Droplet-based light-sheet fluorescence microscopy for high-throughput sample preparation, 3-D imaging and quantitative analysis on a chip.
We report a novel fusion of droplet microfluidics and light-sheet microscopy, to achieve high-throughput sample compartmentalization, manipulation and three-dimensional imaging on a chip. This optofluidic device characterized by orthogonal plane illumination and rapid liquid handling is compact and cost-effective, and capable of preparing sample droplets with tunable size, frequency and ingredient. Each droplet flowing through the device's imaging region is self-scanned by a laser-sheet, three-dimensionally reconstructed and quantitatively analysed. This simple-and-robust platform combines fast 3-D imaging with efficient sample preparation and eliminates the need of a complicated mechanical scan at the same time. Achieving 500 measurements per second and screening over 30 samples per minute, it shows great potential for various lab-on-a-chip biological studies, such as embryo sorting and cell growth assays.


Estrogen inhibits chloride secretion caused by cholera and Escherichia coli enterotoxins in female rat distal colon.
Excessive Cl(-) secretion is the driving force for secretory diarrhea. 17β-Estradiol has been shown to inhibit Cl(-) secretion in rat distal colon through a nongenomic pathway. We examined whether 17β-estradiol inhibits Cl(-) secretion in an animal model of secretory diarrhea and the downstream effectors involved. The effect of 17β-estradiol on cholera toxin and heat-stable enterotoxin induced Cl(-) secretion in rat colonic mucosal sheets was studied by current-voltage clamping. Selective permeabilization of apical or basolateral membranes with amphotericin B or nystatin was used to isolate basolateral K(+) channel and apical Cl(-) channel activity, respectively. 17β-Estradiol dose-dependently inhibited secretory responses to both toxins with IC(50) values of approximately 1nM. This effect was female-gender specific, with no inhibition observed in male tissues. 17β-Estradiol responses were insensitive to the pure anti-estrogen ICI 182,720. 17β-Estradiol exerted its effects downstream of enterotoxin-induced production of second messengers (cAMP and cGMP) but was dependent on PKCδ activation. In nystatin-permeabilized tissues, apical Cl(-) currents were unaffected by 17β-estradiol treatment while basolateral K(+) current was profoundly inhibited by the hormone. This current was sensitive to the specific KCNQ1 channel inhibitors chromanol 293B and HMR-1556. In conclusion, 17β-estradiol inhibits enterotoxin-induced Cl(-) secretion via a PKCδ-dependent mechanism involving inhibition of basolateral KCNQ1 channels. These data elucidate mechanisms of 17β-estradiol inhibition of Cl(-) secretion induced by enterotoxins in intestinal epithelia, which may be relevant for the treatment of diarrheal diseases.


hCAP-D3 expression marks a prostate cancer subtype with favorable clinical behavior and androgen signaling signature.
Growing evidence suggests that only a fraction of prostate cancers detected clinically are potentially lethal. An important clinical issue is identifying men with indolent cancer who might be spared aggressive therapies with associated morbidities. Previously, using microarray analysis we defined 3 molecular subtypes of prostate cancer with different gene-expression patterns. One, subtype-1, displayed features consistent with more indolent behavior, where an immunohistochemical marker (AZGP1) for subtype-1 predicted favorable outcome after radical prostatectomy. Here we characterize a second candidate tissue biomarker, hCAP-D3, expressed in subtype-1 prostate tumors. hCAP-D3 expression, assayed by RNA in situ hybridization on a tissue microarray comprising 225 cases, was associated with decreased tumor recurrence after radical prostatectomy (P=0.004), independent of pathologic tumor stage, Gleason grade, and preoperative prostate-specific antigen levels. Simultaneous assessment of hCAP-D3 and AZGP1 expression in this tumor set improved outcome prediction. We have previously demonstrated that hCAP-D3 is induced by androgen in prostate cells. Extending this finding, Gene Set Enrichment Analysis revealed enrichment of androgen-responsive genes in subtype-1 tumors (P=0.019). Our findings identify hCAP-D3 as a new biomarker for subtype-1 tumors that improves prognostication, and reveal androgen signaling as an important biologic feature of this potentially clinically favorable molecular subtype.


Continuum approximations of individual-based models for epithelial monolayers.
This work examines a 1D individual-based model (IBM) for a system of tightly adherent cells, such as an epithelial monolayer. Each cell occupies a bounded region, defined by the location of its endpoints, has both elastic and viscous mechanical properties and is subject to drag generated by adhesion to the substrate. Differential-algebraic equations governing the evolution of the system are obtained from energy considerations. This IBM is then approximated by continuum models (systems of partial differential equations) in the limit of a large number of cells, N, when the cell parameters vary slowly in space or are spatially periodic (and so may be heterogeneous, with substantial variation between adjacent cells). For spatially periodic cell properties with significant cell viscosity, the relationship between the mean cell pressure and length for the continuum model is found to be history dependent. Terms involving convective derivatives, not normally included in continuum tissue models, are identified. The specific problem of the expansion of an aggregate of cells through cell growth (but without division) is considered in detail, including the long-time and slow-growth-rate limits. When the parameters of neighbouring cells vary slowly in space, the O(1/N(2)) error in the continuum approximation enables this approach to be used even for modest values of N. In the spatially periodic case, the neglected terms are found to be O(1/N). The model is also used to examine the acceleration of a wound edge observed in wound-healing assays.


