Association of Demographic and Program Factors With American Board of Surgery Qualifying and Certifying Examinations Pass Rates.
American Board of Surgery board certification requires passing both a written qualifying examination and an oral certifying examination. No studies have been conducted assessing the effect of sociodemographic variables on board passage rates. To evaluate if trainee sociodemographic factors are associated with board passage rates. This national and multi-institutional prospective observational cohort study of 1048 categorical general surgery trainees starting in 2007-2008 were surveyed. Data collection began in June 2007, follow-up was completed on December 31, 2016, and analysis began September 2018. Survey responses were linked to American Board of Surgery board passage data. Of 662 examinees who had complete survey and follow-up data, 443 (65%) were men and 459 (69%) were white, with an overall board passage rate of 87% (n = 578). In a multinomial regression model, trainees of Hispanic ethnicity were more likely to not attempt the examinations (vs passed both) than non-Hispanic trainees (odds ratio [OR], 4.7; 95% CI, 1.5-14). Compared with examinees who were married with children during internship, examinees who were married without children (OR, 0.3; 95% CI, 0.1-0.8) or were single (OR, 0.4; 95% CI, 0.2-0.9) were less likely to fail the examinations. Logistic regression showed white examinees compared with nonwhite examinees (black individuals, Asian individuals, and individuals of other races) (OR, 1.8; 95% CI, 1.03-3.0) and examinees who performed better on their first American Board of Surgery In-Training Examination (OR, 1.03; 95% CI, 1.02-1.05) were more likely to pass the qualifying examination on the first try. White examinees compared with nonwhite examinees (OR, 1.8; 95% CI, 1.1-2.8), non-Hispanic compared with Hispanic examinees (OR, 2.4; 95% CI, 1.2-4.7), and single women compared with women who were married with children during internship (OR, 10.3; 95% CI, 2.1-51) were more likely to pass the certifying examination on the first try. Resident race, ethnicity, sex, and family status at internship were observed to be associated with board passage rates. There are multiple possible explanations for these worrisome observations that need to be explored. Tracking demographics of trainees to help understand passage rates based on demographics will be important. The American Board of Surgery already has begun addressing the potential for unconscious bias among board examiners by increasing diversity and adding implicit bias training.


Quercetin plays protective role in oxidative induced apoptotic events during chronic chlorpyrifos exposure to rats.
Chlorpyrifos (CPF), an organophosphate insecticide has a wider application throughout the world to protect agricultural crops and vegetables from insects. Polyphenolic compounds are considered as beneficial against toxicities induced by organophosphates. The present study was conducted to understand the neuroprotective role of quercetin in chlorpyrifos-induced apoptotic events in rats. Twenty-four male Sprague Dawley rats weighing 170 to 200 g were divided into four groups viz: Control, chlorpyrifos treated (13.5 mg/kg body wt. alternate day), quercetin treated (50 mg/kg body wt. every day) and combined chlorpyrifos + quercetin treated. All the treatments were carried out for a total duration of 60 days. Protein carbonyl content and acetylcholinesterase activity were estimated in serum along with cerebrum and cerebellum to ascertain neurotoxicity. Further, for appraisal of neurodegeneration as a consequence of apoptosis, protein expressions of Bcl-2, Bax, cytochrome c, caspase-8, and caspase-9 were assessed. The results showed that protein carbonyl contents were markedly increased in both serum and brain tissues (cerebrum and cerebellum) of chlorpyrifos-treated rats when compared with control group and were appreciably improved upon simultaneous supplementation with quercetin. Further, chlorpyrifos treatment revealed a significant decrease in the enzyme activity of acetylcholinesterase in serum as well as in cerebrum and cerebellum, which however was increased upon concomitant treatment with quercetin. In chlorpyrifos-treated animals, we have observed a significant decrease in the protein expression level of Bcl-2, but a remarkable increase in the expression levels of Bax, cytochrome c, caspase-8, and caspase-9 in both cerebrum and cerebellum. Interestingly, when chlorpyrifos-treated animals were supplemented with quercetin, a significant increase in the expression of Bcl-2 and an appreciable decline in the expression levels of Bax, cytochrome c, caspase-8, and caspase-9 was observed. In conclusion, the present study advocates that quercetin may prove to be a useful candidate in containing the oxidative-induced apoptotic events during chlorpyrifos exposure.


Physical activity and lung cancer among non-smokers: a pilot molecular epidemiological study within EPIC.
The association between physical activity, potential intermediate biomarkers and lung cancer risk was investigated in a study of 230 cases and 648 controls nested within the European Prospective Investigation of Cancer and Nutrition. Data on white blood cell aromatic-DNA adducts by (32)P-post-labelling and glutathione (GSH) in red blood cells were available from a subset of cases and controls. Compared with the first quartile, the fourth quartile of recreational physical activity was associated with a lower lung cancer risk (odds ratio (OR) 0.56, 95% confidence interval (CI) 0.35-0.90), higher GSH levels (+1.87 micromol GSH g(-1) haemoglobin, p = 0.04) but not with the presence of high levels of adducts (OR 1.05, 95% CI 0.38-2.86). Despite being associated with recreational physical activity, in these small-scale pilot analyses GSH levels were not associated with lung cancer risk (OR 0.95, 95% CI 0.84-1.07 per unit increase in GSH levels). Household and occupational activity was not associated with lung cancer risk or biomarker levels.


The non-lemniscal auditory cortex in ferrets: convergence of corticotectal inputs in the superior colliculus.
Descending cortical inputs to the superior colliculus (SC) contribute to the unisensory response properties of the neurons found there and are critical for multisensory integration. However, little is known about the relative contribution of different auditory cortical areas to this projection or the distribution of their terminals in the SC. We characterized this projection in the ferret by injecting tracers in the SC and auditory cortex. Large pyramidal neurons were labeled in layer V of different parts of the ectosylvian gyrus after tracer injections in the SC. Those cells were most numerous in the anterior ectosylvian gyrus (AEG), and particularly in the anterior ventral field, which receives both auditory and visual inputs. Labeling was also found in the posterior ectosylvian gyrus (PEG), predominantly in the tonotopically organized posterior suprasylvian field. Profuse anterograde labeling was present in the SC following tracer injections at the site of acoustically responsive neurons in the AEG or PEG, with terminal fields being both more prominent and clustered for inputs originating from the AEG. Terminals from both cortical areas were located throughout the intermediate and deep layers, but were most concentrated in the posterior half of the SC, where peripheral stimulus locations are represented. No inputs were identified from primary auditory cortical areas, although some labeling was found in the surrounding sulci. Our findings suggest that higher level auditory cortical areas, including those involved in multisensory processing, may modulate SC function via their projections into its deeper layers.


Role of BMP signaling and the homeoprotein Iroquois in the specification of the cranial placodal field.
Different types of placodes originate at the anterior border of the neural plate but it is still an unresolved question whether individual placodes arise as distinct ectodermal specializations in situ or whether all or a subset of the placodes originate from a common preplacodal field. We have analyzed the expression and function of the homeoprotein Iro1 in Xenopus and zebrafish embryos, and we have compared its expression with several preplacodal and placodal markers. Our results indicate that the iro1 genes are expressed in the preplacodal region, being one of the earliest markers for this area. We show that an interaction between the neural plate and the epidermis is able to induce the expression of several preplacodal markers, including Xiro1, by a similar mechanism to that previously shown for neural crest induction. In addition, we analyzed the role of BMP in the specification of the preplacodal field by studying the expression of the preplacodal markers Six1, Xiro1, and several specific placodal markers. We experimentally modified the level of BMP activity by three different methods. First, we implanted beads soaked with noggin in early neurula stage Xenopus embryos; second, we injected the mRNA that encodes a dominant negative of the BMP receptor into Xenopus and zebrafish embryos; and third, we grafted cells expressing chordin into zebrafish embryos. The results obtained using all three methods show that a reduction in the level of BMP activity leads to an expansion of the preplacodal and placodal region similar to what has been described for neural crest regions. By using conditional constructs of Xiro1, we performed gain and loss of function experiments. We show that Xiro1 play an important role in the specification of both the preplacodal field as well as individual placodes. We have also used inducible dominant negative and activator constructs of Notch signaling components to analyze the role of these factors on placodal development. Our results indicate that the a precise level of BMP activity is required to induce the neural plate border, including placodes and neural crest cells, that in this border the iro1 gene is activated, and that this activation is required for the specification of the placodes.


Beyond the zebrafish: diverse fish species for modeling human disease.
In recent years, zebrafish, and to a lesser extent medaka, have become widely used small animal models for human diseases. These organisms have convincingly demonstrated the usefulness of fish for improving our understanding of the molecular and cellular mechanisms leading to pathological conditions, and for the development of new diagnostic and therapeutic tools. Despite the usefulness of zebrafish and medaka in the investigation of a wide spectrum of traits, there is evidence to suggest that other fish species could be better suited for more targeted questions. With the emergence of new, improved sequencing technologies that enable genomic resources to be generated with increasing efficiency and speed, the potential of non-mainstream fish species as disease models can now be explored. A key feature of these fish species is that the pathological condition that they model is often related to specific evolutionary adaptations. By exploring these adaptations, new disease-causing and disease-modifier genes might be identified; thus, diverse fish species could be exploited to better understand the complexity of disease processes. In addition, non-mainstream fish models could allow us to study the impact of environmental factors, as well as genetic variation, on complex disease phenotypes. This Review will discuss the opportunities that such fish models offer for current and future biomedical research.


Dorsolateral septum somatostatin interneurons gate mobility to calibrate context-specific behavioral fear responses.
Adaptive fear responses to external threats rely upon efficient relay of computations underlying contextual encoding to subcortical circuits. Brain-wide analysis of highly coactivated ensembles following contextual fear discrimination identified the dorsolateral septum (DLS) as a relay of the dentate gyrus-CA3 circuit. Retrograde monosynaptic tracing and electrophysiological whole-cell recordings demonstrated that DLS somatostatin-expressing interneurons (SST-INs) receive direct CA3 inputs. Longitudinal in vivo calcium imaging of DLS SST-INs in awake, behaving mice identified a stable population of footshock-responsive SST-INs during contextual conditioning whose activity tracked and predicted non-freezing epochs during subsequent recall in the training context but not in a similar, neutral context or open field. Optogenetic attenuation or stimulation of DLS SST-INs bidirectionally modulated conditioned fear responses and recruited proximal and distal subcortical targets. Together, these observations suggest a role for a potentially hard-wired DLS SST-IN subpopulation as arbiters of mobility that calibrate context-appropriate behavioral fear responses.


