Association of the nitric oxide synthase gene polymorphism with an increased risk for progression to diabetic nephropathy in type 2 diabetes.
A mutation of endothelial nitric oxide synthase (ecNOS)-a key enzyme of the endogenous nitrovasodilator system that is essential for the regulation of blood flow and blood pressure-may aggravate the progression to diabetic nephropathy and/or retinopathy. To investigate the association of ecNOS tandem repeat polymorphism with diabetic nephropathy, the ecNOS genotype was assessed in 82 Japanese type 2 diabetic patients without nephropathy, 94 patients with microalbuminuria, 39 patients with nephropathy, and 155 healthy control subjects. The analysis revealed that type 2 diabetic patients with nephropathy (not with microalbuminuria) were significantly different from type 2 diabetic patients without nephropathy and healthy control subjects in genotype distribution (P = 0.0423) and frequency of the ecNOS4a allele (19.2% vs. 7.3 and 7.1%, respectively; P = 0.0078). The odds ratio of progression to diabetic nephropathy in diabetic patients who carry the mutated allele is about 2.87 compared with noncarriers. The stepwise multiple regression analysis in these patients showed that hypertension (F = 9.760) and ecNOS gene polymorphism (F = 5.298) are the relevant variables for nephropathy. However, no association was found between the ecNOS4a allele and hypertension or diabetic retinopathy. These results imply that the ecNOS gene polymorphism may be associated with progression to diabetic nephropathy in Japanese type 2 diabetic patients.


Health status and 6 years survival of 552 90+ Italian sib-ships recruited within the EU Project GEHA (GEnetics of Healthy Ageing).
In a scenario of increasing life expectancy worldwide, it is mandatory to identify the characteristics of a healthy aging phenotype, including survival predictors, and to disentangle those related to environment/lifestyle versus those related to familiarity/genetics. To this aim we comprehensively characterised a cohort of 1,160 Italian subjects of 90 years and over (90+, mean age 93 years; age range 90-106 years) followed for 6 years survival, belonging to 552 sib-ships (familiar longevity) recruited (2005-2008) within the EU-funded GEHA project in three Italian geographic areas (Northern, Central and Southern Italy) different for urban/rural and socio-economical characteristics. On the whole, the following factors emerged as significant predictors of survival after 90 years of age: absence of cognitive impairment and physical disability, high hand grip strength scores and body mass index (BMI) values, "excellent/good" self-reported health, high haemoglobin and total cholesterol levels and low creatinine levels. These parameters, excluding BMI values, were also significantly associated within sib-ships, suggesting a strong familial/genetic component. Geographical micro-heterogeneity of survival predictors emerged, such as functional and physical status being more important in Southern than in Central and Northern Italy. In conclusion, we identified modifiable survival predictors related to specific domains, whose role and importance vary according to the geographic area considered and which can help in interpreting the genetic results obtained by the GEHA project, whose major aim is the comprehensive evaluation of phenotypic and genetic data.


Structure of human O-GlcNAc transferase and its complex with a peptide substrate.
The essential mammalian enzyme O-linked β-N-acetylglucosamine transferase (O-GlcNAc transferase, here OGT) couples metabolic status to the regulation of a wide variety of cellular signalling pathways by acting as a nutrient sensor. OGT catalyses the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine (UDP-GlcNAc) to serines and threonines of cytoplasmic, nuclear and mitochondrial proteins, including numerous transcription factors, tumour suppressors, kinases, phosphatases and histone-modifying proteins. Aberrant glycosylation by OGT has been linked to insulin resistance, diabetic complications, cancer and neurodegenerative diseases including Alzheimer's. Despite the importance of OGT, the details of how it recognizes and glycosylates its protein substrates are largely unknown. We report here two crystal structures of human OGT, as a binary complex with UDP (2.8 Å resolution) and as a ternary complex with UDP and a peptide substrate (1.95 Å). The structures provide clues to the enzyme mechanism, show how OGT recognizes target peptide sequences, and reveal the fold of the unique domain between the two halves of the catalytic region. This information will accelerate the rational design of biological experiments to investigate OGT's functions; it will also help the design of inhibitors for use as cellular probes and help to assess its potential as a therapeutic target.


