Regulation of Drosophila tracheal system development by protein kinase B.
Protein kinase B (PKB, also termed Akt) is a phosphatidylinositol 3' kinase (PI3'K)-dependent enzyme implicated in survival signaling and human tumorigenesis. To identify potential targets of this protein kinase, we employed a genetic screen in Drosophila. Among several genes that genetically interacted with PKB was trachealess (trh), which encodes a bHLH-PAS domain transcription factor required for development of the trachea and other tubular organs. Trh activates expression of the fibroblast growth factor receptor Breathless, which, in turn, is required for directed migration of all tracheal branches. Using a combination of biochemical and transgenic approaches, we show that direct phosphorylation of Trh by PKB at serine 665 is essential for nuclear localization and functional activation of this regulator of branching morphogenesis.


Creating a data exchange strategy for radiotherapy research: towards federated databases and anonymised public datasets.
Disconnected cancer research data management and lack of information exchange about planned and ongoing research are complicating the utilisation of internationally collected medical information for improving cancer patient care. Rapidly collecting/pooling data can accelerate translational research in radiation therapy and oncology. The exchange of study data is one of the fundamental principles behind data aggregation and data mining. The possibilities of reproducing the original study results, performing further analyses on existing research data to generate new hypotheses or developing computational models to support medical decisions (e.g. risk/benefit analysis of treatment options) represent just a fraction of the potential benefits of medical data-pooling. Distributed machine learning and knowledge exchange from federated databases can be considered as one beyond other attractive approaches for knowledge generation within "Big Data". Data interoperability between research institutions should be the major concern behind a wider collaboration. Information captured in electronic patient records (EPRs) and study case report forms (eCRFs), linked together with medical imaging and treatment planning data, are deemed to be fundamental elements for large multi-centre studies in the field of radiation therapy and oncology. To fully utilise the captured medical information, the study data have to be more than just an electronic version of a traditional (un-modifiable) paper CRF. Challenges that have to be addressed are data interoperability, utilisation of standards, data quality and privacy concerns, data ownership, rights to publish, data pooling architecture and storage. This paper discusses a framework for conceptual packages of ideas focused on a strategic development for international research data exchange in the field of radiation therapy and oncology.


Animal models of retinal injury.
Retinal injury is a common cause of profound and intractable loss of vision. Clinical outcomes are poor in both open and closed globe injuries because cell death, scarring, and a failure of tissue and axon regeneration are not ameliorated by current treatments. Much animal research is directed at understanding and modifying these pathologies, although results have yet to translate into clinical practice. Axotomy-induced retinal ganglion cell (RGC) death in mammals can be effectively reduced and axon regeneration enhanced over the short term. After retinal injury in mammals, the retinal pigment epithelium (RPE) and retinal glia either regenerate lost RPE and neuroretinal cells or form nonfunctional scars. An understanding of the mechanisms underlying injury responses is critical to the successful development of therapeutic strategies to promote ocular repair.


The role of co-rumination and adrenocortical attunement in young women's close friendships.
Attunement, or synchrony, of behavior and physiology has been well documented in family, mother-child, and romantic relationships. This study aimed to determine whether attunement of the hypothalamic-pituitary-adrenal (HPA) axis occurs in women's close friendships, and the role of a common social style, co-rumination in that attunement. Saliva samples (later assayed for cortisol) were collected from 37 dyads (74 individuals) during a laboratory task in which they were either asked to work together toward a common goal (control task) or discuss interpersonal problems, providing opportunity for co-rumination. Findings suggest that friends demonstrated adrenocortical attunement prior to engaging in either task, and that the level of attunement prior to the task predicted co-rumination and its components for both groups. Co-rumination, in turn, predicted adrenocortical attunement after the task. These findings suggest that bidirectional attunement of HPA activity may serve a bonding function within women's close friendships. Implications for how these findings fit with the tend-and-befriend hypothesis are discussed.


Treatment outcomes for tinea capitis in a skin of color population.
Tinea capitis periodically undergoes demographic shifts in causative dermatophyte and therapeutic response to oral anti-fungal therapy. To determine prevalent fungal species and response to standard antifungal therapy in inner-city children of color. An IRB-approved chart review of demographic, clinical, diagnostic, and therapeutic data was conducted for children and young adults (0 to 18 years of age) who had scalp fungal culture performed for scalp hyperkeratosis and/or alopecia over a 2.5 year time-period. Supplemental parental phone interview was performed for missing data points. A total of 84 patients with final diagnosis of tinea capitis were identified-52% male, 60.6% African-American, 28.2% Hispanic, and 9.9% Caucasian. Complete resolution at 4 weeks was uncommon in all demographic groups (Hispanic: 11.7%, African-American: 41.3%). The Hispanic group and the youngest patients (aged less than 4 years) were less likely to respond to initial therapy, but the results were not significant. Of the 80 tinea capitis patients initially treated with griseofulvin, 41 out of 54 children (76%) had complete response to micronized suspension +/- crushed tablet (33% required shift to tablets from suspension) and 20 out of 26 (76.9%) cleared on crushed tablets alone. Of the 19 griseofulvin failures, 5 cleared on fluconazole suspension, 7 on terbinafine sprinkles, 3 on itraconazole therapy, and 4 were lost to follow-up. Of the 47 patients who could be evaluated long-term after a single course of oral griseofulvin at 6 weeks or greater, 38 had documented long-term mycological cure (80.8%) and 42 had long-term clinical cure (89%). Trichophyton tonsurans (n=40) was the most prevalent causative species identified on culture, followed by Alternaria species (n=10) and Microsporum canis (n=1). Retrospective chart review: patient population has a high rate of usage of over-the-counter antifungal creams and shampoos, affecting culture results. Tinea capitis is still the most common cause of Trichophyton tonsurans in New York City. Response rates to griseofulvin are similar to rates seen in the 1970s, but require higher dosing and conversion to crushed tablets in partial responders. Usage of crushed ultramicronized griseofulvin, terbinafine sprinkles, itraconazole, and fluconazole are alternative regimens for those children whose tinea capitis does not clear on griseofulvin suspension.


Assessment of efficacy and safety of EUS-guided biliary drainage: a systematic review.
EUS-guided biliary drainage (EUS-BD) has emerged as an alternative procedure after failed ERCP. However, limited data on the efficacy and safety of EUS-BD are available. Therefore, a systematic review was conducted to evaluate the efficacy and safety of EUS-BD and to evaluate transduodenal (TD) and transgastric (TG) approaches. PubMed and EMBASE were searched to identify relevant studies published in the English language for inclusion in this systematic review and meta-analysis. Data from eligible studies were combined to calculate the cumulative technical success rate (TSR), functional success rate (FSR), and adverse-event rate of EUS-BD and the pooled odds ratio of TSR, FSR, and adverse-event rate of the TD approach when compared with the TG approach. Forty-two studies with 1192 patients were included in this study, and the cumulative TSR, FSR, and adverse-event rate were 94.71%, 91.66%, and 23.32%, respectively. The common adverse events associated with EUS-BD were bleeding (4.03%), bile leakage (4.03%), pneumoperitoneum (3.02%), stent migration (2.68%), cholangitis (2.43%), abdominal pain (1.51%), and peritonitis (1.26%). Ten studies were included in the meta-analysis for comparative evaluation of TD and TG approaches for EUS-BD. Compared with the TG approach, the pooled odds ratio of the TSR, FSR, and adverse-event rate of the TD approach were 1.36 (95% CI, .66-2.81; P > .05), .84 (95% CI, .50-1.42; P > .05), and .61 (95% CI, .36-1.03; P > .05), respectively, which indicated no significant difference in the TSR, FSR, and adverse-event rate between the 2 groups. Although it is associated with significant morbidity, EUS-BD is an effective alternative procedure for relieving biliary obstruction. There was no significant difference between the TD and TG approaches for EUS-BD.


Gene expression patterns induced by HPV-16 L1 virus-like particles in leukocytes from vaccine recipients.
Human papillomavirus (HPV) virus-like particle (VLP) vaccines were recently licensed. Although neutralizing Ab titers are thought to be the main effectors of protection against infection, early predictors of long-term efficacy are not yet defined and a comprehensive understanding of innate and adaptive immune responses to vaccination is still lacking. Here, microarrays were used to compare the gene expression signature in HPV-16 L1 VLP-stimulated PBMCs from 17 vaccine and 4 placebo recipients before vaccination and 1 mo after receiving the second immunization. Vaccination with a monovalent HPV-16 L1 VLP vaccine was associated with modulation of genes involved in the inflammatory/defense response, cytokine, IFN, and cell cycle pathways in VLP-stimulated PBMCs. Additionally, there was up-regulation of probesets associated with cytotoxic (GZMB, TNFSF10) and regulatory (INDO, CTLA4) activities. The strongest correlations with neutralizing Ab titers were found for cyclin D2 (CCND2) and galectin (LGALS2). Twenty-two differentially expressed probesets were selected for confirmation by RT-PCR in an independent sample set. Agreement with microarray data was seen for more than two-thirds of these probesets. Up-regulation of immune/defense response genes by HPV-16 L1 VLP, in particular, IFN-induced genes, was observed in PBMCs collected before vaccination, with many of these genes being further induced following vaccination. In conclusion, we identified important innate and adaptive response-related genes induced by vaccination with HPV-16 L1 VLP. Further studies are needed to identify gene expression signatures of immunogenicity and long-term protection with potential utility in prediction of long-term HPV vaccination outcomes in clinical trials.