Interaction between ABO and rhesus blood groups, the site of origin of gastric cancers, and the age and sex of the patient.
ABO and Rhesus blood group data have been examined for 1,680 patients treated for gastric cancer in four London hospitals. The risk of developing gastric cancer was estimated to be 16% higher for group A subjects than for group O subjects, in close agreement with many previous reports throughout the world. More detailed analysis failed to support the suggestion that there was any special correlation between either ABO or Rhesus blood groups and the site of origin of the tumour within the stomach or the sex or age of the patient. Male predominance among the patients was noted to be greater at ages 40-69 years than at other ages and greater for tumours of the upper two thirds of the stomach than for tumours that arose distally.


Drought, ozone, ABA and ethylene: new insights from cell to plant to community.
Recent reports show ethylene-dependent reductions in stomatal sensitivity to abscisic acid (ABA) under ozone stress. These changes reduce stomatal control of plant water loss in drying soil. Here we review evidence that ABA and ethylene, and interactions between these two stress-induced hormones, control many of the responses of intact plants to drought and ozone stress, with emphasis on effects on stomata and shoot growth. We draw attention to convergent signalling and response pathways induced by ozone and drought that can increase production of hydrogen peroxide (H(2)O(2)) and nitric oxide (NO). Stomatal responses to a wider range of stresses and developmental cues may also be controlled via the same sets of signalling pathways. Other hormones, or effectors such as xylem/apoplastic pH or changes in plant water status, also play a role in signalling within and between organs. We discuss the implications, for crops, natural ecosystems and water catchment processes, of ethylene's antagonism of the stomatal response to ABA, against a back-drop of predictions for reduced precipitation and increasing ozone pollution, as part of global climate change and increasing urbanization and industrial development.


Tobacco use is associated with increased recurrence and death from gastric cancer.
Tobacco use increases the risk of developing gastric cancer. We examined the hypothesis that gastric cancer developing in patients with a history of tobacco use may be associated with increased risk of cancer-specific death after curative surgical resection. From the Memorial Sloan-Kettering Cancer Center Gastric Cancer prospective surgical database, we collected baseline demographic data and tumor characteristics from all patients who had undergone curative resection for gastric cancer between 1995 and 2009 and who had not received pre- or postoperative chemo- or radiotherapy. A smoking history was defined as >100 cigarettes' lifetime use. The primary end point was gastric cancer disease-specific survival (DSS); secondary end points were 5-year disease-free survival (DFS) and overall survival (OS). Gastric cancer-specific hazard was modeled by Cox regression. A total of 699 eligible patients were identified with a median age of 70 years (range 25-96 years); 410 (59%) were current or previous smokers. Smoking was associated with gastroesophageal junction/cardia tumors and white non-Hispanic ethnicity. Multivariate analysis included the following variables: tumor stage, age, performance status, diabetes mellitus, gender, and tumor location. In this analysis, the hazard ratio for gastric cancer DSS in smokers was 1.43 (95% confidence interval 1.08-1.91, P=0.01). Smoking was also an independent significant risk factor for worse 5-year DFS (hazard ratio 1.46, P=0.007) and OS (hazard ratio 1.48, P=0.003). Among 516 patients for whom tobacco pack-year usage was available, both heavy (≥20 pack-years) and light (<20 pack-years) tobacco use was significantly associated with DSS, DFS, and OS. Smoking history appears to be an independent risk factor for death from gastric cancer in patients who have undergone curative surgical resection.


Non-communicable diseases in the Asia-Pacific region: Prevalence, risk factors and community-based prevention.
Non-communicable diseases (NCDs) lead to substantial mortality and morbidity worldwide. The most common NCDs are cardiovascular diseases (CVD), diabetes, cancer and chronic respiratory diseases. With the rapid increase in NCD-related deaths in Asia Pacific countries, NCDs are now the major cause of deaths and disease burden in the region. NCDs hamper achievement of the Millennium Development Goals (MDG). People in the low socio-economic group are most affected by NCDs as they have poor access to policies, legislations, regulations and healthcare services meant to combat NCDs. This results in loss of productivity by a decreasing labor force with implications at the macroeconomic level. The 3 major NCDs in the Asia Pacific region are CVDs, cancer and diabetes due to the increasing loss of disability adjusted life years (DALYs). The 4 major behavioral risk factors for NCDs are: tobacco use, alcohol consumption, inadequate physical activity and unhealthy diet. The underlying risk factors are urbanization, globalization, sedentary lifestyle, obesity and hypertension. Strategies to combat NCDs in the Asia Pacific region are as follows: population-based dietary salt reduction, health education, psychological interventions, i.e., cognitive behavioral therapy and motivational-interviewing, taxation and bans on tobacco-related advertisements, implementing smoke-free zones and surveillance by the World Health Organization. Control measures must focus on prevention and strengthening inter-sectorial collaboration.


A qualitative exploration of how Canadian informal caregivers in medical tourism use experiential resources to cope with providing transnational care.
Canadians travelling abroad for privately arranged surgeries paid for out-of-pocket are engaging in what has come to be known as medical tourism. They are often accompanied by friends or family members, who we call caregiver-companions. Caregiver-companions provide care in and across a variety of formal and informal settings, such as in hotels, airplanes and at home. This qualitative study examines the experiences of informal caregivers in medical tourism to learn more about the lived experiences or 'experiential resources' they draw upon to cope with providing care and avoiding caregiver burden. The care-giving literature has demonstrated that such burden can negatively impact caregivers' well-being. The unique, transnational context of care-giving in medical tourism and recent growth in popularity of this practice means that there are few supports or resources currently in place to assist informal caregivers. In this article, we report on an analysis that sought to detail how caregiver-companions draw upon their previous lived experiences to cope with providing transnational care and to minimise or avoid the onset of caregiver burden. We conducted semi-structured telephone interviews with 20 Canadians who had accompanied their friends or family members abroad for surgery between September 2013 and January 2014. Thematic analysis revealed the ways that participants had developed practical strategies to deal with the challenges they faced in medical tourism. The interviews revealed three important experiential resources drawn upon by participants: (i) previous experiences of international travel; (ii) previous experiences of informal care-giving; and (iii) dimensions of the existing relationship with the care recipient. Differences in access to and use of these experiential resources related to participants' perspectives on medical tourism and the outcomes of the trip. By identifying the experiential resources drawn upon by informal caregivers in medical tourism, we can more effectively identify supportive interventions.


Drug-Mediated Shortening of Action Potentials in LQTS2 Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes.
Cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) are now a well-established modality for modeling genetic disorders of the heart. This is especially so for long QT syndrome (LQTS), which is caused by perturbation of ion channel function, and can lead to fainting, malignant arrhythmias and sudden cardiac death. LQTS2 is caused by mutations in KCNH2, a gene whose protein product contributes to IKr (also known as HERG), which is the predominant repolarizing potassium current in CMs. β-blockers are the mainstay treatment for patients with LQTS, functioning by reducing heart rate and arrhythmogenesis. However, they are not effective in around a quarter of LQTS2 patients, in part, because they do not correct the defining feature of the condition, which is excessively prolonged QT interval. Since new therapeutics are needed, in this report, we biopsied skin fibroblasts from a patient who was both genetically and clinically diagnosed with LQTS2. By producing LQTS-hiPSC-CMs, we assessed the impact of different drugs on action potential duration (APD), which is used as an in vitro surrogate for QT interval. Not surprisingly, the patient's own β-blocker medication, propranolol, had a marginal effect on APD in the LQTS-hiPSC-CMs. However, APD could be significantly reduced by up to 19% with compounds that enhanced the IKr current by direct channel binding or by indirect mediation through the PPARδ/protein 14-3-3 epsilon/HERG pathway. Drug-induced enhancement of an alternative potassium current, IKATP, also reduced APD by up to 21%. This study demonstrates the utility of LQTS-hiPSC-CMs in evaluating whether drugs can shorten APD and, importantly, shows that PPARδ agonists may form a new class of therapeutics for this condition.


Utilizing genetic code expansion to modify N-TIMP2 specificity towards MMP-2, MMP-9, and MMP-14.
Matrix metalloproteinases (MMPs) regulate the degradation of extracellular matrix (ECM) components in biological processes. MMP activity is controlled by natural tissue inhibitors of metalloproteinases (TIMPs) that non-selectively inhibit the function of multiple MMPs via interaction with the MMPs' Zn 2+ -containing catalytic pocket. Recent studies suggest that TIMPs engineered to confer MMP specificity could be exploited for therapeutic purposes, but obtaining specific TIMP-2 inhibitors has proved to be challenging. Here, in an effort to improve MMP specificity, we incorporated the metal-binding non-canonical amino acids (NCAAs), 3,4-dihydroxyphenylalanine (L-DOPA) and (8-hydroxyquinolin-3-yl)alanine (HqAla), into the MMP-inhibitory N-terminal domain of TIMP2 (N-TIMP2) at selected positions that interact with the catalytic Zn 2+ ion (S2, S69, A70, L100) or with a structural Ca 2+ ion (Y36). Evaluation of the inhibitory potency of the NCAA-containing variants towards MMP-2, MMP-9 and MMP-14 in vitro revealed that most showed a significant loss of inhibitory activity towards MMP-14, but not towards MMP-2 and MMP-9, resulting in increased specificity towards the latter proteases. Substitutions at S69 conferred the best improvement in selectivity for both L-DOPA and HqAla variants. Molecular modeling revealed how MMP-2 and MMP-9 are better able to accommodate the bulky NCAA substituents at the intermolecular interface with N-TIMP2. The models also showed that, rather than coordinating to Zn 2+ , the NCAA side chains formed stabilizing polar interactions at the intermolecular interface with MMP-2 and MMP-9. The findings illustrate how incorporation of NCAAs can be used to probe and exploit differential tolerance for substitution within closely related protein-protein complexes to achieve improved specificity.