Recovery of critically endangered Nassau grouper (Epinephelus striatus) in the Cayman Islands following targeted conservation actions.
Many large-bodied marine fishes that form spawning aggregations, such as the Nassau grouper (Epinephelus striatus), have suffered regional overfishing due to exploitation during spawning. In response, marine resource managers in many locations have established marine protected areas or seasonal closures to recover these overfished stocks. The challenge in assessing management effectiveness lies largely in the development of accurate estimates to track stock size through time. For the past 15 y, the Cayman Islands government has taken a series of management actions aimed at recovering collapsed stocks of Nassau grouper. Importantly, the government also partnered with academic and nonprofit organizations to establish a research and monitoring program (Grouper Moon) aimed at documenting the impacts of conservation action. Here, we develop an integrated population model of 2 Cayman Nassau grouper stocks based on both diver-collected mark-resight observations and video censuses. Using both data types across multiple years, we fit parameters for a state-space model for population growth. We show that over the last 15 y the Nassau grouper population on Little Cayman has more than tripled in response to conservation efforts. Census data from Cayman Brac, while more sparse, show a similar pattern. These findings demonstrate that spatial and seasonal closures aimed at rebuilding aggregation-based fisheries can foster conservation success.


A novel intramedullary spinal cord tumor model: functional, radiological, and histopathological characterization.
Survival rates for high-grade intramedullary spinal cord tumors (IMSCTs) are approximately 30%, and optimal therapy has yet to be determined. Development of a satisfactory intramedullary tumor model is necessary for testing new therapeutic paradigms that may prolong survival. The authors report the technique, functional progression, radiological appearance, and histopathological features of a novel intramedullary model in rabbits. Ten New Zealand white rabbits were randomized to receive an intramedullary injection of either 25 microl of VX2 carcinoma cells (500,000 cells; six rabbits) or 25 microl of medium (Dulbecco modified Eagle medium; four rabbits) into the midthoracic spinal cord. Postoperatively the rabbits were evaluated twice daily for neurological deficits. High-resolution magnetic resonance (MR) images were acquired preoperatively and weekly postoperatively until onset of paraparesis, at which point the animals were killed, and the midthoracic spines were processed for histopathological examination. The VX2-carcinoma cells grew in 100% of animals injected and resulted in a statistically significant mean onset of paraparesis of 16.8 +/- 1.7 days (p = 0.0035, log-rank test), compared with animals in the control group in which neurological deficits were absent by Day 45. Contrast-enhanced T1-weighted MR imaging best demonstrated space-occupying intramedullary lesions and histopathological findings confirmed the intramedullary location of the tumor. Animals in the control group exhibited no functional, radiographic, or pathological signs of tumor. Progression to paraparesis was consistent in all the VX2-injected animals, with predictable onset of paraparesis occurring approximately 17 days postinjection. Histopathological and radiological characteristics of the VX2 intramedullary tumor are comparable with those of aggressive primary human IMSCTs. Establishment of this novel animal tumor model will facilitate the testing of new therapeutic paradigms for the treatment of IMSCTs.


Argon laser treatment for trichiasis.
The goal of trichiasis treatment is to eliminate misdirected cilia that irritate the eyeball. Established methods for removal of the eyelashes include epilation, electrolysis, and cryotherapy. Cryotherapy is currently the most effective method in widespread use, but has as potential posttreatment complications "visual loss, lid notching, corneal ulcer, acceleration of symblepharon formation, xerosis, cellulitis, activation of herpes zoster, skin depigmentation, and severe soft tissue reaction." (Wood JR, Anderson RL. Complications of cryosurgery. Arch Ophthalmol 1981;99:460-3.) The use of an argon laser allows more precise placement and control of the treatment, with better overall results. We reviewed the clinical course of 77 patients with a diagnosis of trichiasis, and 1 with distichiasis. We have found treatment of trichiasis with an argon laser with the patient under local anesthesia to be an effective office procedure.


Mini profile of potential anticancer properties of propofol.
Propofol (2, 6-diisopropylphenol) is an intravenous sedative-hypnotic agent administered to induce and maintain anesthesia. It has been recently revealed that propofol has anticancer properties including direct and indirect suppression of the viability and proliferation of cancer cells by promoting apoptosis in some cancer cell lines. This study aimed to establish a profile to quantitatively and functionally evaluate the anticancer properties of propofol in three cancer cell lines: non-small cell lung carcinoma cell line A549, human colon carcinoma cell line LoVo, and human breast cancer cell line SK-BR-3. We demonstrated that the expression level of caspase-3, an apoptosis biomarker, significantly increased in a dose-dependent manner after 24-h stimulation with 100 µM propofol in A549 cells, and slightly increased in LoVo cells. However, there was no change in caspase-3 expression in SK-BR-3 cells. High caspase-3 expression in A549 cells may be modulated by the ERK1/2 pathway because phosphorylated ERK1/2 dramatically reduced after propofol treatment. BAX, a major protein that promotes apoptosis in the regulation phase, was highly expressed in A549 cells after treatment with 25 µM propofol. Apoptosis induced by propofol may be associated with cancer cells carrying Kras mutations. Our results suggest that the anti-cancer effects of propofol, which are consistent with those of previous studies, are likely associated with the Kras mutation status. Only Kras mutation in Codon 12 instead of other Kras status has been demonstrated to play an important role in sensitizing the propofol-induced apoptosis in cancer cell lines from our study. These findings may enable us a detailed investigation of propofol/Kras-mediated cancer cell apoptosis in the future.