Patient empowerment in long-term conditions: development and preliminary testing of a new measure.
Patient empowerment is viewed by policy makers and health care practitioners as a mechanism to help patients with long-term conditions better manage their health and achieve better outcomes. However, assessing the role of empowerment is dependent on effective measures of empowerment. Although many measures of empowerment exist, no measure has been developed specifically for patients with long-term conditions in the primary care setting. This study presents preliminary data on the development and validation of such a measure. We conducted two empirical studies. Study one was an interview study to understand empowerment from the perspective of patients living with long-term conditions. Qualitative analysis identified dimensions of empowerment, and the qualitative data were used to generate items relating to these dimensions. Study two was a cross-sectional postal study involving patients with different types of long-term conditions recruited from general practices. The survey was conducted to test and validate our new measure of empowerment. Factor analysis and regression were performed to test scale structure, internal consistency and construct validity. Sixteen predominately elderly patients with different types of long-term conditions described empowerment in terms of 5 dimensions (identity, knowledge and understanding, personal control, personal decision-making, and enabling other patients). One hundred and ninety seven survey responses were received from mainly older white females, with relatively low levels of formal education, with the majority retired from paid work. Almost half of the sample reported cardiovascular, joint or diabetes long-term conditions. Factor analysis identified a three factor solution (positive attitude and sense of control, knowledge and confidence in decision making and enabling others), although the structure lacked clarity. A total empowerment score across all items showed acceptable levels of internal consistency and relationships with other measures were generally supportive of its construct validity. Initial analyses suggest that the new empowerment measure meets basic psychometric criteria. Reasons concerning the failure to confirm the hypothesized factor structure are discussed alongside further developments of the scale.


Selectivity and stability via dendritic nonlinearity.
Inspired by recent studies regarding dendritic computation, we constructed a recurrent neural network model incorporating dendritic lateral inhibition. Our model consists of an input layer and a neuron layer that includes excitatory cells and an inhibitory cell; this inhibitory cell is activated by the pooled activities of all the excitatory cells, and it in turn inhibits each dendritic branch of the excitatory cells that receive excitations from the input layer. Dendritic nonlinear operation consisting of branch-specifically rectified inhibition and saturation is described by imposing nonlinear transfer functions before summation over the branches. In this model with sufficiently strong recurrent excitation, on transiently presenting a stimulus that has a high correlation with feed- forward connections of one of the excitatory cells, the corresponding cell becomes highly active, and the activity is sustained after the stimulus is turned off, whereas all the other excitatory cells continue to have low activities. But on transiently presenting a stimulus that does not have high correlations with feedforward connections of any of the excitatory cells, all the excitatory cells continue to have low activities. Interestingly, such stimulus-selective sustained response is preserved for a wide range of stimulus intensity. We derive an analytical formulation of the model in the limit where individual excitatory cells have an infinite number of dendritic branches and prove the existence of an equilibrium point corresponding to such a balanced low-level activity state as observed in the simulations, whose stability depends solely on the signal-to-noise ratio of the stimulus. We propose this model as a model of stimulus selectivity equipped with self-sustainability and intensity-invariance simultaneously, which was difficult in the conventional competitive neural networks with a similar degree of complexity in their network architecture. We discuss the biological relevance of the model in a general framework of computational neuroscience.


SPEAR Trial: Smartphone Pediatric ElectrocARdiogram Trial.
Smartphone-enabled ECG devices have the potential to improve patient care by enabling remote ECG assessment of patients with potential and diagnosed arrhythmias. This prospective study aimed to assess the usefulness of pediatric ECG tracings generated by the AliveCor device (Oklahoma City, OK) and to assess user satisfaction. Enrolled pediatric patients with documented paroxysmal arrhythmia used the AliveCor device over a yearlong study period. Pediatric electrophysiologists reviewed all transmitted ECG tracings. Patient completed surveys were analyzed to assess user satisfaction. 35 patients were enrolled with the following diagnoses: supraventricular tachycardia (SVT, 57%), atrial fibrillation (AF, 11%), ectopic atrial tachycardia (EAT, 6%), atrial tachycardia (AT, 3%), and ventricular tachycardia (VT, 23%). A total of 238 tracings were received from 20 patients, 96% of which were of diagnostic quality for sinus rhythm, sinus tachycardia, SVT, and AF. 126 patient satisfaction surveys (64% from parents) were completed. 98% of the survey responses indicated that it was easy to obtain tracings, 93% found it easy to transmit the tracings, 98% showed added comfort in managing arrhythmia by having the device, and 93% showed interest in continued use of the device after the study period ended. Smartphone-enabled ECG devices can generate tracings of diagnostic quality in children. User satisfaction was extremely positive. Use of the device to manage certain patients with AF and SVT showcases the future role of remote ECGs in the successful outpatient management of arrhythmias in children by potentially reducing Emergency Department visits and healthcare costs.


New 1,4-dihydropyridines with vasoconstrictor action through activation of Ca++-channels.
We found four new phenylcarbamoyl-substituted 1,4-dihydropyridines which produced vasoconstrictor and vasopressor effects and we further investigated the mode of vasoconstrictor action of one of the derivatives, 2-(2-pyridil)ethyl-4-(2-chlorophenyl)-2,6-dimethyl-5-phenylcarbamo yl-1, 4-dihydropyridine-3-carboxylate (YC-170). In anesthetized dogs. YC-170 (0.1-3 mg/kg i.v.) produced dose-dependent increases in blood pressure, total peripheral resistance and maximum dLVP/dt with slight reductions of heart rate and aortic blood flow. Intracoronary injection of YC-170 (10-1000 micrograms) produced not only a decrease in coronary blood flow but also an immediate reversal of the coronary vasodilation induced by nicardipine (3 micrograms). YC-170 (0.1-3 mg/kg i.v.) also produced a dose-dependent and reversible vasopressor effect in both anesthetized and pithed rats. The vasopressor response to YC-170 in pithed rats was not attenuated by either hexamethonium, prazosin, yohimbine, ketanserin or reserpine but was antagonized by either nicardipine, nifedipine, verapamil or diltiazem. In isolated rabbit aorta, YC-170 (3 X 10(-6) to 3 X 10(-5) M) induced a dose-dependent and reversible contraction which was not affected by either phentolamine, prazosin, mepyramine, ketanserin or atropine but removed by either nicardipine, verapamil or a Ca++-free medium. YC-170 (1 X 10(-6) to 3 X 10(-5) M) displaced [3H]nitrendipine binding to the canine cardiac membrane in an apparently competitive manner with a Ki value of 1.7 X 10(-6) M. The results suggest that the new phenylcarbamoyl-substituted dihydropyridines, including YC-170, exert a direct vasoconstrictor effect, which appears to be associated with an influx of Ca++ through Ca++ channels.


Life-Threatening Malnutrition in Very Severe ME/CFS.
Very severe Myalgic Encephalomyelitis (ME), (also known as Chronic Fatigue Syndrome) can lead to problems with nutrition and hydration. The reasons can be an inability to swallow, severe gastrointestinal problems tolerating food or the patient being too debilitated to eat and drink. Some patients with very severe ME will require tube feeding, either enterally or parenterally. There can often be a significant delay in implementing this, due to professional opinion, allowing the patient to become severely malnourished. Healthcare professionals may fail to recognize that the problems are a direct consequence of very severe ME, preferring to postulate psychological theories rather than addressing the primary clinical need. We present five case reports in which delay in instigating tube feeding led to severe malnutrition of a life-threatening degree. This case study aims to alert healthcare professionals to these realities.


The minigrant model: a strategy to promote local implementation of state cancer plans in Appalachian communities.
East Tennessee State University (ETSU) was awarded a grant through an interagency agreement between the Centers for Disease Control and Prevention and the Appalachian Regional Commission to promote cancer control activities between state comprehensive cancer control (CCC) coalitions and local Appalachian communities. We invited representatives from CCC coalitions and Appalachian communities to a forum to develop a plan of action. The attendees recommended a minigrant model that uses a request for proposals (RFP) strategy to encourage CCC coalitions and Appalachian communities to collaboratively conduct forums and roundtables locally. They set criteria to guide the development of the RFPs and the agendas for the roundtables and forums that ensured new communication and collaboration between the CCC coalitions and the Appalachian communities. We established the roundtable agenda to focus on the presentation and discussion of state and local Appalachian community cancer risk, incidence, and death rates and introduction of state cancer plans. The forums had a more extensive agenda to present cancer data, describe state cancer plans, and describe successful cancer control programs in local Appalachian communities. This article describes the ETSU minigrant model that supports forums and roundtables and reports how this strategy improves cooperative partnerships between CCC coalitions and Appalachian communities in the local implementation of state cancer plans in Appalachia.


Barrett oesophagus.
Barrett oesophagus (BE), the only known histological precursor of oesophageal adenocarcinoma (EAC), is a condition in which the squamous epithelium of the oesophagus is replaced by columnar epithelium as an adaptive response to gastro-oesophageal reflux. EAC has one of the fastest rising incidences of cancers in Western countries and has a dismal prognosis. BE is usually detected during endoscopic examination, and diagnosis is confirmed by the histological presence of intestinal metaplasia. Advances in genomics and transcriptomics have improved our understanding of the pathogenesis and malignant progression of intestinal metaplasia. As the majority of EAC cases are diagnosed in individuals without a known history of BE, screening for BE could potentially decrease disease-related mortality. Owing to the pre-malignant nature of BE, endoscopic surveillance of patients with BE is imperative for early detection and treatment of dysplasia to prevent further progression to invasive EAC. Developments in endoscopic therapy have resulted in a major shift in the treatment of patients with BE who have dysplasia or early EAC, from surgical resection to endoscopic resection and ablation. In addition to symptom control by optimization of lifestyle and pharmacological therapy with proton pump inhibitors, chemopreventive strategies based on NSAIDs and statins are currently being investigated for BE management.