A Systematic Review and Meta-Analysis Evaluating the Efficacy of a Gluten-Free Diet and a Low FODMAPs Diet in Treating Symptoms of Irritable Bowel Syndrome.
Dietary triggers such as gluten and highly fermentable oligo-, di- and monosaccharides and polyols (FODMAP)-containing foods have been associated with worsening irritable bowel syndrome (IBS) symptoms. However, the true impact of dietary restriction on IBS symptoms has remained unclear. The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) examining the efficacy of exclusion diets (we focused on low FODMAP and gluten-free diets (GFD)) in IBS. We conducted a search of the literature using the electronic databases MEDLINE (1946 to November 2017), EMBASE (1974 to November 2017), Cochrane Central Register of Controlled Trials (November 2017), and Cochrane Database of Systematic Reviews (2005 to November, 2017) for RCTs of exclusion diets in IBS. Two independent reviewers screened citations and a third reviewer resolved disagreement. Two independent reviewers performed eligibility assessment and data abstraction. For inclusion, RCTs that evaluated an exclusion diet versus an alternative or usual diet and assessed improvement in either global IBS symptoms or abdominal pain were required. Data were synthesized as relative risk of symptoms remaining using a random effects model. Quality of evidence was assessed using GRADE methodology. A total of 1726 citations were identified. After full-text screening a total of nine studies were eligible for the systematic review. There were two RCTs of a GFD, involving 111 participants. Both selected patients who responded to a GFD and then randomized them to continue the diet or have the diet "spiked" with gluten. A GFD was associated with reduced global symptoms compared with a control diet (RR = 0.42; 95% CI 0.11 to 1.55; I2 = 88%), although this was not statistically significant. There were seven RCTs comparing a low FODMAP diet with various control interventions in 397 participants. A low FODMAP diet was associated with reduced global symptoms compared with control interventions (RR = 0.69; 95% CI 0.54 to 0.88; I2 = 25%). The three RCTS that compared low FODMAP diet with rigorous control diets had the least heterogeneity between studies, but also the least magnitude of effect. The overall quality of the data was "very low" according to GRADE criteria. There is insufficient evidence to recommend a GFD to reduce IBS symptoms. There is very low quality evidence that a low FODMAP diet is effective in reducing symptoms in IBS patients.


[Pre- and probiotics increase host-cell immunological competence, improve bowel movement, and prevent the onset of colon cancer--an analysis based on movements of intestinal microbiota].
The activation of host immunological competence through improvement of the intestinal environment by pre and probiotics has been reported. NK cell activity, the bactericidal phagocytic activities of neutrophils in peripheral blood, and bowel movements and short chain fatty acids (SCFAs) in intestinal microbiota increase after the administration of pre- and probiotics. SCFAs shift to acidosis of the intestinal environment and advance apoptosis. Furthermore, SCFAs promote intestinal peristaltic movements through SCFA receptors such as GPT 41 and GPR43, located in the intestinal epithelium. It is known that the acceleration of intestinal apoptosis prevents the onset of colon cancer. Improvement of the intestinal environment leads to an increase in host-cell immunological competence, bowel movements, and the prevention of colon cancer.


Maintaining network security: how macromolecular structures cross the peptidoglycan layer.
Peptidoglycan plays a vital role in bacterial physiology, maintaining cell shape and resisting cellular lysis from high internal turgor pressures. Its integrity is carefully maintained by controlled remodeling during growth and division by the coordinated activities of penicillin-binding proteins, lytic transglycosylases, and N-acetylmuramyl-l-alanine amidases. However, its small pore size (∼2 nm) and covalently closed structure make it a formidable barrier to the assembly of large macromolecular cell-envelope-spanning complexes involved in motility and secretion. Here, we review the strategies used by Gram-negative bacteria to assemble such macromolecular complexes across the peptidoglycan layer, while preserving its essential structural role. In addition, we discuss evidence that suggests that peptidoglycan can be integrated into cell-envelope-spanning complexes as a structural and functional extension of their architecture.


The role of reducing intakes of saturated fat in the prevention of cardiovascular disease: where does the evidence stand in 2010?
Current dietary recommendations advise reducing the intake of saturated fatty acids (SFAs) to reduce coronary heart disease (CHD) risk, but recent findings question the role of SFAs. This expert panel reviewed the evidence and reached the following conclusions: the evidence from epidemiologic, clinical, and mechanistic studies is consistent in finding that the risk of CHD is reduced when SFAs are replaced with polyunsaturated fatty acids (PUFAs). In populations who consume a Western diet, the replacement of 1% of energy from SFAs with PUFAs lowers LDL cholesterol and is likely to produce a reduction in CHD incidence of ≥2-3%. No clear benefit of substituting carbohydrates for SFAs has been shown, although there might be a benefit if the carbohydrate is unrefined and has a low glycemic index. Insufficient evidence exists to judge the effect on CHD risk of replacing SFAs with MUFAs. No clear association between SFA intake relative to refined carbohydrates and the risk of insulin resistance and diabetes has been shown. The effect of diet on a single biomarker is insufficient evidence to assess CHD risk. The combination of multiple biomarkers and the use of clinical endpoints could help substantiate the effects on CHD. Furthermore, the effect of particular foods on CHD cannot be predicted solely by their content of total SFAs because individual SFAs may have different cardiovascular effects and major SFA food sources contain other constituents that could influence CHD risk. Research is needed to clarify the role of SFAs compared with specific forms of carbohydrates in CHD risk and to compare specific foods with appropriate alternatives.


Measurement accuracy of FBG used as a surface-bonded strain sensor installed by adhesive.
Material and dimensional properties of surface-bonded fiber Bragg gratings (FBGs) can distort strain measurement, thereby lowering the measurement accuracy. To accurately assess measurement precision and correct obtained strain, a new model, considering reinforcement effects on adhesive and measured object, is proposed in this study, which is verified to be accurate enough by the numerical method. Meanwhile, a theoretical strain correction factor is obtained, which is demonstrated to be significantly sensitive to recoating material and bonding length, as suggested by numerical and experimental results. It is also concluded that a short grating length as well as a thin but large-area (preferably covering the whole FBG) adhesive can enhance the correction precision.


A destructive cascade mediated by CCL2 facilitates prostate cancer growth in bone.
Monocyte chemoattractant protein 1 (CCL2) is a recently identified prominent regulator of prostate cancer growth and metastasis. The purpose of this study was to investigate the mechanistic role of CCL2 in prostate cancer growth in bone. The present study found that CCL2 was up-regulated in osteoblasts (3-fold by PC-3 and 2-fold by VCaP conditioned medium) and endothelial cells (2-fold by PC-3 and VCaP conditioned medium). Parathyroid hormone-related protein (PTHrP) treatment of osteoblastic cells up-regulated CCL2 and was blocked by a PTHrP antagonist, suggesting that prostate cancer-derived PTHrP plays an important role in elevation of osteoblast-derived CCL2. CCL2 indirectly increased blood vessel formation in endothelial cells through vascular endothelial growth factor-A, which was up-regulated 2-fold with administration of CCL2 in prostate cancer cells. In vivo, anti-CCL2 treatment suppressed tumor growth in bone. The decreased tumor burden was associated with decreased bone resorption (serum TRAP5b levels were decreased by 50-60% in anti-CCL2-treated animals from VCaP or PC-3 cell osseous lesions) and microvessel density was decreased by 70% in anti-CCL2-treated animals with bone lesions from VCaP cells. These data suggest that a destructive cascade is driven by tumor cell-derived, PTHrP-mediated induction of CCL2, which facilitates tumor growth via enhanced osteoclastic and endothelial cell activity in bone marrow. Taken together, CCL2 mediates the interaction between tumor-derived factors and host-derived chemokines acting in cooperation to promote skeletal metastasis.


Cirrhosis in a Young Child Due to Fatty Liver; Importance of Early Screening: A Case Report and Review of the Literature.
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is the presence of chronic hepatic steatosis in the absence of infections, steatogenic medication use, metabolic/genetic disorders, malnutrition, or ethanol consumption. NAFLD encompasses a spectrum of liver damage varying from non-alcoholic fatty liver (NAFL) on the most clinically benign end of the spectrum to cirrhosis on the opposite extreme, where most liver-related morbidity and mortality occurs. CASE REPORT We report a case of a 9-year-old boy with history of obesity (BMI 32.1 kg/m² - 99th percentile) and non-alcoholic fatty liver disease, who was referred to our pediatric gastroenterology clinic with a 1-week history of vomiting and right upper-quadrant abdominal pain. A review of the past medical history revealed transaminitis for the last 4 years and a dietary regimen for the last 2 years with poor compliance and follow-up. An extensive workup revealed an SGPT of 327 unit/L, SGOT 186 unit/L, and triglycerides of 208 mg/dL; infectious, metabolic, genetic, and autoimmune etiologies were ruled-out. The median liver stiffness measured by Fibroscan was 14 kPa, consistent with F4 fibrosis, and the cap median value was 271 dB/mW, reflective of S2 steatosis. An ultrasound-guided core liver biopsy revealed steatohepatitis with bridging and encircling fibrosis consistent with early/evolving cirrhosis. CONCLUSIONS Although cirrhosis is rarely seen in pediatric patients with NAFLD, it should always be considered. Secondly, Fibroscan, a non-invasive imaging procedure, is a useful tool to assess the level of fibrosis and steatosis in patients with NAFLD; early evaluation of our patient could potentially have limited the progression to cirrhosis.


The effect of electronic cigarettes on dental enamel color.
The use of electronic cigarettes (ECIGs) has recently increased as an alternative to conventional smoking tobacco products. The literature is scarce on the effects of ECIGs on dental and oral structures. Therefore, the objective of this study was to observe whether ECIG aerosol could alter the color of dental enamel. Sixty-three bovine enamel specimens were randomly separated into groups (n = 7) and treated with aerosols with different e-liquid flavors (neutral, menthol, and tobacco) and nicotine content (0, 12, and 18 mg). The initial color assessment was performed using a spectrophotometer (Easy Shade-Vita). Dental enamel was exposed to 20 cycles of ECIG aerosol in a smoking machine, and the final color was measured. The color change was evaluated using ΔEab, ΔE00, and Whiteness Index (WID ) formulae. Differences in L* a* b* coordinates were calculated, and data were analyzed (two-way ANOVA, uncorrected Fisher's LSD post hoc test, α = 0.05). Luminosity (ΔL) was reduced by aerosols with almost all levels of nicotine content and neutral and menthol flavors. Flavored e-liquids caused more color change (P < .05) according to ΔEab and ΔE00. ΔE values from both formulae exceeded the thresholds for perceptible visual alterations of color. WID increased after ECIGs exposure for menthol and tobacco and decreased for neutral flavors. ECIG aerosol from e-liquids with different nicotine contents and flavors altered enamel color. Menthol and tobacco e-liquids may alter the enamel color decreasing the yellowness of the enamel compared to neutral e-liquid. Electronic cigarettes can cause perceptible changes in tooth color, altering dental esthetics.