Pharmacological PKA inhibition: all may not be what it seems.
Signaling through the cyclic adenosine monophosphate-dependent protein kinase [protein kinase A (PKA)] is an important and widely studied area of signal transduction research. This signaling pathway is commonly investigated through the use of the pharmacological PKA inhibitors H89 and KT 5720. Both of these compounds are thought to block PKA actions through competitive inhibition of the adenosine triphosphate site on the PKA catalytic subunit. Recently, a number of studies have identified actions of H89 and KT 5720 that are independent of their effects on PKA. These nonspecific effects are widespread; they include actions on other protein kinases and signaling molecules and also on basic cellular functions, such as transcription. Here, I summarize the nonspecific effects of these two compounds and compare their actions with those of other PKA inhibitors.


A study of fluid provision and consumption in elderly patients in a long-stay rehabilitation hospital.
Adequate hydration is key to good clinical care and essential for preventing problems in elderly patients such as constipation, pressure sores and confusion. The present study aimed to evaluate fluid provision and consumption in elderly patients against current standards for Scottish hospitals. A service evaluation, of fluid provision and consumption over 24 h by elderly orthopaedic rehabilitation patients in a long-stay hospital in Scotland was conducted. Fluids provided and consumed from trolley services, those at meal times and beverages from jugs of water were measured. The average fluid content of a jug, cup and glass on each ward was determined. Each jug of water provided was recorded, as was the acceptance of hot and cold drinks offered. Intake was determined by measuring the leftover water in each jug when these were refreshed and any leftover liquid in patients' cups deducted from that provided. Observations were made with respect to the presentation and encouragement of fluids. Fifty-eight patients (12 males, 46 female, aged ≥65 years) were monitored, of whom 56 were provided with more than the recommended minimum fluid per day [mean (SEM) = 2379 (82) mL]; however, mean intake was lower than recommended [mean (SEM) = 1302 (60) mL; P = 0.002]. Provision of drinks from a trolley service [mean (SEM) = 956 (44) mL] was less than fluid from jugs [mean (SEM) = 1398 (54) mL; P = 0.002]; however, the consumption of drinks from the trolley was greater [77% consumed, mean (SEM) = 770 (46) mL] than from jugs [41% mean (SEM) = 514 (36) mL; P < 0.001]. Patients consumed significantly more fluid from individual beverages than jugs. Consideration of the method of fluid provision is important with respect to influencing fluid intakes.


Stromal cell-derived factor-1alpha promotes melanoma cell invasion across basement membranes involving stimulation of membrane-type 1 matrix metalloproteinase and Rho GTPase activities.
Tissue invasion by tumor cells involves their migration across basement membranes through activation of extracellular matrix degradation and cell motility mechanisms. Chemokines binding to their receptors provide chemotactic cues guiding cells to specific tissues and organs; they therefore could potentially participate in tumor cell dissemination. Melanoma cells express CXCR4, the receptor for the chemokine stromal cell-derived factor-1alpha (SDF-1alpha). Using Matrigel as a model, we show that SDF-1alpha promotes invasion of melanoma cells across basement membranes. Stimulation of membrane-type 1 matrix metalloproteinase (MT1-MMP) activity by SDF-1alpha was necessary for invasion, involving at least up-regulation in the expression of this metalloproteinase, as detected in the highly metastatic BLM melanoma cell line. Moreover, SDF-1alpha triggered the activation of the GTPases RhoA, Rac1, and Cdc42 on BLM cells, and expression of dominant-negative forms of RhoA and Rac1, but not Cdc42, substantially impaired the invasion of transfectants in response to SDF-1alpha, as well as the increase in MT1-MMP expression. Furthermore, CXCR4 expression on melanoma cells was notably augmented by transforming growth factor-beta1, a Matrigel component, whereas anti-transforming growth factor-beta antibodies inhibited increases in CXCR4 expression and melanoma cell invasion toward SDF-1alpha. The identification of SDF-1alpha as a potential stimulatory molecule for MT1-MMP as well as for RhoA and Rac1 activities during melanoma cell invasion, associated with an up-regulation in CXCR4 expression by interaction with basement membrane factors, could contribute to better knowledge of mechanisms stimulating melanoma cell dissemination.