Mannose 6-phosphate receptor-mediated endocytosis of acid hydrolases: internalization of beta-glucuronidase is accompanied by a limited dephosphorylation.
Endocytosis of acid hydrolases via the cell surface mannose 6-phosphate (Man 6-P) receptor results in the delivery of the enzymes to lysosomes. To examine the fate of the ligand-associated phosphorylated high mannose oligosaccharides, we have analyzed the asparagine-linked oligosaccharides attached to beta-glucuronidase after uptake and processing by Man 6-P receptor-positive mouse L cells. beta-Glucuronidase, double-labeled with [2-3H]mannose and [35S]methionine, was isolated from the growth medium of mouse P388D1 cells. 80% of the [3H]mannose associated with the secreted enzyme was recovered as high mannose-type oligosaccharides, and 24-37% of these units were phosphorylated. Three species of phosphorylated oligosaccharides were identified; high mannose-type units containing either one or two phosphomonoesters, and hybrid-type units containing one phosphomonoester and one sialic acid residue. After endocytosis by the L cells, the beta-glucuronidase molecules migrated faster on an SDS gel, suggesting that the enzymes had been processed within lysosomes. Examination of the cell-associated beta-glucuronidase molecules indicated that: (a) the percentage of phosphorylated oligosaccharides remained comparable to the input form of the enzyme, even after a 24-h chase period, (b) the presence of a single species of phosphorylated oligosaccharide that contained one phosphomonoester, and (c) the positioning of the phosphate within the intracellular monophosphorylated species was comparable to the positioning of the phosphate within the two phosphomonoester species originally secreted by the P388D1 cells. Therefore, the internalized beta-glucuronidase molecules undergo a limited dephosphorylation; oligosaccharides containing two phosphomonoesters are converted to monophosphorylated species, but the one phosphomonoester forms are conserved. A comparison of the phosphorylated oligosaccharides recovered from ligands internalized by the L cells at 37 degrees and 20 degrees C indicated that: (a) molecules internalized at 20 degrees C retain a higher percentage of phosphorylated structures; and (b) at both temperatures the predominant phosphorylated oligosaccharide contains a single phosphomonoester group. The results indicate that the Man 6-P recognition marker persists after endocytosis and delivery to lysosomes and support the possibility that the limited dephosphorylation of the oligosaccharides may occur en route to these organelles.


Image reconstruction in diffuse optical tomography based on simplified spherical harmonics approximation.
The use of higher order approximations to the Radiative transport equation, through simplified spherical harmonics expansion (SP(N)) in optical tomography are presented. It is shown that, although the anisotropy factor can be modeled in the forward problem, its sensitivity to the measured boundary data is limited to superficial regions and more importantly, due to uniqueness of the inverse problem it cannot be determined using frequency domain data. Image reconstruction through the use of higher ordered models is presented. It is demonstrated that at higher orders (for example SP7) the image reconstruction becomes highly under-determined due to the large increase in the number of unknowns which cannot be adequately recovered. However, reconstruction of diffuse parameters, namely optical absorption and reduced scatter have shown to be more accurate where only the sensitivity matrix used in the inverse problem is based on SP(N) method and image reconstruction is limited to these two diffuse parameters.


Acute Effects of the Elevation Training Mask on Strength Performance in Recreational Weight lifters.
Jagim, AR, Dominy, TA, Camic, CL, Wright, G, Doberstein, S, Jones, MT, and Oliver, JM. Acute effects of the elevation training mask on strength performance in recreational weightlifters. J Strength Cond Res 32(2): 482-489, 2018-The Elevation Training Mask 2.0 (ETM) is a novel device that purportedly simulates altitude training. The purpose of this study was to investigate the acute effects of the ETM on resistance exercise performance, metabolic stress markers, and ratings of mental fatigue. Twenty male recreational weight lifters completed 2 training sessions of back squat and bench press (6 sets of 10 repetitions at 85% of 5-repetition maximum and seventh set to failure) as well as a maximal effort sprint test (18% body mass) with the mask (ETM) and without the mask (NM). Training evaluation included baseline and postexercise blood lactate and oxygen saturation measures. Performance evaluation included peak and average velocity bar velocity, total volume load, total work, total repetitions completed, and sprint performance. Adverse side effects were reported in 12% (n = 3) of participants, which included feelings of light headedness, anxiety, and discomfort. No differences were found in repetitions or total workload in back squat (p = 0.07) or bench press (p = 0.08) between conditions. A lower peak velocity was identified during the back squat, bench press, and sprint test in the ETM condition (p = 0.04). Blood lactate values were lower after bench press and sprint during the ETM condition (p < 0.001). Significantly lower ratings of alertness and focus for task were found after squat, bench press, and sprint test in the ETM condition compared with the NM condition (p < 0.001). Wearing the ETM during bouts of resistance training did not hinder the ability to achieve desired training volumes during the resistance training session. However, wearing the ETM does seem to attenuate the ability to maintain working velocity during training bouts and negatively influence ratings of alertness and focus for task.


Life-threatening motor vehicle crashes in bright sunlight.
Bright sunlight may create visual illusions that lead to driver error, including fallible distance judgment from aerial perspective. We tested whether the risk of a life-threatening motor vehicle crash was increased when driving in bright sunlight.This longitudinal, case-only, paired-comparison analysis evaluated patients hospitalized because of a motor vehicle crash between January 1, 1995 and December 31, 2014. The relative risk of a crash associated with bright sunlight was estimated by evaluating the prevailing weather at the time and place of the crash compared with the weather at the same hour and location on control days a week earlier and a week later.The majority of patients (n = 6962) were injured during daylight hours and bright sunlight was the most common weather condition at the time and place of the crash. The risk of a life-threatening crash was 16% higher during bright sunlight than normal weather (95% confidence interval: 9-24, P < 0.001). The increased risk was accentuated in the early afternoon, disappeared at night, extended to patients with different characteristics, involved crashes with diverse features, not apparent with cloudy weather, and contributed to about 5000 additional patient-days in hospital. The increased risk extended to patients with high crash severity as indicated by ambulance involvement, surgical procedures, length of hospital stay, intensive care unit admission, and patient mortality. The increased risk was not easily attributed to differences in alcohol consumption, driving distances, or anomalies of adverse weather.Bright sunlight is associated with an increased risk of a life-threatening motor vehicle crash. An awareness of this risk might inform driver education, trauma staffing, and safety warnings to prevent a life-threatening motor vehicle crash. Epidemiologic Study, level III.


Toxicity assessment and modelling of Moringa oleifera seeds in water purification by whole cell bioreporter.
Moringa oleifera has been used as a coagulation reagent for drinking water purification, especially in developing countries such as Malawi. This research revealed the cytoxicity and genotoxicity of M. oleifera by Acinetobacter bioreporter. The results indicated that significant cytoxicity effects were observed when the powdered M. oleifera seeds concentration is from 1 to 50 mg/L. Through direct contact, ethanolic-water extraction and hexane extraction, the toxic effects of hydrophobic and hydrophilic components in M. oleifera seeds were distinguished. It suggested that the hydrophobic lipids contributed to the dominant cytoxicity, consequently resulting in the dominant genotoxicity in the water-soluble fraction due to limited dissolution when the M. oleifera seeds granule concentration was from 10 to 1000 mg/L. Based on cytoxicity and genotoxicity model, the LC50 and LC90 of M. oleifera seeds were 8.5 mg/L and 300 mg/L respectively and their genotoxicity was equivalent to 8.3 mg mitomycin C per 1.0 g dry M. oleifera seed. The toxicity of M. oleifera has also remarkable synergistic effects, suggesting whole cell bioreporter as an appropriate and complementary tool to chemical analysis for environmental toxicity assessment.


Pistachios increase serum antioxidants and lower serum oxidized-LDL in hypercholesterolemic adults.
Pistachios are high in lutein, beta-carotene, and gamma-tocopherol relative to other nuts; however, studies of the effects of pistachios on oxidative status are lacking. We conducted a randomized, crossover controlled-feeding study to evaluate 2 doses of pistachios on serum antioxidants and biomarkers of oxidative status in 28 hypercholesterolemic adults (LDL-cholesterol >or=2.86 mmol/L). Participants consumed 3 isoenergetic diets for 4 wk each after a 2-wk baseline Western diet. Experimental diets included a lower-fat control diet without pistachios (25% total fat) with 1 serving/d (i.e. 32-63 g/d; energy adjusted) of pistachios (1 PD; 10% energy from pistachios; 30% total fat) or with 2 servings/d (63-126 g/d; energy adjusted) of pistachios (2 PD; 20% energy from pistachios; 34% total fat). When participants consumed the pistachio-enriched diets, they had higher plasma lutein (P < 0.0001), alpha-carotene, and beta-carotene (P < 0.01) concentrations than after the baseline diet. After consuming the pistachio diets, participants had greater plasma lutein (P < 0.001) and gamma-tocopherol (P < 0.05; 2 PD only) relative to the lower-fat control diet. After the 2 PD diet period, participants also had lower serum oxidized-LDL concentrations than following the baseline diet period (P < 0.05). After both the 1 PD and 2 PD diet periods, they had lower serum oxidized-LDL concentrations than after the control diet period (P < 0.05). The change in oxidized-LDL from baseline correlated positively with the change in LDL-cholesterol across all treatments (r = 0.42; P < 0.005). After controlling for the change in serum LDL-cholesterol as a covariate, increases in serum lutein and gamma-tocopherol following the 2 PD period were still modestly associated with decreases in oxidized-LDL (r = -0.36, P = 0.06 and r = -0.35, P = 0.08, respectively). This suggests that a heart-healthy diet including pistachios contributes to the decrease in the serum oxidized-LDL concentration through cholesterol-lowering and may provide an added benefit as a result of the antioxidants the pistachios contain.