Prognosis Driven Rehabilitation After Rotator Cuff Repair Surgery.
Rehabilitation after rotator cuff repair surgery has been the focus of several clinical trials in the past decade. Many illuminate new evidence with regard to the prognosis of structural and functional success after surgery. A selective literature search was performed and personal physiotherapeutic and surgical experiences are reported. Post-operative rehabilitation parameters, namely the decision to delay or allow early range of motion after surgery, play a large role in the overall success after surgery. Using a prognosis driven rehabilitation program offers clinicians a means of prescribing optimal rehabilitation parameters while ensuring structural and functional success. This commentary aims to synthesize the evidence in a spectrum of prognostic factors to guide post-operative rehabilitation. The optimal rehabilitation program after rotator cuff repair surgery is debatable; therefore, we suggest using a spectrum of prognostic factors to determine a rehabilitation program suited to ensure structural and functional success, quickly and safely.


Diagnosis of Duchenne muscular dystrophy: experiences of parents of sufferers.
Sixty nine parents of boys suffering from Duchenne muscular dystrophy were interviewed at home. The interview explored the parents' experiences at the time of their son's diagnosis. Many families had experienced distressing delays (average 2.5 years) between the time they first became aware of symptoms and the time of the diagnosis. On only 18 occasions were both parents told of the diagnosis together. One third of the parents were "not satisfied" with the way the diagnosis had been communicated. Parents want to know as soon as possible if there is something wrong with their child. They should be told the diagnosis together and in private. Full information should be given and a series of contacts should be arranged.


LC method for the therapeutic drug monitoring of lamotrigine: evaluation of the assay performance and validation of its application in the routine area.
An accurate and precise high-performance liquid chromatographic method using diode array detection for the determination of lamotrigine in human plasma has been developed and validated for use in pharmacokinetic studies. A validation strategy based on the accuracy profiles was used to select the most appropriate regression model and to determine the limits of quantitation as well as the concentration range. On the other hand, the present paper also shows this validation approach as a suitable tool to guaranty the quality of the results obtained by the use of the analytical validated methodology for plasma lamotrigine determination in a routine setting and to ensure the risk of obtaining the future measurements outside the previously fixed acceptance limits.


Dynamic Ins2 Gene Activity Defines β-Cell Maturity States.
Transcriptional and functional cellular specialization has been described for insulin-secreting β-cells of the endocrine pancreas. However, it is not clear whether β-cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments using FACS and single-cell RNA sequencing, in β-cells from Ins2GFP knockin mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ∼25% of β-cells exhibited significantly higher activity at the evolutionarily conserved insulin gene, Ins2. Live cell imaging over days captured Ins2 gene activity dynamics in single β-cells. Autocorrelation analysis revealed a subset of oscillating cells, with mean oscillation periods of 17 h. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single-cell RNA sequencing showed that Ins2(GFP)HIGH β-cells were enriched for markers of β-cell maturity. Ins2(GFP)HIGH β-cells were also significantly less viable at all glucose concentrations and in the context of endoplasmic reticulum stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human β-cells, can be accounted for by dynamic states of insulin gene activity.


Phytoplasma SAP11 effector destabilization of TCP transcription factors differentially impact development and defence of Arabidopsis versus maize.
Phytoplasmas are insect-transmitted bacterial pathogens that colonize a wide range of plant species, including vegetable and cereal crops, and herbaceous and woody ornamentals. Phytoplasma-infected plants often show dramatic symptoms, including proliferation of shoots (witch's brooms), changes in leaf shapes and production of green sterile flowers (phyllody). Aster Yellows phytoplasma Witches' Broom (AY-WB) infects dicots and its effector, secreted AYWB protein 11 (SAP11), was shown to be responsible for the induction of shoot proliferation and leaf shape changes of plants. SAP11 acts by destabilizing TEOSINTE BRANCHED 1-CYCLOIDEA-PROLIFERATING CELL FACTOR (TCP) transcription factors, particularly the class II TCPs of the CYCLOIDEA/TEOSINTE BRANCHED 1 (CYC/TB1) and CINCINNATA (CIN)-TCP clades. SAP11 homologs are also present in phytoplasmas that cause economic yield losses in monocot crops, such as maize, wheat and coconut. Here we show that a SAP11 homolog of Maize Bushy Stunt Phytoplasma (MBSP), which has a range primarily restricted to maize, destabilizes specifically TB1/CYC TCPs. SAP11MBSP and SAP11AYWB both induce axillary branching and SAP11AYWB also alters leaf development of Arabidopsis thaliana and maize. However, only in maize, SAP11MBSP prevents female inflorescence development, phenocopying maize tb1 lines, whereas SAP11AYWB prevents male inflorescence development and induces feminization of tassels. SAP11AYWB promotes fecundity of the AY-WB leafhopper vector on A. thaliana and modulates the expression of A. thaliana leaf defence response genes that are induced by this leafhopper, in contrast to SAP11MBSP. Neither of the SAP11 effectors promote fecundity of AY-WB and MBSP leafhopper vectors on maize. These data provide evidence that class II TCPs have overlapping but also distinct roles in regulating development and defence in a dicot and a monocot plant species that is likely to shape SAP11 effector evolution depending on the phytoplasma host range.


Detection of a cfr(B) Variant in German Enterococcus faecium Clinical Isolates and the Impact on Linezolid Resistance in Enterococcus spp.
The National Reference Centre for Staphylococci and Enterococci in Germany has received an increasing number of clinical linezolid-resistant E. faecium isolates in recent years. Five isolates harbored a cfr(B) variant gene locus the product of which is capable of conferring linezolid resistance. The cfr(B)-like methyltransferase gene was also detected in Clostridium difficile. Antimicrobial susceptibility was determined for cfr(B)-positive and linezolid-resistant E. faecium isolates and two isogenic C. difficile strains. All strains were subjected to whole genome sequencing and analyzed with respect to mutations in the 23S rDNA, rplC, rplD and rplV genes and integration sites of the cfr(B) variant locus. To evaluate methyltransferase function, the cfr(B) variant of Enterococcus and Clostridium was expressed in both E. coli and Enterococcus spp. Ribosomal target site mutations were detected in E. faecium strains but absent in clostridia. Sequencing revealed 99.9% identity between cfr(B) of Enterococcus and cfr of Clostridium. The methyltransferase gene is encoded by transposon Tn6218 which was present in C. difficile Ox3196, truncated in some E. faecium and absent in C. difficile Ox3206. The latter finding explains the lack of linezolid and chloramphenicol resistance in C. difficile Ox3206 and demonstrates for the first time a direct correlation of elevated linezolid MICs in C. difficile upon cfr acquisition. Tn6218 insertion sites revealed novel target loci for integration, both within the bacterial chromosome and as an integral part of plasmids. Importantly, the very first plasmid-association of a cfr(B) variant was observed. Although we failed to measure cfr(B)-mediated resistance in transformed laboratory strains the occurrence of the multidrug resistance gene cfr on putatively highly mobile and/or extrachromosomal DNA in clinical isolates is worrisome with respect to dissemination of antibiotic resistances.


Curcumin Inhibits Non-Small Cell Lung Cancer Cells Metastasis through the Adiponectin/NF-κb/MMPs Signaling Pathway.
Adipose tissue is now considered as an endocrine organ involved in metabolic and inflammatory reactions. Adiponectin, a 244-amino acid peptide hormone, is associated with insulin resistance and carcinogenesis. Curcumin (diferuloylmethane) is the principal curcuminoid of the popular Indian spice, turmeric. Curcumin possesses antitumor effects, including the inhibition of neovascularization and regulation of cell cycle and apoptosis. However, the effects of adiponectin and curcumin on non-small cell lung cancer (NSCLC) remain unclear. In this study, we evaluated the expression of adiponectin in paired tumors and normal lung tissues from 77 patients with NSCLC using real-time polymerase chain reaction, western blotting, and immunohistochemistry. Kaplan-Meier survival analysis showed that patients with low adiponectin expression ratio (<1) had significantly longer survival time than those with high expression ratio (>1) (p = 0.015). Curcumin inhibited the migratory and invasive ability of A549 cells via the inhibition of adiponectin expression by blocking the adiponectin receptor 1. Curcumin treatment also inhibited the in vivo tumor growth of A549 cells and adiponectin expression. These results suggest that adiponectin can be a prognostic indicator of NSCLC. The effect of curcumin in decreasing the migratory and invasive ability of A549 cells by inhibiting adiponectin expression is probably mediated through NF-κB/MMP pathways. Curcumin could be an important potential adjuvant therapeutic agent for lung cancer in the future.


Cellular responses to Staphylococcus aureus alpha-toxin in chronic rhinosinusitis with nasal polyps.
In contrast to Staphylococcus aureus-derived superantigenic exotoxins, the role of non-superantigenic exotoxins in the pathogenesis of eosinophilic airway diseases remains obscure. We sought to characterize S. aureus alpha-toxin-induced cellular responses in chronic rhinosinusitis with nasal polyps (CRSwNP). Dispersed nasal polyp cells and uncinate tissue cells were prepared from patients with CRS with and without nasal polyps, respectively. Cells were incubated with various concentrations of alpha-toxin or staphylococcal enterotoxin B and then the levels of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in the cell supernatants were determined. The pathophysiological significance of alpha-toxin-induced cytokine production was also determined including radiological severity of rhinosinusitis, tissue and blood eosinophilia, serum total IgE level, and 1-s forced expiratory volume/forced vital capacity ratio (FEV1/FVC). Nasal polyp cells produced substantial amounts of IL-5, IL-13, IFN-γ, IL-17A, and IL-10 in response to alpha-toxin. Cytokine production was higher in nasal polyp cells than in uncinate tissue cells. The potency of alpha-toxin in stimulating IL-5, IL-13, and IL-10 production was comparable to that of enterotoxin. Alpha-toxin-induced IFN-γ, IL-17A, and IL-10 production significantly and negatively correlated with the degree of eosinophil infiltration into nasal polyps. Conversely, alpha-toxin-induced IFN-γ and IL-10 production significantly and positively correlated with FEV1/FVC. IL-10 production was significantly lower in asthmatic patients compared to non-asthmatics S. aureus-derived alpha-toxin can provoke cellular responses in nasal polyps. These responses, especially failure to synthesize IL-10, may play a role in the pathophysiology of CRSwNP.