Hepatitis B viral surface mutations in patients with adefovir resistant chronic hepatitis B with A181T/V polymerase mutations.
The hepatitis B virus (HBV) polymerase gene has overlapping reading frames with surface genes, which allows to alter the amino acid codon of the surface genes. In adefovir (ADV) treated chronic hepatitis B patients carrying rtA181T/rtA181V mutations, overlap with surface gene mutations such as sW172stop/sL173F has been reported. However, the clinical consequences of such surface mutations have not been determined. The aim of this study was to determine the surface gene sequence in ADV-resistant patients carrying the A181T/V mutation and to describe the clinical significance. Of the 22 patients included in this study, 13 were ADV-resistant with rtA181T/V mutations (polymerase mutation group, Group P) and nine were antiviral treatment-naïve (control group, Group C). The Pre-S1 gene mutation, V60A, was detected in 11 patients (Group P=8, Group C=3). A start codon mutation in the Pre-S2 gene was found in five patients (Group P=3, Group C=2). An S gene mutation, sA184V, was found in nine patients, all of whom were in group P. Although sW172stop and sL173F mutations were detected, reduced HBsAg titer was not observed. Further study of these mutations and their clinical implications are needed.


Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors.
Mammalian target of rapamycin (mTOR) inhibitors are a class of targeted cancer therapeutic agents with clinical benefit for multiple tumor types. Oral ulcerations are a common side effect of mTOR inhibitors; however, the clinical findings resemble aphthous stomatitis rather than the mucositis seen with chemotherapy. Consequently, the appearance of aphthous-like oral ulcerations has been referred to as mTOR inhibitor-associated stomatitis (mIAS). The severity of mIAS can be minimized by following common preventive steps and initiating treatment at the first sign of mouth discomfort, thereby reducing the likelihood of treatment discontinuation. mIAS can be managed through prophylactic measures, such as patient education in oral hygiene and avoidance of triggers. Patients who develop mIAS may be treated topically using rinses or other local therapies, including corticosteroids. In severe cases, dose modifications may be required. Oncology nurses have an important role in the management of patients with cancer and are well positioned to offer strategies for minimizing the occurrence and impact of mIAS.


Creating Individualized Education Material for Diabetes Patients Using the eDiabetes Platform.
Diabetes mellitus (DM) is a chronic disease that affects many people in Switzerland and around the world. Once diagnosed, a patient has to continuously monitor blood glucose, manage medications or inject insulin. Technical skills and competencies as well as knowledge on disease management have to be acquired right after being diagnosed. Diabetes consultants support patients in this process and provide educational material. While the process of generating patient-tailored material is currently complex and time consuming, in future, the eDiabetes platform can help. The platform developed in cooperation with the consulting section of the Swiss Diabetes Society offers the opportunity to create individual patient information and instructions to teach technical skills and knowledge on diabetes. Further, an integrated forum allows exchanging information and discussing issues regarding diabetes counselling on a secure platform. Usability tests showed that eDiabetes is easy to use and provides benefits for diabetes consultants and patients.


Neuronal activity in human lateral temporal cortex related to short-term verbal memory, naming and reading.
Extracellular microelectrode recordings were obtained from lateral temporal cortex that was subsequently resected in patients undergoing craniotomies under local anaesthesia for treatment of medically intractable epilepsy. During these recordings patients performed visually presented measures of overt and silent naming and word reading, short-term verbal memory and a control task requiring matching of angles. These measures were designed so that the same visual stimuli elicited language, short-term memory or spatial responses. Statistically significant changes within and between these various measures were identified. Technically satisfactory recordings were obtained from 17 populations reflecting activity predominantly from 1 neuron, in 13 patients. Two populations demonstrated no significant changes in any measured functions. Only 1 population showed changes suggesting a relation to visual perception. Four populations in or adjacent to the superior temporal gyrus altered activity with overt speech. Four other populations in the anterior temporal lobe altered activity during silent, but not overt speech. Some relation to language or memory was established for 13 of the 17 populations: 1 altered activity during reading alone, 6 during memory alone, and 6 to both. Most of the recording sites showing these language and memory changes were not essential for those functions based on surface electrical stimulation mapping. Thus the area of temporal lobe that participates in language and memory, as indicated by changes in neuronal activity, is substantially larger than the areas essential for those functions as determined by stimulation mapping. Within that participatory area, changes related to language were most often an increase in activity sustained throughout the task, a pattern suggestive of mechanisms of selective attention. Changes related to memory most often included a sustained increase in activity at the time of entry of information into memory, and again at retrieval, with decreased activity during the time the memory was stored. A few neuronal populations demonstrated relative inhibition of activity during the memory task, compared with control measures.