Variants identified in a GWAS meta-analysis for blood lipids are associated with the lipid response to fenofibrate.
A recent large-scale meta-analysis of genome-wide studies has identified 95 loci, 59 of them novel, as statistically significant predictors of blood lipid traits; we tested whether the same loci explain the observed heterogeneity in response to lipid-lowering therapy with fenofibrate. Using data from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 861) we fit linear mixed models with the genetic markers as predictors and high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and triglyceride concentrations as outcomes. For all four traits, we analyzed both baseline levels and changes in response to treatment with fenofibrate. For the markers that were significantly associated with fenofibrate response, we fit additional models evaluating potential epistatic interactions. All models were adjusted for age, sex, and study center as fixed effects, and pedigree as a random effect. Statistically significant associations were observed between the rs964184 polymorphism near APOA1 (P-value≤0.0001) and fenofibrate response for HDL and triglycerides. The association was replicated in the Pharmacogenetics of Hypertriglyceridemia in Hispanics study (HyperTG, n = 267). Suggestive associations with fenofibrate response were observed for markers in or near PDE3A, MOSC1, FLJ36070, CETP, the APOE-APOC1-APOC4-APOC2, and CILP2. Finally, we present strong evidence for epistasis (P-value for interaction = 0.0006 in GOLDN, 0.05 in HyperTG) between rs10401969 near CILP2 and rs4420638 in the APOE-APOC1-APOC4-APOC2 cluster with total cholesterol response to fenofibrate. In conclusion, we present evidence linking several novel and biologically relevant genetic polymorphisms to lipid lowering drug response, as well as suggesting novel gene-gene interactions in fenofibrate pharmacogenetics.


Classifying pain in transoral endoscopic thyroidectomy.
Knowledge of visual analog scale (VAS) pain assessment for transoral endoscopic thyroidectomy vestibular approach (TOETVA) is limited. The purpose of this analysis was to classify the postoperative discomfort scores in patients undergoing TOETVA compared to open thyroidectomy. Observational clinical study of patients who underwent thyroidectomy by VAS pain assessment from September 2016 to March 2017. Patients were stratified into two groups: patients eligible for TOETVA (Group TOETVA) and non-candidates for endoscopic intervention (open thyroidectomy approach-OTA). VAS was recorded in the recovery room, at 24 h, + 2, + 5, + 15, + 30, + 90 days, and 6 months after surgery. Pain assessment was stratified in VAS-lower lip, VAS-chin, VAS-jaw, VAS-anterior neck, VAS-cervical/back, VAS-swallowing, VAS-brushing, VAS-speaking, and VAS-shaving. Secondary outcome assessed were analgesic rescue dose, morbidity, operative notes, hospital stay, and histopathology. 41 TOETVA and 45 OTA constituted the analysis. There were differences between the TOETVA and OTA for age, gland volume, mean nodule diameter, coexistence thyroiditis, bilateral procedures, and use of drain. Operative time was longer in TOETVA. Results indicated that TOETVA was associated with reduced neck, cervical back, and swallowing VAS scores in the 24 h after surgery. Conversely, jaw and brushing teeth resulted in higher VAS score in TOETVA group. OTA patients never experienced lower lip or chin pain. The use of rescue analgesics did not differ between the two groups. VAS was used to measure treatment outcome in TOETVA. VAS scores achieved overall a minimal clinical importance difference from the two procedures. There appears to be both a short- and long-term different range of interpretations of pain between TOETVA and OTA.


Simple and accurate determination of global tau(R) in proteins using (13)C or (15)N relaxation data.
In the study of protein dynamics by (13)C or (15)N relaxation measurements different models from the Lipari-Szabo formalism are used in order to determine the motion parameters. The global rotational correlation time tau(R) of the molecule must be estimated prior to the analysis. In this Communication, the authors propose a new approach in determining an accurate value for tau(R) in order to realize the best fit of R(2) for the whole sequence of the protein, regardless of the different type of motions atoms may experience. The method first determines the highly structured regions of the sequence. For each corresponding site, the Lipari-Szabo parameters are calculated for R(1) and NOE, using an arbitrary value for tau(R). The chi(2) for R(2), summed over the selected sites, shows a clear minimum, as a function of tau(R). This minimum is used to better estimate a proper value for tau(R).


Knowledge of risk factors and risk behaviors related to coronary heart disease among blue and white collar males.
In this report the data regarding coronary heart disease (CHD) from the 1990 Health Promotion and Disease Prevention Supplement of the National Health Interview Survey are used to examine the relationship between risk factor knowledge and health related behaviors among currently employed white collar (N = 5,349) and blue collar (N = 4,158) men workers. Blue collar employees have less knowledge about CHD risk factors, less favorable risk factors status, and poorer health practices than their white collar workers. Despite these findings within each occupational group, the relationship of knowledge to either risk factor status or health practices is similar. Knowledge is generally related to the attempts to change behaviors. However, for the different risk factors, the associations vary. For example, knowledge of cigarette smoking as a risk factor of CHD is negatively associated with reported ever smoking or current smoking, but not with heavy smoking. In contrast, knowledge of overweight, high serum cholesterol, and high blood pressure as CHD risk factors is not associated with risk factor status. These results suggest that while difference in level of knowledge and risk profiles remain between blue collar and white collar employees, the associations between knowledge and risk profiles are similar. Programs located at worksites must continue to provide education opportunities about the risk factors, especially among blue collar workers.