A sound approach: Exploring a rapid and non-destructive ultrasonic pulse echo system for vegetable oils characterization.
A rapid and non-destructive ultrasonic pulse echo system was developed for vegetable oils characterization. To understand the differences in the ultrasonic properties of the oils, physical traits, such as their viscosity and density, were related to the ultrasonic data. In turn, these physical traits were correlated with the fatty acid compositions of the oils. Eighty oil samples, including 30 extra virgin olive oil (EVOO), 15 refined olive oil, 15 pomace olive oil, 10 rapeseed oil, 5 sunflower oil and 5 peanut oil samples, were analysed for their sound properties, viscosities, densities and fatty acid compositions. It was observed that the ultrasonic velocity of EVOO decreased linearly with increase in temperature, the temperature coefficient of ultrasonic velocity in EVOO was -2.92 m·s-1·°C-1. The ultrasonic velocity of EVOO (1453 ± 2 m/s) differed significantly from those of pomace olive oil and the oils of other botanical origin, but not from the velocity of refined olive oil. Ultrasonic velocity was positively correlated with the density and negatively correlated with the viscosity of the oils. The higher density and lower viscosity of the oils were in turn related to a higher unsaturation degree of the oils. Hence, oils with a higher proportion of unsaturated fat present higher densities and lower viscosities, which resulted in higher ultrasonic velocity values. Ultrasonic measurements allow rapid, non-destructive analysis, and this first application for characterization of these oils is promising.


1,8-cineole, a TRPM8 agonist, is a novel natural antagonist of human TRPA1.
Essential oils are often used in alternative medicine as analgesic and anti-inflammatory remedies. However, the specific compounds that confer the effects of essential oils and the molecular mechanisms are largely unknown. TRPM8 is a thermosensitive receptor that detects cool temperatures and menthol whereas TRPA1 is a sensor of noxious cold. Ideally, an effective analgesic compound would activate TRPM8 and inhibit TRPA1. We screened essential oils and fragrance chemicals showing a high ratio of human TRPM8-activating ability versus human TRPA1-activating ability using a Ca2+-imaging method, and identified 1,8-cineole in eucalyptus oil as particularly effective. Patch-clamp experiments confirmed that 1,8-cineole evoked inward currents in HEK293T cells expressing human TRPM8, but not human TRPA1. In addition, 1,8-cineole inhibited human TRPA1 currents activated by allyl isothiocyanate, menthol, fulfenamic acid or octanol in a dose-dependent manner. Furthermore, in vivo sensory irritation tests showed that 1,8-cineole conferred an analgesic effect on sensory irritation produced by TRPA1 agonists octanol and menthol. Surprisingly, 1,4-cineole, which is structurally similar and also present in eucalyptus oil, activated both human TRPM8 and human TRPA1. 1,8-cineole is a rare natural antagonist of human TRPA1 that has analgesic and anti-inflammatory effects possibly due to its inhibition of TRPA1.


The spectrum of opportunistic diseases complicating sarcoidosis.
Sarcoidosis is an inflammatory disease marked by a paradoxical immune status. The anergic state, which results from various immune defects, contrasts with the inflammatory formation of granulomas. Sarcoidosis patients may be at risk for opportunistic infections (OIs) and a substantial number of cases have been reported, even in untreated sarcoidosis. It is not clear how OIs in patients with sarcoidosis are different from other groups at risk. In this review, we discuss the most common OIs: mycobacterial infection (including tuberculosis), cryptococcosis, progressive multifocal leukoencephalopathy, and aspergillosis. Unlike peripheral lymphocytopenia, corticosteroids are a major risk factor for OIs but the occurrence of Ols in untreated patients suggests more complex predisposing mechanisms. Opportunistic infections presenting with extrapulmonary features are often misdiagnosed as new localizations of sarcoidosis. Aspergillomas mostly develop on fibrocystic lungs. Overall, physicians should be aware of the possible occurrence of OIs during sarcoidosis, even in untreated patients.


Alzheimer's disease-like pathology in senescence-accelerated OXYS rats can be partially retarded with mitochondria-targeted antioxidant SkQ1.
We previously showed that mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) at nanomolar concentrations is capable of preventing and slowing down some cerebral dysfunctions in accelerated-senescence OXYS rats. Here we demonstrate that OXYS rats develop behavior, learning, and memory deficits against a background of neurodegeneration signs detected by magnetic resonance tomography and amyloid-β (Aβ) pathology similar to those seen in Alzheimer's disease (AD). Long-term treatment with SkQ1 (250 nmol/kg body weight daily from the age of 1.5 to 23 months) reduced the age-related alterations in behavior and spatial memory deficit in Morris water maze in OXYS and Wistar rats. Furthermore, this is the first report that SkQ1 treatment slows down pathological accumulation of AβPP, Aβ, and hyperphosphorylation of tau-protein in OXYS rats, as well as age-dependent changes in healthy Wistar rats. Our results support the possibility of using the OXYS strain as a rat model of AD-like pathology. It seems probable that the mitochondria-targeted antioxidant SkQ1 can be a good prophylactic strategy to maintain brain health and to treat AD.


Targeting cancer stem cells with sulforaphane, a dietary component from broccoli and broccoli sprouts.
Many studies have supported the protective effects of broccoli and broccoli sprouts against cancer. The chemopreventive properties of sulforaphane, which is derived from the principal glucosinolate of broccoli and broccoli sprouts, have been extensively studied. Recent research into the effects of sulforaphane on cancer stem cells (CSCs) has drawn lots of interest. CSCs are suggested to be responsible for initiating and maintaining cancer, and to contribute to recurrence and drug resistance. A number of studies have indicated that sulforaphane may target CSCs in different types of cancer through modulation of NF-κB, SHH, epithelial-mesenchymal transition and Wnt/β-catenin pathways. Combination therapy with sulforaphane and chemotherapy in preclinical settings has shown promising results. In this article, we focus on the effects of sulforaphane on CSCs and self-renewal pathways, as well as giving a brief review of recent human studies using broccoli sprout preparations.


Modulators of the hedgehog signaling pathway.
Since its discovery by C. Nüsslein-Volhard and E. F. Wieschaus, hedgehog (hh) signaling has come a long way. Today it is regarded as a key regulator in embryogenesis where it governs processes like cell proliferation, differentiation, and tissue patterning. Furthermore, in adults it is involved in the maintenance of stem cells, and in tissue repair and regeneration. But hh signaling has a second-much darker-face: it plays an important role in several types of human cancers where it promotes growth and enables proliferation of tumor stem cells. The etiology of medulloblastoma and basal cell carcinoma is tightly linked to aberrant hh activity, but also cancers of the prostate, the pancreas, the colon, the breasts, rhabdomyosarcoma, and leukemia, are dependent on irregular hh activity. Recent clinical studies have shown that hh signaling can be the basis of an important new class of therapeutic agents with far-reaching implications in oncology. Thus, modulation of hh signaling by means of small molecules has emerged as a valuable tool in combating these hh-dependent cancers. Cyclopamine, a unique natural product with a fascinating history, was the first identified inhibitor of hh signaling and its story is closely linked to the progress in the whole field. In this review we will trace the story of cyclopamine, give an overview on the biological modes of hh signaling both in untransformed and malignant cells, and finally present potent modulators of the hh pathway-many of them already in clinical studies. For more than 30 years now the knowledge on hh signaling has grown steadily-an end to this development is far from being conceivable.


The cross-cultural nature of the relationship between schizotypy and mixed-handedness.
Positive schizotypy is associated with non-right-handedness, which includes left- and mixed-handedness. However, because the underlying mechanisms might be different, it is important to examine whether both left- and mixed-handedness are associated with a high incidence of schizotypy. During 2009-2010, we used both the Perceptual Aberration Scale and Schizotypal Personality Questionnaire to assess 1315 undergraduate students in Taiwan for schizotypy and the Annett handedness questionnaire to assess handedness. Among the three-way classifications based on Annett's grouping, the fully left-handed group appeared to have the lowest score of positive schizotypy; next was the fully right-handed group and then the mixed-handed. Among the three-way classifications driven from cluster analysis, mixed-handers showed highest score of positive schizotypy. When handedness was treated continuously, both direction (e.g., Hand Preference Index) and consistency (e.g., Either hand use score) indicators were significantly correlated with schizotypy. The results of regression analyses showed that the quadratic handedness measure were negatively associated with schizotypy. The results remained similar after correcting for social pressure on left-handedness. In conclusion, the relationship between schizotypy and mixed-handedness appears to be cross-cultural. The dichotomous classification of handedness, right- vs. non-right-handedness, appears to be insufficient. Additional studies on the distinct mechanisms of mixed- and left-handedness are warranted.


Repeated bouts of eccentrically biased endurance exercise stimulate salivary IgA secretion rate.
To determine the salivary secretory immunoglobulin A (sIgA) response to repeated bouts of unaccustomed, downhill running (eccentrically biased) and examine potential protective immunological adaption from a repeated bout effect. Eleven active but untrained males (age: 19.7±0.4 years; VO2peak: 47.8± 3.6 ml · kg(-1) · min (-1)) performed two 60 min bouts (Run 1 and Run 2) of downhill running (-13.5% gradient), separated by 14 days, at a speed eliciting 75% of their VO2peak on a level grade. Saliva samples were collected before (baseline), immediately post exercise (IPE), and every hour for 12 h and every 24 h for 6 days after each run. Salivary sIgA concentration was measured and sIgA secretion rate was calculated. Results were analysed using repeated measures ANOVA (12 h period: 2x14; 24 h intervals: 2x7; p ≤ 0.05) with Tukey post-hoc tests where appropriate. Results are reported as means ± SE. There was a significant (p < 0.0001) interaction effect for sIgA secretion rate, IPE, with higher values after Run 2, as well as a significant (p < 0.01) time effect with elevated levels IPE and between 24 h and 144 h. There was a run effect (p < 0.0001), with the sIgA secretion rate significantly higher after Run 2. Repeated bouts of unaccustomed, eccentrically biased exercise induced alterations in the salivary sIgA secretion rate. This may serve as a protective mucosal adaptation to exercise-induced tissue damage.


Tumorigenesis in Mlh1 and Mlh1/Apc1638N mutant mice.
An3 1 KAL I MutL homologue 1 (MLH1) is a member of the family of proteins required for DNA mismatch repair. Germ-line mutations in MLH1 lead to the cancer susceptibility syndrome hereditary nonpolyposis colorectal cancer (HNPCC). We generated mice carrying a null mutation in the Mlh1 gene. We showed that mice heterozygous and homozygous for the Mlh1 gene are predisposed to developing tumors of the gastrointestinal (GI) tract, lymphomas, and a number of other tumor types. We also examined the role of adenomatous polyposis coli gene (Apc) gene mutations in the GI tumors of Mlh1 mutant mice by different methods and showed that the GI tumors in Mlh1 mice express little or no adenomatous polyposis coli protein. When an Apc gene mutation was bred into the Mlh1 mutant mice, the GI tumor incidence increased 40-100-fold. The wild-type Apc allele in these tumors was found to contain mutations. Together, these results show that we have developed two mouse models for human HNPCC and that the mechanisms of tumor development in the GI tract of these mice involve loss of Apc gene function in a manner very similar to that seen in the GI tumors of HNPCC.