Cortical and subcortical responses to high and low effective placebo treatments.
The effectiveness of placebo treatments depends on the recipient's expectations, which are at least in part shaped by previous experiences. Thus, positive past experience together with an accordant verbal instruction should enhance outcome expectations and subsequently lead to higher placebo efficacy. This should be reflected in subjective valuation reports and in activation of placebo-related brain structures. We tested this hypothesis in a functional magnetic resonance imaging study, where subjects experienced different levels of pain relief and conforming information about price levels for two placebo treatments during a manipulation phase, thereby establishing a weak and a strong placebo. As expected, both placebos led to a significant pain relief and the strong placebo induced better analgesic efficacy. Individual placebo value estimates reflected treatment efficacy, i.e. subjects were willing to pay more money for the strong placebo even though pain stimulation was completed at this time. On the neural level, placebo effects were associated with activation of the rostral anterior cingulate cortex, the anterior insula, and the ventral striatum and deactivations in the thalamus and secondary somatosensory cortex. However, only placebo-related responses in rostral anterior cingulate cortex were consistent across both the anticipation of painful stimuli and their actual administration. Most importantly, rostral anterior cingulate cortex responses were higher for the strong placebo, thus mirroring the behavioral effects. These results directly link placebo analgesia to anticipatory activity in the ventral striatum, a region involved in reward processing, and highlight the role of the rostral anterior cingulate cortex, as its activity consistently scaled with increasing analgesic efficacy.


Schistosomiasis prophylaxis in vivo using N,N-diethyl-m-toluamide (DEET).
Topical N,N-Diethyl-m-toluamide (DEET) was studied as a schistosomiasis prophylactic in vivo for the use of individuals with limited exposure. Fifteen subjects, on a 3-week expedition to Lake Malawi in September 2001, applied 50% DEET to their skin after exposure to lake water. No subjects developed evidence of a new infection at 3-month follow-up.


A comprehensive systematic review and meta-analysis of pharmacological and dietary supplement interventions in paediatric autism: moderators of treatment response and recommendations for future research.
Autism spectrum disorders (ASDs) are pervasive and multifactorial neurodevelopmental conditions, characterized by impairments in social communication and interaction, and restricted, repetitive patterns of behaviour, interests or activities. Treatment options to ameliorate symptoms of ASDs are limited. Heterogeneity complicates the quest for personalized medicine in this population. Our aim was to investigate if there are baseline characteristics of patients that moderate response or trial design features that impede the identification of efficacious interventions for ASDs. Literature searches of EMBASE, MEDLINE and PsycINFO identified 43 studies for qualitative assessment of baseline characterization of participants and 37 studies for quantitative analysis of moderators of treatment response. Criteria included blinded randomized controlled trials (RCTs) in paediatric ASD, with at least 10 participants per arm or 20 overall, of oral treatments, including pharmacological interventions and dietary supplements. Random-effects meta-analysis of 1997 participants (81% male) identified three moderators associated with an increase in treatment response: trials located in Europe and the Middle-East; outcome measures designated primary status; and the type of outcome measure. Inconsistent reporting of baseline symptom severity and intellectual functioning prevented analysis of these variables. Qualitative synthesis of baseline characteristics identified at least 31 variables, with only age and gender reported in all trials. Biological markers were included in six RCTs. Few trials reported adequate baseline characteristics to permit detailed analysis of response to treatment. Consideration of geographical location, baseline severity and intellectual function is required to ensure generalizability of results. The use of biological markers and correlates in ASD trials remains in its infancy. There is great need to improve the application of baseline characterization and incorporation of biological markers and correlates to permit selection of participants into homogeneous subgroups and to inform response to treatment in ASD.


Fetal and neoplastic expression of the neurotensin gene in the human colon.
The authors identified various colon cancers that express the gene for the gut peptide neurotensin (NT/N). In addition, the authors sought to delineate the temporal pattern of NT/N gene expression in the human fetal colon. Expression of NT/N is localized to the mucosa of the adult small bowel but also has been identified in the fetal colon, which resembles the small bowel until the end of the second trimester. Ectopic NT/N expression has been shown in certain types of colon cancer, suggesting a reversion to a fetal phenotype. Sensitive ribonuclease protection assays were used to determine NT/N expression in colon cancers and adjacent normal mucosa as well as colon cancers established as tumor xenografts and fetal colon samples. NT/N gene expression was shown in 4 of 12 (25%) human colon cancer xenografts and in 11 of 40 (28%) freshly resected colon adenocarcinomas; NT/N gene expression was not expressed in any of the samples of normal colonic mucosa adjacent to the tumors. The NT/N gene was expressed maximally in the fetal colon between 16 and 18 weeks' gestation; NT/N expression was decreased between 19 and 22 weeks and was not apparent in either the 24-week fetal colon or the adult samples. The NT/N gene expression is expressed transiently in the fetal colon during a development stage that is characterized by morphologic similarity to the small bowel. In addition, NT/N is reexpressed in approximately one fourth of the human colon cancers, indicating that neoplastic transformation leads to reversion to a fetal phenotype in certain types of colon cancer. The NT/N gene will provide a useful model to further define the complex differentiation pathways in the normal gut as well as the process of fetal "dedifferentiation" in certain types of colon cancer.


PKR induces the expression of NLRP3 by regulating the NF-κB pathway in Porphyromonas gingivalis-infected osteoblasts.
The double-stranded RNA-dependent kinase (PKR), which is activated by double stranded RNA, induces inflammation by regulating NF-κB signaling. The NLR family pyrin domain-containing 3 (NLRP3) inflammasome also modulates inflammation in response to infection. Porphyromonas gingivalis (P.gingivalis) is an oral bacterium which is implicated in the pathogenesis of periodontal diseases. We previously reported that PKR is a key modulator of bone metabolism and inflammation in the periodontal tissue. PKR was also reported to induce inflammation in response to microbes by regulating the NLRP3 inflammasome, suggesting that PKR could affect inflammation along with NLRP3 in periodontal diseases. In this study, we investigated the effects of PKR on NLRP3 expression and NF-κB activity in P. gingivalis infected osteoblasts. We first constructed a SNAP26b-tagged P.gingivalis (SNAP-P. g.) and traced its internalization into the cell. SNAP-P. g. increased the activity of PKR and NF-κB and also induced NLRP3 expression in osteoblasts. Inhibition of NF-κB attenuated SNAP-P. g.-induced NLRP3 expression. The knockdown of PKR using shRNA decreased both the activity of NF-κB and the expression of NLRP3 induced by SNAP-P.g.. We therefore concluded that in osteoblasts, P. gingivalis activated PKR, which in turn increased NLRP3 expression by activating NF-κB. Our results suggest that PKR modulates inflammation by regulating the expression of the NLRP3 inflammasome through the NF-κB pathway in periodontal diseases.


Sensing Traffic Density Combining V2V and V2I Wireless Communications.
Wireless technologies are making the development of new applications and services in vehicular environments possible since they enable mobile communication between vehicles (V2V), as well as communication between vehicles and infrastructure nodes (V2I). Usually, V2V communications are dedicated to the transmission of small messages mainly focused on improving traffic safety. Instead, V2I communications allow users to access the Internet and benefit from higher level applications. The combination of both V2V and V2I, known as V2X communications, can increase the benefits even further, thereby making intelligent transportation systems (ITS) a reality. In this paper, we introduce V2X-d, a novel architecture specially designed to estimate traffic density on the road. In particular, V2X-d exploits the combination of V2V and V2I communications. Our approach is based on the information gathered by sensors (i.e., vehicles and road side units (RSUs)) and the characteristics of the roadmap topology to accurately make an estimation of the instant vehicle density. The combination of both mechanisms improves the accuracy and coverage area of the data gathered, while increasing the robustness and fault tolerance of the overall approach, e.g., using the information offered by V2V communications to provide additional density information in areas where RSUs are scarce or malfunctioning. By using our collaborative sensing scheme, future ITS solutions will be able to establish adequate dissemination protocols or to apply more efficient traffic congestion reduction policies, since they will be aware of the instantaneous density of vehicles.


Are neurodegenerative disorder and psychotic manifestations avoidable brain dysfunctions with adequate dietary omega-3?
The present mismatch between what our brain needs, and the modern diet neglects our marine heritage. Last century, the priority in nutrition and food production was to achieve a high protein diet and somatic growth and function. The dietary content of omega-3 (N-3) required by the brain was neglected although evidence for the essentiality of certain fatty acids was published in 1929 and specifically re-affirmed for omega 3 in the brain in the 1970s. Cognitive decline with age and neurodegenerative disorder with dementia are now rising. This review describes signs of N-3 deficit in Alzheimer and Parkinson Disease, where maximum change involves the primary sites: olfactory cortex and the hippocampus. The olfactory agnosia observed in schizophrenia supports an N-3 deficit as does a reduction of key ologodendrocyte- and myelin-related genes in this disorder and affective disorder, where a rise in dementia accords with a deficit of N-3 also in this disorder. N-3 normalizes cerebral excitability at all levels. That the two disorders are localized at the extremes of excitability, is supported by their opposing treatments: convulsant neuroleptics and anti-epileptic antidepressants. An adequate N-3 diet will probably prevent most psychotic episodes and prove that neurodegenerative disorder with dementia is also to a large extent not only preventable but avoidable.


Role of the "YxGG/A" motif of Phi29 DNA polymerase in protein-primed replication.
We have analyzed the functional significance of the phi29 DNA polymerase "YxGG/A" motif in initiation and replication reactions involving the terminal protein (TP) as a primer. This motif, located between the proposed limits of the polymerase and exonuclease domains, has been shown to be very important for the coordination between synthesis and degradation in phi29 DNA polymerase. Mutations in this region affected the polymerization/exonucleolysis (pol/exo) balance, due to its importance for DNA template binding stability at both active sites. Here, we show that the YxGG/A motif of phi29 DNA polymerase is necessary for the formation of a stable complex between TP and phi29 DNA polymerase, affecting initiation and transition during replication of phi29 TP-DNA. The phenotypes in TP-primed reactions in nine of 11 mutant polymerases, showed reduced initiation and/or replication activities using TP-DNA as template. High dATP concentrations allowed the reduced initiation activities of some of these mutant polymerases to reach the wild-type level. The reduction in their affinity for the initiating nucleotide is likely due to their reduced interaction with the TP. Besides, the YxGG/A motif of phi29 DNA polymerase controls the pol/exo balance in the transition step immediately after TP-primed initiation, before DNA polymerase and TP dissociate. Thus, from the first elongation step, the phenotypes of the mutant polymerases parallel those obtained in DNA-primed replication: wild-type, high and low pol/exo balance. A detailed analysis of different transition intermediates suggests that mutants at the YxGG/A motif switch from interaction with TP to DNA once the TP has been extended with six nucleotides.