DNA interstrand crosslink repair during G1 involves nucleotide excision repair and DNA polymerase zeta.
The repair mechanisms acting on DNA interstrand crosslinks (ICLs) in eukaryotes are poorly understood. Here, we provide evidence for a pathway of ICL processing that uses components from both nucleotide excision repair (NER) and translesion synthesis (TLS) and predominates during the G1 phase of the yeast cell cycle. Our results suggest that repair is initiated by the NER apparatus and is followed by a thwarted attempt at gap-filling by the replicative Polymerase delta, which likely stalls at the site of the remaining crosslinked oligonucleotide. This in turn leads to ubiquitination of PCNA and recruitment of the damage-tolerant Polymerase zeta that can perform TLS. The ICL repair factor Pso2 acts downstream of the incision step and is not required for Polymerase zeta activation. We show that this combination of NER and TLS is the only pathway of ICL repair available to the cell in G1 phase and is essential for viability in the presence of DNA crosslinks.


Confocal fluorescence microscope with dual-axis architecture and biaxial postobjective scanning.
We present a novel confocal microscope that has dual-axis architecture and biaxial postobjective scanning for the collection of fluorescence images from biological specimens. This design uses two low-numerical-aperture lenses to achieve high axial resolution and long working distance, and the scanning mirror located distal to the lenses rotates along the orthogonal axes to produce arc-surface images over a large field of view (FOV). With fiber optic coupling, this microscope can potentially be scaled down to millimeter dimensions via microelectromechanical systems (MEMS) technology. We demonstrate a benchtop prototype with a spatial resolution < or =4.4 microm that collects fluorescence images with a high SNR and a good contrast ratio from specimens expressing GFP. Furthermore, the scanning mechanism produces only small differences in aberrations over the image FOV. These results demonstrate proof of concept of the dual-axis confocal architecture for in vivo molecular and cellular imaging.


Antimicrobial lock therapy in central-line associated bloodstream infections: a systematic review.
Antimicrobial lock therapy (ALT) seems a promising approach for treatment of central line associated bloodstream infections (CLABSI). The recent introduction of molecules such as daptomycin and tigecycline, alone or in combination with other molecules, improved chances of efficacy of ALT, due to their activity on the bacterial biofilm. Our aim was to review the literature concerning ALT for CLABSI, including data concerning novel molecules. We included case-control studies evaluating two or more molecules as ALT in central venous catheter infections extracted from the Medline database. Among 221 available articles in Pubmed, 54 were selected for their particular interest concerning ALT. Incidence of CLABSI is high worldwide. Mechanisms of catheter infection include contamination by skin bacteria, hand contamination and hematogenous diffusion. Catheter-infection is associated with biofilm formation, which reduces the efficacy of ALT. The most promising situation for ALT to succeed in salvaging a catheter appears to be coagulase-negative Staphylococcus infection, which is the main causative agent of CLABSI. Daptomycin, Tigecycline, Ethanol and Taurolidine appear as the best options for treating CLABSI; data are mostly available for Daptomycin, which showed, alone or associated with Rifampin, good in vitro potency on biofilm, but few in vivo data exist on efficacy. The introduction of novel molecules has increased chances of catheter salvage with ALT in case of CLABSI, but further in vivo studies are needed.


Recent advances in cross-cultural measurement in psychiatric epidemiology: utilizing 'what matters most' to identify culture-specific aspects of stigma.
While stigma measurement across cultures has assumed growing importance in psychiatric epidemiology, it is unknown to what extent concepts arising from culture have been incorporated. We utilize a formulation of culture-as the everyday interactions that 'matter most' to individuals within a cultural group-to identify culturally-specific stigma dynamics relevant to measurement. A systematic literature review from January 1990 to September 2012 was conducted using PsycINFO, Medline and Google Scholar to identify articles studying: (i) mental health stigma-related concepts; (ii) ≥ 1 non-Western European cultural group. From 5292 abstracts, 196 empirical articles were located. The vast majority of studies (77%) utilized adaptations of existing Western-developed stigma measures to new cultural groups. Extremely few studies (2.0%) featured quantitative stigma measures derived within a non-Western European cultural group. A sizeable amount (16.8%) of studies employed qualitative methods to identify culture-specific stigma processes. The 'what matters most' perspective identified cultural ideals of the everyday activities that comprise 'personhood' of 'preserving lineage' among specific Asian groups, 'fighting hard to overcome problems and taking advantage of immigration opportunities' among specific Latino-American groups, and 'establishing trust among religious institutions due to institutional discrimination' among African-American groups. These essential cultural interactions shaped culture-specific stigma manifestations. Mixed method studies (3.6%) corroborated these qualitative results. Quantitatively-derived, culturally-specific stigma measures were lacking. Further, the vast majority of qualitative studies on stigma were conducted without using stigma-specific frameworks. We propose the 'what matters most' approach to address this key issue in future research.


Oleic acid and ergosterol supplementation mitigates oxidative stress in wine strains of Saccharomyces cerevisiae.
During fermentation of high-sugar-containing medium lacking lipid nutrients, wine yeasts undergo oxidative stress and oxidative damage to cell membranes and proteins. Considering that cell membranes are important stress sensors, and that under hypoxic conditions wine yeasts modulate cell membranes composition by incorporating lipids available in the growth medium, in the present work, the effects of lipid nutrition on wine yeast oxidative stress response were evaluated on two strains of Saccharomyces cerevisiae. Biomarkers of oxidative stress, oxidative damage and antioxidant response were evaluated together with viability and acetic acid production during fermentation of a synthetic must lacking lipid nutrients as compared to added oleic acid and ergosterol. The results show that the availability of lipid nutrients causes a significant reduction in the intracellular content of reactive oxygen species and in the oxidative damage to membranes and proteins, as indicated by flow cytometry of cells stained with dihydroethidum (DHE) and propidium iodide (PI) and by Western blot of protein carbonyls. Accordingly, lipid nutrients feeding results in the increase in cell viability and superoxide activity, and the reduction in trehalose accumulation, proteinase A activity and production of acetic acid. In summary, these results are compatible with the hypothesis that the supplementation of lipid nutrients mitigates oxidative stress and oxidative damage in wine strains of S. cerevisiae during growth under unfavourable conditions.


Prenatal and neonatal risk factors for childhood myeloid leukemia.
Information about the etiology of childhood myeloid leukemia is limited. A population-based nested case-control study of prenatal and neonatal risk factors for childhood myeloid leukemia was performed with the use of the Swedish National Cancer Register and the Swedish Birth Register. A total of 98 cases of myeloid leukemia were identified in successive birth cohorts from 1973 through 1989. From the Birth Register, five controls were matched to each case. Fourteen of the 98 cases with myeloid leukemia and none of the controls had Down syndrome [odds ratio (OR) = infinity; 95% confidence interval (CI) = 21.0-infinity]. The risk for myeloid leukemia also increased among children who had physiological jaundice (OR = 2.5; 95% CI = 1.2-5.0; children who had been treated with phototherapy (OR = 7.5; 95% CI = 1.8-31.9); or who had been treated in an incubator (OR = 3.5; 95% CI = 1.2-10.2). Excluding cases with Down syndrome, however, decreased these risks, so that their 95% lower confidence interval included the no-effect value. Maternal age < 20 years old (OR = 2.5; 95% CI = 1.1-6.0), hypertension (OR = 2.4; 95% CI = 1.2-5.0), Cesarean section (OR = 2.5; 95% CI = 1.3-4.9), maternal smoking (OR = 2.4; 95% CI = 0.9-6.5), and being one of a multiple birth (OR = 3.6; 95% CI = 1.1-11.3) increased the risk for myeloid leukemia among those without Down syndrome. When the analyses were repeated, by restricting the cases to those with acute myeloid leukemia, the risk associated with young maternal age declined and became nonsignificant.(ABSTRACT TRUNCATED AT 250 WORDS)


Longitudinal assessment of high blood pressure in children with nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) affects 9.6% of children and may put these children at elevated risk of high blood pressure and subsequent cardiovascular morbidity and mortality. Therefore, we sought to determine the prevalence of and risk factors for high blood pressure in children with NAFLD. Cohort study performed by the NIDDK NASH Clinical Research Network. There were 484 children with NAFLD ages 2 to 17 at enrollment; 382 children were assessed both at enrollment and 48 weeks afterwards. The main outcomes were high blood pressure at baseline and persistent high blood pressure at both baseline and 48 weeks. Prevalence of high blood pressure at baseline was 35.8% and prevalence of persistent high blood pressure was 21.4%. Children with high blood pressure were significantly more likely to have worse steatosis than children without high blood pressure (mild 19.8% vs. 34.2%, moderate 35.0% vs. 30.7%, severe 45.2% vs. 35.1%; P = 0.003). Higher body mass index, low-density lipoprotein, and uric acid were independent risk factors for high blood pressure (Odds Ratios: 1.10 per kg/m2, 1.09 per 10 mg/dL, 1.25 per mg/dL, respectively). Compared to boys, girls with NAFLD were significantly more likely to have persistent high blood pressure (28.4% vs.18.9%; P = 0.05). In conclusion, NAFLD is a common clinical problem that places children at substantial risk for high blood pressure, which may often go undiagnosed. Thus blood pressure evaluation, control, and monitoring should be an integral component of the clinical management of children with NAFLD.


Abortion counselling and the informed consent dilemma.
An obstacle to abortion exists in the form of abortion 'counselling' that discourages women from terminating their pregnancies. This counselling involves providing information about the procedure that tends to create feelings of guilt, anxiety and strong emotional reactions to the recognizable form of a human fetus. Instances of such counselling that involve false or misleading information are clearly unethical and do not prompt much philosophical reflection, but the prospect of truthful abortion counselling draws attention to a delicate issue for healthcare professionals seeking to respect patient autonomy. This is the fact that even accurate information about abortion procedures can have intimidating effects on women seeking to terminate a pregnancy. Consequently, a dilemma arises regarding the information that one ought to provide to patients considering an abortion: on the one hand, the mere offering of certain types of information can lead to intimidation; on the other hand, withholding information that some patients would consider relevant to their decision-making is objectionably paternalistic on any standard account of the physician-patient relationship. This is an unsettling conclusion for the possibility of setting fixed professional guidelines regarding the counselling offered to women who are considering abortion. Thus, abortion ought to be viewed as an illuminating example of a procedure for which the process of securing informed consent ought to be highly context-sensitive and responsive to the needs of each individual patient. This result underscores the need for health care professionals to cultivate trusting relationships with patients and to develop finely tuned powers of practical judgment.