Pigment cell movement is not required for generation of Turing patterns in zebrafish skin.
The zebrafish is a model organism for pattern formation in vertebrates. Understanding what drives the formation of its coloured skin motifs could reveal pivotal to comprehend the mechanisms behind morphogenesis. The motifs look and behave like reaction-diffusion Turing patterns, but the nature of the underlying physico-chemical processes is very different, and the origin of the patterns is still unclear. Here we propose a minimal model for such pattern formation based on a regulatory mechanism deduced from experimental observations. This model is able to produce patterns with intrinsic wavelength, closely resembling the experimental ones. We mathematically prove that their origin is a Turing bifurcation occurring despite the absence of cell motion, through an effect that we call differential growth. This mechanism is qualitatively different from the reaction-diffusion originally proposed by Turing, although they both generate the short-range activation and the long-range inhibition required to form Turing patterns.


Overlapping genes in the human and mouse genomes.
Increasing evidence suggests that overlapping genes are much more common in eukaryotic genomes than previously thought. In this study we identified and characterized the overlapping genes in a set of 13,484 pairs of human-mouse orthologous genes. About 10% of the genes under study are overlapping genes, the majority of which are different-strand overlaps. The majority of the same-strand overlaps are embedded forms, whereas most different-strand overlaps are not embedded and in the convergent transcription orientation. Most of the same-strand overlapping gene pairs show at least a tenfold difference in length, much larger than the length difference between non-overlapping neighboring gene pairs. The length difference between the two different-strand overlapping genes is less dramatic. Over 27% of the different-strand-overlap relationships are shared between human and mouse, compared to only approximately 8% conservation for same-strand-overlap relationships. More than 96% of the same-strand and different-strand overlaps that are not shared between human and mouse have both genes located on the same chromosomes in the species that does not show the overlap. We examined the causes of transition between the overlapping and non-overlapping states in the two species and found that 3' UTR change plays an important role in the transition. Our study contributes to the understanding of the evolutionary transition between overlapping genes and non-overlapping genes and demonstrates the high rates of evolutionary changes in the un-translated regions.


In Vivo Transcriptional Activation Using CRISPR/Cas9 in Drosophila.
A number of approaches for Cas9-mediated transcriptional activation have recently been developed, allowing target genes to be overexpressed from their endogenous genomic loci. However, these approaches have thus far been limited to cell culture, and this technique has not been demonstrated in vivo in any animal. The technique involving the fewest separate components, and therefore the most amenable to in vivo applications, is the dCas9-VPR system, where a nuclease-dead Cas9 is fused to a highly active chimeric activator domain. In this study, we characterize the dCas9-VPR system in Drosophila cells and in vivo. We show that this system can be used in cell culture to upregulate a range of target genes, singly and in multiplex, and that a single guide RNA upstream of the transcription start site can activate high levels of target transcription. We observe marked heterogeneity in guide RNA efficacy for any given gene, and we confirm that transcription is inhibited by guide RNAs binding downstream of the transcription start site. To demonstrate one application of this technique in cells, we used dCas9-VPR to identify target genes for Twist and Snail, two highly conserved transcription factors that cooperate during Drosophila mesoderm development. In addition, we simultaneously activated both Twist and Snail to identify synergistic responses to this physiologically relevant combination. Finally, we show that dCas9-VPR can activate target genes and cause dominant phenotypes in vivo, providing the first demonstration of dCas9 activation in a multicellular animal. Transcriptional activation using dCas9-VPR thus offers a simple and broadly applicable technique for a variety of overexpression studies.


Surgical Treatment of Nonsyndromic Craniosynostosis.
Studies on the treatment of nonsyndromic craniosynostosis demonstrate decreasing morbidity and mortality; however, complication rates still range from 5% to 14%. Here, the authors present their last 10 years' experience treatment of nonsyndromic single suture craniosynostosis. A retrospective review was performed on patients who underwent open surgical treatment of nonsyndromic craniosynostosis over 10 years. Patient characteristics and clinical outcomes were reviewed. Radiological analysis of intracranial volumes was performed using Amira software. The authors' technique for treatment of sagittal synostosis was the Foreshortening and Lateral Expansion of the Cranium Activated by Gravity (FLAG) procedure. The authors identified 106 patients with a median age of 0.8 years. Sagittal synostosis was most common (n = 65, 61%). Seventeen percent underwent distraction of the cranial vault; the remainder underwent traditional remodeling procedures. The average operative time was 131 minutes, blood loss was 296 mL (30 mL/kg), and intraoperative transfusion was 332 mL (34 mL/kg). There were 2 postoperative complications. Six patients required an additional major operation years later, most commonly for increased intracranial pressure. The authors separately analyzed 50 patients with sagittal synostosis treated with the FLAG procedure. There were no postoperative complications, and only 4 patients required reoperation. The average operative time for the FLAG procedure was 97.3 minutes. Intracranial volume increased by 191.45 mL (28.3-427.5 mL) with 28% average relative cranial vault expansion (4.5%-93.2%). Surgical correction of craniosynostosis using the FLAG technique is safe and effective with minimal morbidity and long standing results. Treatment should involve a structured approach, which minimizes operative times and decreases complication rates.


Expression of innate immunity genes and damage of primary human pancreatic islets by epidemic strains of Echovirus: implication for post-virus islet autoimmunity.
Three large-scale Echovirus (E) epidemics (E4,E16,E30), each differently associated to the acute development of diabetes related autoantibodies, have been documented in Cuba. The prevalence of islet cell autoantibodies was moderate during the E4 epidemic but high in the E16 and E30 epidemic. The aim of this study was to evaluate the effect of epidemic strains of echovirus on beta-cell lysis, beta-cell function and innate immunity gene expression in primary human pancreatic islets. Human islets from non-diabetic donors (n = 7) were infected with the virus strains E4, E16 and E30, all isolated from patients with aseptic meningitis who seroconverted to islet cell antibody positivity. Viral replication, degree of cytolysis, insulin release in response to high glucose as well as mRNA expression of innate immunity genes (IFN-b, RANTES, RIG-I, MDA5, TLR3 and OAS) were measured. The strains of E16 and E30 did replicate well in all islets examined, resulting in marked cytotoxic effects. E4 did not cause any effects on cell lysis, however it was able to replicate in 2 out of 7 islet donors. Beta-cell function was hampered in all infected islets (P<0.05); however the effect of E16 and E30 on insulin secretion appeared to be higher than the strain of E4. TLR3 and IFN-beta mRNA expression increased significantly following infection with E16 and E30 (P<0.033 and P<0.039 respectively). In contrast, the expression of none of the innate immunity genes studied was altered in E4-infected islets. These findings suggest that the extent of the epidemic-associated islet autoimmunity may depend on the ability of the viral strains to damage islet cells and induce pro-inflammatory innate immune responses within the infected islets.


Hypotensive action of naturally occurring diterpenes: a therapeutic promise for the treatment of hypertension.
Plants have always been an exemplary source of drugs and many of the currently available medicines have been directly or indirectly derived from them. For this reason, the research, development and use of natural products as therapeutic agents, especially those derived from plants, have been increasing in recent years. A great deal of attention has focused on the naturally occurring antispasmodic phytochemicals as potential drugs for the treatment of cardiovascular diseases. Arterial hypertension is a common and progressive disorder that poses a major risk for cardiovascular and renal diseases. Recent data have revealed that the global burden of hypertension is an important and increasing public health problem worldwide and that the level of awareness, treatment and control of hypertension varies considerably among countries. The research on naturally occurring blood pressure-lowering agents is rapidly expanding due to the high potential of such molecules as new antihypertensive drugs. Recently, a great number of plant-derived substances, such as diterpenoids, have been evaluated as possible antihypertensive agents. Naturally occurring diterpenes such as forskolin and stevioside, exhibit vasorelaxant action and inhibit vascular contractility by different mechanisms of action. In this review we will discuss the mechanisms underlying the hypotensive action displayed by diterpenes and their potential use in human hypertension. We will also discuss the use of these compounds in the treatment of glaucoma, which is characterized by increased intraocular pressure (IOP).


The additional value of a night splint to eccentric exercises in chronic midportion Achilles tendinopathy: a randomised controlled trial.
To assess whether the use of a night splint is of added benefit on functional outcome in treating chronic midportion Achilles tendinopathy. This was a single-blind, prospective, single centre, randomised controlled trial set in the Sports Medical Department, The Hague Medical Centre, The Netherlands. Inclusion criteria were: age 18-70 years, active participation in sports, and tendon pain localised at 2-7 cm from distal insertion. Exclusion criteria were: insertional disorders, partial or complete ruptures, or systemic illness. 70 tendons were included and randomised into one of two treatment groups: eccentric exercises with a night splint (night splint group, n = 36) or eccentric exercises only (eccentric group, n = 34). Both groups completed a 12-week heavy-load eccentric training programme. One group received a night splint in addition to eccentric exercises. At baseline and follow-up at 12 weeks, patient satisfaction, Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A) score and reported compliance were recorded by a single-blind trained researcher who was blinded to the treatment. After 12 weeks, patient satisfaction in the eccentric group was 63% compared with 48% in the night splint group. The VISA-A score significantly improved in both groups; in the eccentric group from 50.1 to 68.8 (p = 0.001) and in the night splint group from 49.4 to 67.0 (p<0.001). There was no significant difference between the two groups in VISA-A score (p = 0.815) and patient satisfaction (p = 0.261). A night splint is not beneficial in addition to eccentric exercises in the treatment of chronic midportion Achilles tendinopathy.


Modification of serotonergic and noradrenergic neurotransmissions by repeated administration of monoamine oxidase inhibitors: electrophysiological studies in the rat central nervous system.
The net effect of repeated administration of monoamine oxidase inhibitors (MAOI) on central serotonergic (5-HT) and noradrenergic (NE) neurotransmissions was studied by assessing the responsiveness of hippocampal pyramidal neurons to microiontophoretically applied 5-HT and NE and the response of these neurons to the electrical activation of the 5-HT and NE ascending pathways. Brain monoamine oxidase (MAO) activity as well as the levels of 5-HT, NE and their metabolites were determined in order to verify the biochemical effects of the drugs administered. Twenty-one-day treatments with clorgyline and deprenyl inhibited very selectively MAO-A and MAO-B, respectively, whereas a treatment with phenelzine inhibited both forms of the enzyme. Whole brain concentrations of 5-HT and NE were increased by the antidepressant drugs clorgyline and phenelzine whereas deprenyl, an MAOI type B ineffective in endogenous depression, increased only NE levels after a 21-day treatment. The responsiveness of hippocampal pyramidal neurons to 5-HT was decreased by the long-term clorgyline treatment, but not by deprenyl and phenelzine, whereas that to NE was not altered by any of the treatments. The suppression of firing of these same neurons induced by the stimulation of the 5-HT pathway was increased by clorgyline and phenelzine, but not by deprenyl. The effect of the stimulation of the dorsal NE bundle was not modified by any of the treatments. These data show that prolonged inhibition of MAO-A, but not that of MAO-B, results in an enhanced 5-HT neurotransmission.(ABSTRACT TRUNCATED AT 250 WORDS)


Dietary guidance for pulses: the challenge and opportunity to be part of both the vegetable and protein food groups.
Pulses are a dry, edible variety of beans, peas, and lentils that have been consumed for 10,000 years. Pulses are rich in plant-based protein and fiber, as well as micronutrients such as iron and potassium. The satiating effect of both fiber and protein assists in managing weight and combating obesity. The high fiber content and low glycemic index of pulses aid people with diabetes in maintaining blood glucose and insulin levels. Pulse consumption may improve serum lipid levels to reduce the risk of cardiovascular disease. Pulses developed as a member of both the protein and vegetable food groups as a result of its high content of plant-based protein and dietary fiber. The last two revisions of the Dietary Guidelines saw the transformation from the MyPyramid "meat and beans group" to the MyPlate "protein foods group," a nutrient name rather than a food source. Research suggests that consumers better identify with food source examples rather than nutrient names. The 2015 Dietary Guidelines also came with a new area: sustainable diets. Encouraging the consumption of sustainable food sources, like pulses, is imperative to ensuring a secure, healthy food supply for the U.S. population over time and for future generations.


CD83: a regulatory molecule of the immune system with great potential for therapeutic application.
CD83 has been known for a decade to be one of the best markers for mature dendritic cells (DCs). The recognition of CD83 was greatly changed since CD83 in thymus was unveiled to be essential for the generation of CD4+ T cells by the study using CD83-deficient mice. It was recently shown that both activated DCs and B cells release soluble form of CD83 and that low levels of soluble CD83 are present in normal human sera. Both in vivo and in vitro studies demonstrated that soluble CD83 has immunosuppressive roles such as the inhibition of DC-mediated T cell stimulation and the maturation of DCs. CD83 appears to have regulatory functions for immune response in light of observations that the soluble form of CD83 can inhibits immune reactions while being strongly up-regulated during DC maturation and activation. In addition, the fact that various cell types including thymic epithelial cells, activated T and B cells and activated DCs express CD83 suggests the universal role in immune function. Because of these immuno-regulatory functions, the therapeutic application of CD83 is highly anticipated in many pathological states including malignancy and autoimmune disease.


Isolation of Succinivibrionaceae implicated in low methane emissions from Tammar wallabies.
The Tammar wallaby (Macropus eugenii) harbors unique gut bacteria and produces only one-fifth the amount of methane produced by ruminants per unit of digestible energy intake. We have isolated a dominant bacterial species (WG-1) from the wallaby microbiota affiliated with the family Succinivibrionaceae and implicated in lower methane emissions from starch-containing diets. This was achieved by using a partial reconstruction of the bacterium's metabolism from binned metagenomic data (nitrogen and carbohydrate utilization pathways and antibiotic resistance) to devise cultivation-based strategies that produced axenic WG-1 cultures. Pure-culture studies confirm that the bacterium is capnophilic and produces succinate, further explaining a microbiological basis for lower methane emissions from macropodids. This knowledge also provides new strategic targets for redirecting fermentation and reducing methane production in livestock.


Impaired beta-cell functions induced by chronic exposure of cultured human pancreatic islets to high glucose.
In type 2 diabetes, chronic hyperglycemia has been suggested to be detrimental to beta-cell function, causing reduced glucose-stimulated insulin secretion and disproportionately elevated proinsulin. In the present study, we investigated the effect on several beta-cell functions of prolonged in vitro exposure of human pancreatic islet cultures to high glucose concentrations. Islets exposed to high glucose levels (33 mmol/l) for 4 and 9 days showed dramatic decreases in glucose-induced insulin release and in islet insulin content, with increased proportion of proinsulin-like peptides relative to insulin. The depletion in insulin stores correlated with the reduction in insulin mRNA levels and human insulin promoter transcriptional activity. We also demonstrated that high glucose dramatically lowered the binding activity of pancreatic duodenal homeobox 1 (the glucose-sensitive transcription factor), whereas the transcription factor rat insulin promoter element 3b1 activator was less influenced and insulin enhancer factor 1 remained unaffected. Most of these beta-cell impairments were partially reversible when islets first incubated for 6 days in high glucose were transferred to normal glucose (5.5 mmol/l) concentrations for 3 days. We conclude that cultured human islets are sensitive to the deleterious effect of high glucose concentrations at multiple functional levels, and that such mechanisms may play an important role in the decreased insulin production and secretion of type 2 diabetic patients.


Cross-bridge kinetics of rabbit single extraocular and limb muscle fibers.
To gain insights into the functional significance of myosin heavy-chain (MyHC) heterogeneity by comparing the mechanical kinetic properties of single rabbit extraocular muscle (EOM) fibers with those of limb fibers. EOMs are known to contain developmental and EOM-specific MyHCs in addition to those present in limb muscles, and MyHCs profoundly influence muscle mechanics. Isometric cross-bridge kinetics were analyzed in Ca(2+)-activated single glycerinated fibers from rabbit EOM and limb fast and slow muscles at 15 degrees C by means of mechanical perturbation analysis. The plots of stiffness and phase against frequency display a characteristic frequency, f(min), at which stiffness is minimum, and phase shift is zero. The value of f(min) is independent of Ca(2+) or force level but reflects the kinetics of cross-bridge cycling. Analysis of 121 limb fast fibers gave f(min) values ranging from 10 to 26 Hz. f(min) for the 10 slow soleus fibers was 0.5 Hz. Analysis of 170 EOM fibers gave f(min) values in the range for fast limb fibers, but in addition yielded f(min) values below (4-9 Hz) and above (27-33 Hz) this range. The wider range of mechanical kinetic characteristics in EOM fibers compared with limb fibers is likely due to the expression of developmental (low f(min)) and EOM-specific (high f(min)) MyHCs in addition to isoforms present in adult limb muscles. The considerable diversity of functional characteristics in EOM fibers is likely to be important for rotating the eyeball at various speeds during tracking and for executing saccades over a wide range of angles.


The Development of the Chinese Intermittent Exotropia Questionnaire.
The Intermittent Exotropia Questionnaire (IXTQ) is a child, proxy, and parent report of health-related quality of life specific to children with intermittent exotropia (IXT). The present study aimed to develop a Chinese-language version of the IXTQ (CIXTQ) and evaluate its validity and reliability when used in Chinese IXT children and their parents. The IXTQ was translated into Chinese. One hundred seventy-five IXT children (2 to 17 years old) and 151 orthotropic control children (2 to 17 years old) along with one of their parents were recruited. Children 5 to 17 years old completed the 5- to 7-year-old or the 8- to 17-year-old child questionnaire of the CIXTQ according to their age. Parents of all children (2 to 17 years old) completed the proxy and parent questionnaires of the CIXTQ. Psychometric properties of the CIXTQ were examined for floor and ceiling effects, construct validity, item-internal consistency, discriminative validity, Cronbach α coefficient and test-retest reliability. No items were found to have strong floor or ceiling effects. Principal component analysis identified that the CIXTQ had a similar structure to the original English version. The median scores of each questionnaire in the CIXTQ among children with IXT and their parents were significantly lower than those among control subjects (P < .001). Cronbach α coefficients ranged from 0.869 to 0.931, and test-retest reliabilities ranged from 0.898 to 0.981, for each questionnaire in the CIXTQ. The CIXTQ is a useful tool to evaluate the influence of IXT on health-related quality of life among Chinese IXT children and their parents.


Evidence-based medicine at the intersection of research interests between academic health sciences librarians and medical educators: a review of the literature.
In 2008, the Association of Academic Health Sciences Libraries established an Education Research Task Force (ERTF) to plan research addressing research priorities outlined in key Association of American Medical Colleges reports. ERTF members conducted a literature review to describe the state of collaborative research at the intersection of medical education and health sciences librarianship. Analysis of initial results revealed instruction in evidence-based medicine (EBM) was a shared interest and is thus the focus of this review. Searches on EBM teaching programs were conducted, and results were posted to a shared online citation management service. Individual articles were assessed and assigned metadata describing subject matter, scope, and format. Article analysis identified key themes. Most papers were descriptive narratives of curricular development. Evaluation studies were also prominent and often based on student satisfaction or self-reported competency. A smaller number of controlled studies provide evidence of impacts of librarian involvement in EBM instruction. Scholarship of EBM instruction is of common interest between medical educators and health sciences librarians. Coauthorship between the groups and distribution of literature points to a productive collaboration. An emerging literature of controlled studies measuring the impact of cross-disciplinary efforts signals continued progress in the arena of EBM instruction.