Modulation of annexin I and cyclooxygenase-2 in smokeless tobacco-induced inflammation and oral cancer.
Smokeless tobacco usage is a growing public health concern in the United States. Epidemiological evidence shows a correlation between use of chewing tobacco, lesions of the oral cavity and the incidence of oral and other cancers. However, the molecular mechanism(s) underlying the oral cancer causation are yet unknown. The major constituents of tobacco are known to cause inflammation, DNA damage and cell death. We propose modulation of inflammatory mediators by smokeless tobacco as a novel mechanism for the development of oral cancer. Exposure of hamster cheek pouches to smokeless tobacco extract (STE) results in cleavage of the anti-inflammatory peptide from the anti-inflammatory protein annexin I. Annexin I is produced from cultured oral epithelial cells and its expression is modulated by STE. We further show that STE exposure of oral epithelial cells results in upregulation of the pro-inflammatory protein COX-2. COX-2 is also upregulated in immortalized human oral epithelial cells, human squamous cell carcinoma cells and in primary tumor tissues from head and neck cancer. In summary, we find that exposure to smokeless tobacco results in loss of the anti-inflammatory activity of annexin I and upregulation of the pro-inflammatory COX-2 in oral cells. The dual effect of these regulatory events leads the cells down the carcinogenic pathway.


Behavior of a viscoelastic valveless pump: a simple theory with experimental validation.
A valveless pump generates a unidirectional net flow of fluid around a closed loop of soft viscoelastic tubing that is rhythmically compressed at one point. The tubing must have at least two sections with two different stiffnesses. When a short segment of the tube is squeezed asymmetrically at certain frequencies, net flow of fluid around the loop can occur without valves. Partial differential equations for the pressures, volumes, and flows define a simple one-dimensional model of such a pump, based upon elementary physical principles. Numerical computations on a personal computer can predict measured net flows. Net flow varies with the frequency and waveform of compression used to excite the pump, as well as with the site of compression and the stiffness and viscosity of the tubing. Net flows on the order of 1 ml/sec are obtained in a water-filled loop including 46 cm of stiffer plastic (Tygon) laboratory tubing and 70 cm of softer latex rubber tubing. The heretofore mysterious phenomenon of valveless pumping can be described in terms of classical Newtonian physics, in which viscous damping in the walls of the pump is included. Studying valveless pumps in the laboratory and modeling their behavior numerically provides a low-cost, engaging, and instructive exercise for research and teaching in biomedical engineering.


Trend and Outcomes of Video Laryngoscope Use Across PICUs.
Video (indirect) laryngoscopy is used as a primary tracheal intubation device for difficult airways in emergency departments and in adult ICUs. The use and outcomes of video laryngoscopy compared with direct laryngoscopy has not been quantified in PICUs or cardiac ICUs. Retrospective review of prospectively collected observational data from a multicenter tracheal intubation database (National Emergency Airway Registry for Children) from July 2010 to June 2015. Thirty-six PICUs/cardiac ICUs across the United States, Canada, Japan, New Zealand, and Singapore. Any patient admitted to a PICU or a pediatric cardiac ICU and undergoing tracheal intubation. Use of direct laryngoscopy versus video laryngoscopy for tracheal intubation. There were 8,875 tracheal intubations reported in the National Emergency Airway Registry for Children database, including 7,947 (89.5%) tracheal intubations performed using direct laryngoscopy and 928 (10.5%) tracheal intubations performed using video laryngoscopy. Wide variability in video laryngoscopy use exists across PICUs (median, 2.6%; range, 0-55%). Video laryngoscopy was more often used in older children (p < 0.001), in children with history of a difficult airway (p = 0.01), in children intubated for ventilatory failure (p < 0.001), and to facilitate the completion of an elective procedure (p = 0.048). After adjusting for patient-level covariates, a secular trend, and site-level variance, the use of video laryngoscopy significantly increased over a 5-year period compared with fiscal year 2011 (odds ratio, 6.7; 95% CI, 1.7-26.8 for fiscal year 2014 and odds ratio, 11.2; 95% CI, 3.2-38.9 for fiscal year 2015). The use of video laryngoscopy was independently associated with a lower occurrence of tracheal intubation adverse events (adjusted odds ratio, 0.57; 95% CI, 0.42-0.77; p < 0.001) but not with a lower occurrence of severe tracheal intubation adverse events (adjusted odds ratio, 0.86; 95% CI, 0.56-1.32; p = 0.49) or fewer multiple attempts at endotracheal intubation (adjusted odds ratio, 0.93; 95% CI, 0.71-1.22; p = 0.59). Using National Emergency Airway Registry for Children data, we described patient-centered adverse outcomes associated with video laryngoscopy compared with direct laryngoscopy for tracheal intubation in the largest reported international cohort of children to date. Data from this study may be used to design sufficiently powered prospective studies comparing patient-centered outcomes for video laryngoscopy versus direct laryngoscopy during endotracheal intubation.


Validation of bovine oestrous-specific synthetic molecules with trained scent dogs; similarities between natural and synthetic oestrous smell.
Oestrous detection is crucial for successful dairy cow reproduction. Bulls identify cows in oestrus by oestrous-specific odours especially in urine and vaginal fluid. These have been used to train dogs to detect cows in heat. To improve and simplify the dog training, a spray containing synthetic oestrous molecules was developed. The objective of this study was to test the spray on similarities to the natural substance thus to assess its suitability as a training substance for heat detection dogs. Ten privately owned dogs of various breeds were trained. Dogs should be trained either to differentiate natural vaginal fluid from cows in oestrus and dioestrus (n = 5), or spray with or without synthetic oestrous molecules (n = 5). Dogs trained on natural fluid and on spray could detect the oestrous odour they had been trained on with an overall accuracy of 69.0% and 82.4%, respectively (p = 0.019). To validate the synthetic molecules, dogs trained with synthetic molecules had to detect oestrous odour in natural fluid without further training (accuracy 37.6%). Dogs trained on natural fluid detected the synthetic molecules with an accuracy of 50.0% (50% vs 37.4%, p < 0.05). Dogs can recognize natural vaginal fluid from cows in oestrus after they have been trained with synthetic oestrous molecules, but accuracy needs to be improved.


Changing rate of urban creep and urban expansion over time and its impact upon the hydrologic response of a catchment.
Most previous quantitative research conducted on urban creep and urban expansion has focused on small areas, short time periods, case studies with fairly uniform housing stock and demographic makeup, and the characterisation of urban creep and expansion exclusively in terms of impervious area changes without quantification of the consequential hydrological impact, i.e., increase in surface runoff volume and peak flows in a catchment. This study, using satellite imagery, catchment characteristics data, geographic information system and hydrologic modelling, presents, for the first time, a long-term analysis of urban creep and expansion. The case study is the Ouseburn catchment in Newcastle upon Tyne, a wide-ranging catchment made up of rural, suburban and urban areas, over a period of seven decades. The rate of increase of impervious surfaces is found not to be constant in time; the significant impact of this variation on the catchment's hydrologic response is quantified. This has overall caused a substantial flow volume increase in the Ouseburn over the study period, e.g. 48% for a 1 in 5 years rainfall event. The conclusions obtained are likely representative of many large towns and cities across the United Kingdom and the methodology presented can be easily replicated in other study areas.


Studies on bromobenzene-induced hepatotoxicity using in vivo MR microscopy with surgically implanted RF coils.
Using surgically implanted RF coils at 300 MHz, three-dimensional microscopic MR images of rat liver were obtained in vivo to follow the development of pathology induced by bromobenzene exposure. Formalin fixed specimens of liver from these animals were also imaged using in vitro MR microscopy, followed by conventional optical microscopy. All MR images were acquired using a spin-warp pulse sequence with TR = 950 ms and TE = 23 ms. The in vivo images were reconstructed as 256(2) x 32 arrays with a voxel size of (50 microns)2 x 219 microns, while the in vitro images were reconstructed as 256(2) x 128 arrays, giving an isotropic resolution at (39 microns)3. Based on results from six animals, we have found in all animals exposed to bromobenzene, image intensity decreased in specific hepatic tissue regions. These regions were well correlated to low signal intensity areas observed in in vitro MR images at higher resolution. Conventional optical microscopy indicated that the low signal intensity regions corresponded to areas of necrosis. The decrease in signal intensity is consistent with increased local diffusion coefficients as a result of necrosis. This study demonstrates that MR microscopy with implanted RF coils can be successfully used to follow tissue pathological changes in living tissues.


Nuclear pore protein gp210 is essential for viability in HeLa cells and Caenorhabditis elegans.
Gp210 is an evolutionarily conserved membrane protein of the nuclear pore complex (NPC). We studied the phenotypes produced by RNAi-induced downregulation of gp210 in both human (HeLa) cells and Caenorhabditis elegans embryos. HeLa cell viability requires Gp210 activity. The dying cells accumulated clustered NPCs and aberrant membrane structures at the nuclear envelope, suggesting that gp210 is required directly or indirectly for nuclear pore formation and dilation as well as the anchoring or structural integrity of mature NPCs. Essential roles for gp210 were confirmed in C. elegans, where RNAi-induced reduction of gp210 caused embryonic lethality. The nuclear envelopes of embryos with reduced gp210 also had aberrant nuclear membrane structures and clustered NPCs, confirming that gp210 plays critical roles at the nuclear membrane through mechanisms that are conserved from nematodes to humans.


Sweden: income and suicide.
Previous publications have reported two conflicting patterns describing the relationship between income and suicide in Sweden; positive and negative. Methodologically the studies have differed, and the analysis has been limited to a few areas. To better understand the relationship, a nationwide, cross-sectional, ecological study of the 290 municipalities in Sweden was planned. OLS regression analyses showed the overall and female suicide rates were negatively related to income, while the effect on male suicide rates was not statistically significant. The results confirm earlier findings of a negative relationship between income and suicide.