Spred2 Regulates High Fat Diet-Induced Adipose Tissue Inflammation, and Metabolic Abnormalities in Mice.
Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome.


Thrombosis: a major contributor to global disease burden.
Thrombosis is the common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused 1 in 4 deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. To review the literature on the global burden of disease caused by VTE. We performed a systematic review of the literature on the global disease burden because of VTE in low-, middle-, and high-income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1000 individuals in the population. The incidence increased to between 2 and 7 per 1000 among those aged ≥70 years. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted life-years lost in low- and middle-income countries, and second in high-income countries, responsible for more disability-adjusted life-years lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low-, middle-, and high-income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems and to evaluate whether improved use of preventive measures will reduce the burden.


Red meat intake and risk of coronary heart disease among US men: prospective cohort study.
To study total, processed, and unprocessed red meat in relation to risk of coronary heart disease (CHD) and to estimate the effects of substituting other protein sources for red meat with CHD risk. Prospective cohort study with repeated measures of diet and lifestyle factors. Health Professionals Follow-Up Study cohort, United States, 1986-2016. 43 272 men without cardiovascular disease or cancer at baseline. The primary outcome was total CHD, comprised of acute non-fatal myocardial infarction or fatal CHD. Cox models were used to estimate hazard ratios and 95% confidence intervals across categories of red meat consumption. Substitution analyses were conducted by comparing coefficients for red meat and the alternative food in models, including red meat and alternative foods as continuous variables. During 1 023 872 person years of follow-up, 4456 incident CHD events were documented of which 1860 were fatal. After multivariate adjustment for dietary and non-dietary risk factors, total, unprocessed, and processed red meat intake were each associated with a modestly higher risk of CHD (hazard ratio for one serving per day increment: 1.12 (95% confidence interval 1.06 to 1.18) for total red meat, 1.11 (1.02 to 1.21) for unprocessed red meat, and 1.15 (1.06 to 1.25) for processed red meat). Compared with red meat, the intake of one serving per day of combined plant protein sources (nuts, legumes, and soy) was associated with a lower risk of CHD (0.86 (0.80 to 0.93) compared with total red meat, 0.87 (0.79 to 0.95) compared with unprocessed red meat, and 0.83 (0.76 to 0.91) compared with processed red meat). Substitutions of whole grains and dairy products for total red meat and eggs for processed red meat were also associated with lower CHD risk. Substituting high quality plant foods such as legumes, nuts, or soy for red meat might reduce the risk of CHD. Substituting whole grains and dairy products for total red meat, and eggs for processed red meat, might also reduce this risk.


Help-Seeking Behavior and Health Care Navigation by Bhutanese Refugees.
The objective of this study was to document barriers to care, help-seeking behaviors, and the impact of a community-based patient navigation intervention on patient activation levels among Bhutanese refugees in the U.S. Data sources comprised 35 intake and 34 post-intervention interviews with program participants, 14 intake and 14 post-intervention interviews with patient navigators, and 164 case notes. Textual data were analyzed using the constant comparison method. Patient activation level was assessed at both time points. Participants had limited English proficiency (97 %), limited literacy (69 %), and the lowest level of patient activation (69 %). Participants routinely experienced complex insurance access, coverage, and payment problems and had limited healthcare-related life skills. Help-seeking began within social networks, with high reliance on bilingual, literate family members perceived to have experience with "the system." Help-seeking was not stigmatized and was instead consistent with societal norms valuing mutual assistance. Participants preferred helpers to act as proxies and required repeated social modeling by peers to gain confidence applying healthcare-related life skills. Following the intervention, only one-third reported the lowest level of patient activation (35 %) and one-third were highly activated (32 %). Bhutanese refugees overcome healthcare access barriers by seeking help from a network of support that begins within the community. Community health workers serving as patient navigators are readily sought out, and this approach is concordant with cultural expectations for mutual assistance. Community health workers serving immigrant groups should model healthcare-related life skills in addition to providing direct assistance.


Health status of female Moldovan migrants to Italy by health literacy level and age group: a descriptive study.
Migration flows from Eastern Europe to Italy have been large and continue to grow. The purpose of this study was to examine the health status of a population of Moldovan migrant women, and their access to health care services in northern Italy, by age group and health literacy level. We administered an ad-hoc questionnaire to adult Moldovan women. A bivariate analysis was conducted to test the association between health literacy and age groups with other variables (lifestyles, symptoms and diseases, access to health services). A stepwise logistic regression analysis was run to test the association between access to primary care and health literacy. Moreover, the study compare Moldovan women data with a sample of Italian women of the same age range living in North-Eastern region. Our sample included 170 Moldovan women (aged 46.5 ± 12.3) in five occupational categories: home care workers (28.2%); cleaners (27.1%); health care workers (5.9%); other occupations (28.8%); and unemployed (10%). Active smokers were twice as prevalent among the women with a low health literacy. Health literacy level also determined access to primary healthcare services. For all age groups, the Moldovan sample reported a higher prevalence of allergies, lumbar disorders and depression than the Italian controls. The reported prevalence of some diseases was higher among Moldovan migrant women than among Italian resident women. Health literacy was associated with the migrant women's lifestyle and the use of primary health care services, as previously seen for the autochthonous population.


Using the functional response of a consumer to predict biotic resistance to invasive prey.
Predators sometimes provide biotic resistance against invasions by nonnative prey. Understanding and predicting the strength of biotic resistance remains a key challenge in invasion biology. A predator's functional response to nonnative prey may predict whether a predator can provide biotic resistance against nonnative prey at different prey densities. Surprisingly, functional responses have not been used to make quantitative predictions about biotic resistance. We parameterized the functional response of signal crayfish (Pacifastacus leniusculus) to invasive New Zealand mud snails (Potamopyrgus antipodarum; NZMS) and used this functional response and a simple model of NZMS population growth to predict the probability of biotic resistance at different predator and prey densities. Signal crayfish were effective predators of NZMS, consuming more than 900 NZMS per predator in a 12-h period, and Bayesian model fitting indicated their consumption rate followed a type 3 functional response to NZMS density. Based on this functional response and associated parameter uncertainty, we predict that NZMS will be able to invade new systems at low crayfish densities (< 0.2 crayfish/m2) regardless of NZMS density. At intermediate to high crayfish densities (> 0.2 crayfish/m2), we predict that low densities of NZMS will be able to establish in new communities; however, once NZMS reach a threshold density of -2000 NZMS/m2, predation by crayfish will drive negative NZMS population growth. Further, at very high densities, NZMS overwhelm predation by crayfish and invade. Thus, interacting thresholds of propagule pressure and predator densities define the probability of biotic resistance. Quantifying the shape and uncertainty of predator functional responses to nonnative prey may help predict the outcomes of invasions.


Can Cytotoxic Effects Induced by Industrial Chemicals be Time-dependent?
Short-term and delayed cytotoxic effects of selected water-soluble and water-insoluble industrial chemicals (dimethyl sulphoxide, ethyl alcohol, methyl alcohol, ammonium nitrate, benzalkonium chloride, butoxyethanol and propylene glycol) were tested on confluent 3T3-L1 mouse fibroblasts by using the neutral red uptake (NRU) assay and the MTT assay. The NRU and MTT assays were performed after exposure to a chemical for 10 minutes and 3 hours and then again 7 days later. The results indicate that the system of testing used permits the assessment of both early and delayed cytotoxic effects of different classes of chemicals. Our experiments revealed that three out of the seven substances tested (butoxyethanol, dimethyl sulphoxide and propylene glycol) exhibited similar cytotoxic effects when assessed after exposure for 10 minutes and 7 days later. The results for ammonium nitrate, ethyl alcohol and methyl alcohol, tested after exposure for 10 minutes and 7 days later, did not significantly differ from each other. However, we noted that the cytotoxic effects observed 7 days after exposure were more pronounced than those found for the same concentration, after exposure for 3 hours. One chemical tested (benzalkonium chloride) had almost no cytotoxic effect after exposure for 10 minutes and 3 hours, but showed a strong cytotoxic effect 7 days after exposure. Our study indicated that the cytotoxic effect might be time-dependent in some chemicals, thus inducing a delayed effect in vitro. In our opinion, it is advisable to assess the cytotoxicity of a chemical after exposure for 3 hours (for immediate effects) and again 7 days later (for delayed effects).


Patterns of sexual behaviour in a rural population in north-western Tanzania.
The HIV epidemic in sub-Saharan Africa has been characterised by the predominance of heterosexual transmission. Patterns of sexual behaviour have been implicated in the spread of the epidemic, but few quantitative data are available on sexual behaviour in rural populations in Africa. This paper reports data from a survey of 1117 adults aged 15-54 years selected randomly from twelve rural communities in Mwanza Region, Tanzania. Sexual debut occurred early, 50% of women and 46% of men reporting first sex before age 16. On average, women married 1.8 years and men 6.1 years after their sexual debut. In women, age at sexual debut appears to have increased over time, in parallel with an increase in age at first marriage. Men were generally married later, to women around five to ten years younger than themselves. Marital dissolution and remarriage were common in both sexes. Reported numbers of sexual partners were compared with those recorded in a population survey in Britain. More men reported 10 or more lifetime partners, or three or more partners in the past year, in rural Mwanza (48% and 29%) than in Britain (24% and 6%). Women reported fewer partners, and results were broadly similar to British data. Casual sex during the past year was reported by 53% of the men and 15% of the women, but only 2% of men reported sexual contact with bar girls or commercial sex workers. Only 20% of men and 3% of women had ever used a condom. Interventions are needed to reduce the high levels of sexual partner change and casual sex, and low levels of condom use, recorded in this rural population. Targeting of interventions to traditional "core groups" may be of limited value in rural areas, and additional strategies are needed, focusing particularly on teenagers who are at high risk of HIV and other sexually transmitted diseases.