Stimulus-specific induction of phospholipid and arachidonic acid metabolism in human neutrophils.
Phospholipid remodeling resulting in arachidonic acid (AA) release and metabolism in human neutrophils stimulated by calcium ionophore A23187 has been extensively studied, while data obtained using physiologically relevant stimuli is limited. Opsonized zymosan and immune complexes induced stimulus-specific alterations in lipid metabolism that were different from those induced by A23187. [3H]AA release correlated with activation of phospholipase A2 (PLA2) but not with cellular activation as indicated by superoxide generation. The latter correlated more with calcium-dependent phospholipase C (PLC) activation and elevation of cellular diacylglycerol (DAG) levels. When cells that had been allowed to incorporate [3H]AA were stimulated with A23187, large amounts of labeled AA was released, most of which was metabolized to 5-HETE and leukotriene B4. Stimulation with immune complexes also resulted in the release of [3H]AA but this released radiolabeled AA was not metabolized. In contrast, stimulation with opsonized zymosan induced no detectable release of [3H]AA. Analysis of [3H]AA-labeled lipids in resting cells indicated that the greatest amount of label was incorporated into the phosphatidylinositol (PI) pool, followed closely by phosphatidylcholine and phosphatidylserine, while little [3H]AA was detected in the phosphatidylethanolamine pool. During stimulation with A23187, a significant decrease in labeled PI occurred and labeled free fatty acid in the pellet increased. With immune complexes, only a small decrease was seen in labeled PI while the free fatty acid in the pellets was unchanged. In contrast, opsonized zymosan decreased labeled PI, and increased labeled DAG. Phospholipase activity in homogenates from human neutrophils was also assayed. A23187 and immune complexes, but not zymosan, significantly enhanced PLA2 activity in the cell homogenates. On the other hand, PLC activity was enhanced by zymosan and immune complexes. Stimulated increases in PLC activity correlated with enhanced superoxide generation induced by the stimulus.


Regional climate affects salmon lice dynamics, stage structure and management.
Regional variation in climate can generate differences in population dynamics and stage structure. Where regional differences exist, the best approach to pest management may be region-specific. Salmon lice are a stage-structured marine copepod that parasitizes salmonids at aquaculture sites worldwide, and have fecundity, development and mortality rates that depend on temperature and salinity. We show that in Atlantic Canada and Norway, where the oceans are relatively cold, salmon lice abundance decreases during the winter months, but ultimately increases from year to year, while in Ireland and Chile, where the oceans are warmer, the population size grows monotonically without any seasonal declines. In colder regions, during the winter the stage structure is dominated by the adult stage, which is in contrast to warmer regions where all stages are abundant year round. These differences translate into region-specific recommendations for management: regions with slower population growth have lower critical stocking densities, and regions with cold winters have a seasonal dependence in the timing of follow-up chemotherapeutic treatments. Predictions of our salmon lice model agree with empirical data, and our approach provides a method to understand the effects of regional differences in climate on salmon lice dynamics and management.


The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes.
We investigated the effects of rosiglitazone on NEFA and triglyceride metabolism in type 2 diabetes. In a double-blind, placebo-controlled, cross-over study of rosiglitazone in diet-treated type 2 diabetic subjects, we measured arteriovenous differences and tissue blood flow in forearm muscle and subcutaneous abdominal adipose tissue, used stable isotope techniques, and analysed gene expression. Responses to a mixed meal containing [1,1,1-(13)C]tripalmitin were assessed. Rosiglitazone induced insulin sensitisation without altering fasting NEFA concentrations (-6.6%, p=0.16). Postprandial NEFA concentrations were lowered by rosiglitazone compared with placebo (-21%, p=0.04). Adipose tissue NEFA release was not decreased in the fasting state by rosiglitazone treatment (+24%, p=0.17) and was associated with an increased fasting hormone-sensitive lipase rate of action (+118%, p=0.01). Postprandial triglyceride concentrations were decreased by rosiglitazone treatment (-26%, p<0.01) despite unchanged fasting concentrations. Rosiglitazone did not change concentrations of triglyceride-rich lipoprotein remnants. Adipose tissue blood flow increased with rosiglitazone (+32%, p=0.03). Postprandial triglyceride [(13)C]palmitic acid concentrations were unchanged, whilst NEFA [(13)C]palmitic acid concentrations were decreased (p=0.04). In muscle, hexokinase II mRNA expression was increased by rosiglitazone (+166%, p=0.001) whilst the expression of genes involved in insulin signalling was unchanged. Adipose tissue expression of FABP4, LPL and FAT/CD36 was increased. Rosiglitazone decreases postprandial NEFA and triglyceride concentrations. This may represent decreased spillover of NEFAs from adipose tissue depots. Decreased delivery of NEFAs to the liver may lead to lowered postprandial triglyceride concentrations. Upregulation of hexokinase II expression in muscle may contribute to insulin sensitisation by rosiglitazone.


Resistance Training Combined With Diet Decreases Body Fat While Preserving Lean Mass Independent of Resting Metabolic Rate: A Randomized Trial.
The purpose of this study was to determine the effects of resistance training only (RT; n = 10), dietary intervention only (DIET; n = 10), resistance training plus diet (RT+DIET; n = 10), and control (CON; n = 10) on body composition and resting metabolic rate (RMR) in a cohort of 40 premenopausal female volunteers. Subjects in DIET and RT+DIET were provided with daily macronutrient and calorie goals based on DXA and RMR tests, with protein maintained at 3.1 g/kg/day. Subjects in the RT and RT+DIET groups performed a supervised progressive RT program consisting of exercises for all the major muscle groups of the body. Results showed a significant month-by-group interaction for change in fat mass with no significant linear trend for control. The three treatment groups all showed significant linear decreases in fat mass, but the slope of the decrease became progressively steeper from the RT, to DIET, to RT+DIET. A significant linear increase for lean mass was seen for resistance training only. There was a nonsignificant increase in RMR in all groups from Month 0 to Month 4 but no significant month by group interaction. In conclusion, significant reductions in fat mass were achieved by all experimental groups, but results were maximized by RT+DIET. Only the RT group showed significant increases in lean mass.


Using Unlicensed Health Coaches to Improve Care for Insured Patients with Diabetes and Hypertension: Patient and Physician Perspectives on Recruitment and Uptake.
Health coach programs using low-cost unlicensed providers have largely targeted uninsured or underserved populations, raising questions about uptake and effectiveness for insured patients. This observational study evaluated the referral process, uptake, and effectiveness of a health coach program for patients with diabetes and/or hypertension at a multispecialty clinic. Data included appointment observations; interviews with patients, physicians, and health coaches; patient and physician characteristics; and measures of utilization and clinical outcomes. Out of 1313 eligible patients, 308 (23.5%) were referred over a 12-month period and 169 (54.9%) had at least 1 health coach appointment. Although the health coach program did not change patients' biometrics, physicians and patients reported improved care processes and reduced physician workload. Barriers to enrollment included variability in physician referral practices, patient willingness, and scheduling difficulties. Modifications to physician and health coach workflow are needed to determine the program's true effectiveness.


Occupant-centered optimization framework to evaluate and design new dynamic shading typologies.
Dynamic solar shading has the potential to dramatically reduce the energy consumption in buildings while at the same time improving the thermal and visual comfort of its occupants. Many new typologies of shading systems that have appeared recently, but it is difficult to compare those new systems to existing typologies due to control algorithm being rule-based as opposed to performance driven. Since solar shading is a design problem, there is no single right answer. What is the metric to determine if a system has reached its optimal kinematic design? Shading solutions should come from a thorough iterative and comparative process. This paper provides an original and flexible framework for the design and performance optimization of dynamic shading systems based on interpolation of simulations and global minimization. The methodology departs from existing rule-based strategies and applies to existing and to complex shading systems with multiple degree-of-freedom mobility. The strategy for control is centered on meeting comfort targets for work plane illuminance while minimizing the energy needed to operate space. The energy demand for thermal comfort and work plane daylight quantity (illuminance) are evaluated with Radiance and EnergyPlus based on local weather data. Applied to a case study of three typologies of dynamic shading, the results of the methodology inform the usefulness and quality of each degree-of-freedom of the kinematic systems. The case study exemplifies the iterative benefits of the methodology by providing detailed analytics on the behavior of the shades. Designers of shading systems can use this framework to evaluate their design and compare them to existing shading systems. This allows creativity to be guided so that eventually building occupants benefit from the innovation in the field.


Vaccine-driven virulence evolution: consequences of unbalanced reductions in mortality and transmission and implications for pertussis vaccines.
Many vaccines have heterogeneous effects across individuals. Additionally, some vaccines do not prevent infection, but reduce disease-associated mortality and transmission. Both of these factors will alter selection pressures on pathogens and thus shape the evolution of pathogen virulence. We use a mathematical modelling framework to show that (i) the balance of how vaccines reduce transmission versus mortality and (ii) individual variability in protection conferred both shape the evolution of pathogen virulence. Epidemiological (burden of disease) and evolutionary (pathogen virulence) outcomes are both worse when vaccines confer smaller reductions in transmission than in mortality. Furthermore, outcomes are modulated by variability in vaccine effects, with increased variability limiting the extent of virulence evolution but in some cases preventing eradication. These findings are pertinent to current concerns about the global resurgence of pertussis and the efficacy of pertussis vaccines, as the two classes of these vaccines may reduce disease symptoms without preventing infection and differ in their ability to reduce transmission. Furthermore, these findings point to the importance of generating precise predictions for virulence evolution in Bordetella pertussis (and other similar pathogens) by incorporating empirical characterizations of vaccine effects into models capturing the epidemiological details of this system.


Automating sequence-based detection and genotyping of SNPs from diploid samples.
The detection of sequence variation, for which DNA sequencing has emerged as the most sensitive and automated approach, forms the basis of all genetic analysis. Here we describe and illustrate an algorithm that accurately detects and genotypes SNPs from fluorescence-based sequence data. Because the algorithm focuses particularly on detecting SNPs through the identification of heterozygous individuals, it is especially well suited to the detection of SNPs in diploid samples obtained after DNA amplification. It is substantially more accurate than existing approaches and, notably, provides a useful quantitative measure of its confidence in each potential SNP detected and in each genotype called. Calls assigned the highest confidence are sufficiently reliable to remove the need for manual review in several contexts. For example, for sequence data from 47-90 individuals sequenced on both the forward and reverse strands, the highest-confidence calls from our algorithm detected 93% of all SNPs and 100% of high-frequency SNPs, with no false positive SNPs identified and 99.9% genotyping accuracy. This algorithm is implemented in a software package, PolyPhred version 5.0, which is freely available for academic use.