Quantitative sequence analysis of FBN1 premature termination codons provides evidence for incomplete NMD in leukocytes.
We improved, evaluated, and used Sanger sequencing for quantification of single nucleotide polymorphism (SNP) variants in transcripts and gDNA samples. This improved assay resulted in highly reproducible relative allele frequencies (e.g., for a heterozygous gDNA 50.0+/-1.4%, and for a missense mutation-bearing transcript 46.9+/-3.7%) with a lower detection limit of 3-9%. It provided excellent accuracy and linear correlation between expected and observed relative allele frequencies. This sequencing assay, which can also be used for the quantification of copy number variations (CNVs), methylations, mosaicisms, and DNA pools, enabled us to analyze transcripts of the FBN1 gene in fibroblasts and blood samples of patients with suspected Marfan syndrome not only qualitatively but also quantitatively. We report a total of 18 novel and 19 known FBN1 sequence variants leading to a premature termination codon (PTC), 26 of which we analyzed by quantitative sequencing both at gDNA and cDNA levels. The relative amounts of PTC-containing FBN1 transcripts in fresh and PAXgene-stabilized blood samples were significantly higher (33.0+/-3.9% to 80.0+/-7.2%) than those detected in affected fibroblasts with inhibition of nonsense-mediated mRNA decay (NMD) (11.0+/-2.1% to 25.0+/-1.8%), whereas in fibroblasts without NMD inhibition no mutant alleles could be detected. These results provide evidence for incomplete NMD in leukocytes and have particular importance for RNA-based analyses not only in FBN1 but also in other genes.


A randomized clinical trial of home intervention for children with failure to thrive.
To evaluate the efficacy of a home-based intervention on the growth and development of children with nonorganic failure to thrive (NOFTT). Randomized clinical trial. The NOFTT sample included 130 children (mean age, 12.7 months; SD, 6.4) recruited from urban pediatric primary care clinics serving low income families. All children were younger than 25 months with weight for age below the fifth percentile. Eligibility criteria included gestational age of at least 36 weeks, birth weight appropriate for gestational age, and no significant history of perinatal complications, congenital disorders, chronic illnesses, or developmental disabilities. Children were randomized into two groups: clinic plus home intervention (HI) (n = 64) or clinic only (n = 66). There were no group differences in children's age, gender, race, or growth parameters, or on any of the family background variables. Most children were raised by single, African-American mothers who received public assistance. Eighty-nine percent of the families (116 of 130) completed the 1-year evaluation. All children received services in a multidisciplinary growth and nutrition clinic. A community-based agency provided the home intervention. Families in the HI group were scheduled to receive weekly home visits for 1 year by lay home visitors, supervised by a community health nurse. The intervention provided maternal support and promoted parenting, child development, use of informal and formal resources, and parent advocacy. Growth was measured by standard procedures and converted to z scores for weight for height and height for age to assess wasting and stunting. Cognitive and motor development were measured with the Bayley Scales of Infant Development, and language development was measured by the Receptive/Expressive Emergent Language Scale. Both scales were administered at recruitment and at the 12-month follow-up. Parent-child interaction was measured by observing mothers and children during feeding at recruitment and at the 12-month follow-up, and the quality of the home was measured by the Home Observation Measure of the Environment 18 months after recruitment. Repeated-measures multivariate analyses of covariance were used to examine changes in children's growth and development and parent-child interaction. Analyses of covariance were used to examine the quality of the home. Independent variables were intervention status and age at recruitment (1.0 to 12.0 vs 12.1 to 24.9 months). Maternal education was a covariate in all analyses. When changes in developmental status and parent-child interaction were examined, weight for height and height for age at recruitment were included as covariates. Children's weight for age, weight for height, and height for age improved significantly during the 12-month study period, regardless of intervention status. Children in the HI group had better receptive language over time and more child-oriented home environments than children in the clinic-only group. The impact of intervention status on cognitive development varied as a function of children's ages at recruitment, with younger children showing beneficial effects of home intervention. There were no changes in motor development associated with intervention status. During the study period, children gained skills in interactive competence during feeding, and their parents became more controlling during feeding, but differences were not associated with intervention status. Findings support a cautious optimism regarding home intervention during the first year of life provided by trained lay home visitors. Early home intervention can promote a nurturant home environment effectively and can reduce the developmental delays often experienced by low income, urban infants with NOFTT: Subsequent investigations of home intervention should consider alternative options for toddlers with NOFTT:


Geographical Differences in Dietary Exposure to Perfluoroalkyl Acids between Manufacturing and Application Regions in China.
Emissions of perfluoroalkyl acids (PFAAs) have increased in China over the past decade, but human exposure pathways are poorly understood. Here we analyzed 15 PFAAs in commonly consumed food items and calculated body weight normalized dietary intake rates (estimated dietary intake, EDIs) in an area with ongoing PFAA production (Hubei province; n = 121) and an urbanized coastal area (Zhejiang province; n = 106). Geographical differences in concentrations were primarily observed for perfluorooctanesulfonic acid (PFOS) and perfluorohexanesulfonic acid (PFHxS) in animal food items and short-chain PFAAs in vegetable food items. The average EDI of ∑PFAAs for adults in Hubei (998 ng kg-1 day-1) was more than 2 orders of magnitude higher than that in Zhejiang (9.03 ng kg-1 day-1). In Hubei province, the average EDI of PFOS for adults (87 ng kg-1 day-1) was close to or exceeded advisory guidelines used in other countries indicating health risks for the population from long-term exposure. Yet, PFOS could only account for about 10% of the EDI of ∑PFAAs in the Hubei province, which was dominated by short-chain PFAAs through consumption of vegetables. The large contribution of short-chain PFAAs to the total EDIs in manufacturing areas emphasize the need for improved exposure and hazard assessment tools of these substances.


A variational Bayes algorithm for fast and accurate multiple locus genome-wide association analysis.
The success achieved by genome-wide association (GWA) studies in the identification of candidate loci for complex diseases has been accompanied by an inability to explain the bulk of heritability. Here, we describe the algorithm V-Bay, a variational Bayes algorithm for multiple locus GWA analysis, which is designed to identify weaker associations that may contribute to this missing heritability. V-Bay provides a novel solution to the computational scaling constraints of most multiple locus methods and can complete a simultaneous analysis of a million genetic markers in a few hours, when using a desktop. Using a range of simulated genetic and GWA experimental scenarios, we demonstrate that V-Bay is highly accurate, and reliably identifies associations that are too weak to be discovered by single-marker testing approaches. V-Bay can also outperform a multiple locus analysis method based on the lasso, which has similar scaling properties for large numbers of genetic markers. For demonstration purposes, we also use V-Bay to confirm associations with gene expression in cell lines derived from the Phase II individuals of HapMap. V-Bay is a versatile, fast, and accurate multiple locus GWA analysis tool for the practitioner interested in identifying weaker associations without high false positive rates.


Reliability and validity of admissions tools used to select students for the health professions.
The selection of students for the health professions is typically a very competitive multi-staged process that includes assessment of both cognitive abilities and personal qualities. The need for reliable and valid assessment measures is obvious. This review of the health professions literature examines the evidence to support the use of various selection tools. It is clear that pre-admission overall grade point average (GPA) is the best predictor of academic performance in all of the health professions; however, the relationship between pre-admission GPA and clinical performance is less clear. The Medical College Admission Test is a good predictor of performance of medical students in terms of in-course grades and licencing examination scores but a similar test does not exist in the other health professions. Controversy remains as to the value of personal interviews and written submissions as selection tools, although it is clear that training of assessors and explicit rating guidelines enhance their reliability and validity. Ongoing research is needed to find more reliable and valid ways of assessing non-cognitive characteristics of applicants.


Peripheral monocytes derived from patients with cystic fibrosis and healthy donors secrete NGAL in response to Pseudomonas aeruginosa infection.
Patients with cystic fibrosis (CF) develop chronic bacterial infections in the respiratory tract, reflecting dysfunctional innate immunity. Neutrophil gelatinase-associated lipocalin (NGAL) has 2 functions: one as an antibacterial host defense protein and the other as a physiological iron carrier. Neutrophil gelatinase-associated lipocalin (NGAL) has been validated as a biomarker for early kidney disease. The aim of this study was to determine whether NGAL could serve as a marker of acute pulmonary exacerbations in CF by measuring NGAL levels in serum samples from subjects with CF during stable clinic visits and during hospitalization for pulmonary exacerbations and comparing these levels to healthy controls and to patients without CF with significant infection. In addition, we aimed to determine if innate immunity cells other than neutrophils act as a source of NGAL. Circulating NGAL levels were measured by enzyme-linked immunosorbent assay in serum samples from 30 subjects with CF when hospitalized for an acute pulmonary exacerbation, 33 subjects with CF during stable clinic visits, 33 patients with sepsis, and 21 healthy controls. Secreted NGAL from CF and healthy control peripheral monocytes infected with Pseudomonas aeruginosa was also measured by enzyme-linked immunosorbent assay. Serum NGAL levels were elevated in the patients with CF compared to the healthy controls (P < 0.001). However, no difference in serum NGAL levels was found between subjects with CF with stable disease compared to subjects with CF undergoing pulmonary exacerbation. Furthermore, peripheral monocytes from CF and subjects without CF secreted NGAL upon infection with Pseudomonas aeruginosa and thereby may be contributing to the circulating NGAL levels observed. Our data show that peripheral monocytes secrete NGAL, and serum NGAL levels are widely distributed among subjects with CF, being elevated both when clinically stable and during a pulmonary exacerbation and thus NGAL is not a sensitive biomarker for pulmonary exacerbations.