Introducing the idea of 'assumed shared food narratives' in the context of social networks: reflections from a qualitative study conducted in Nottingham, England.
This study explores the ways in which social networks might shape accounts about food practices. Drawing on insights from the work of Christakis and Fowler () whose claims about the linkages between obesity and social networks have been the subject of vigorous debate in the sociological literature, we present qualitative data from a study of women's' accounts of social networks and food practices, conducted in Nottingham, England. We tentatively suggest that whilst social networks in their broadest sense, might shape what was perceived to be normal and acceptable in relation to food practices (and provide everyday discursive resources which normalise practice), the relationship between the two is more complex than the linear relationship proposed by Christakis and Fowler. Here, we introduce the idea of assumed shared food narratives (ASFNs), which, we propose, sheds light on motive talk about food practices, and which also provide practical and discursive resources to actors seeking to protect and defend against 'untoward' behaviour, in the context of public health messages around food and eating. We suggest that understanding ASFNs and the ways in which they are embedded in social networks represents a novel way of understanding food and eating practices from a sociological perspective.


Professional activity. How is family physicians' work time changing?
To examine hours worked professionally, work preferences, and changes in both of these and their correlates. Repeated surveys done in 1993 and 1999. Ontario family practices. Cohort of physicians certified in family medicine between 1989 and 1991 after family medicine residency who were surveyed in 1993 when they resided in Ontario. Self-reported hours spent weekly on professional activities, desired hours of professional work, and balance between work and other activities. Fifty-three percent (293) of 553 physicians responded to the 1999 survey; 91% had remained family physicians; 85% of these had participated in the 1993 survey. The difference between the hours that family physicians preferred to work professionally and their actual hours of work had increased since 1993. Childless physicians, women physicians with preschool children, and women physicians married to other physicians worked fewer hours professionally than other physicians in 1999. Female physicians and physicians without children worked closer to their preferred hours than other physicians. Reporting a preference to work fewer hours professionally in 1993 was linked with a reduction in professional activities by 1999. Greater attention should be paid in physician resource planning to the family life cycle of female physicians. Lifestyle changes could lead to a reduction in professional activity among these physicians.


Polyphenol-Rich Cranberry Extracts Modulate Virulence of Streptococcus mutans-Candida albicans Biofilms Implicated in the Pathogenesis of Early Childhood Caries.
Purpose: The purpose of this study was to investigate the effects of polyphenol-rich cranberry extracts on dual-species Streptococcus mutans-Candida. albicans biofilms implicated in contributing to the severity of early childhood caries. Methods: S. mutans-C. albicans biofilms were grown on saliva-coated hydroxyapatite discs (s-HA) mounted on the high-throughput Amsterdam Active Attachment model. The s-HA discs were treated with the cranberry extracts/vehicle control for five minutes just before biofilm growth and subsequently, for similar exposure times, after 12 hours and 24 hours of biofilm growth. The treated 24-hour-old biofilms were then assessed for acidogenicity, metabolic activity, exopolysaccharide (EPS)/microbial biovolumes, structural organization, and colony forming unit (CFU) counts. Results: Treatment with 500 to 1,000 μg/mL of the cranberry extracts produced significant reductions in acidogenicity and metabolic activity (P<0.0001) compared to the control-treated biofilms. A significant decrease in biovolumes of the EPS (P=0.003) and microbial biofilm components (P=0.007) was also seen. Qualitative assessment of confocal biofilm images revealed that the cranberry extract disrupted biofilm structural architecture. Finally, significantly fewer S. mutans (P=0.006) and C. albicans (P=0.036) CFUs were recovered from the cranberry-treated biofilms than from the control-treated bio-films. Conclusions: Cranberry extracts inhibited cariogenic virulence properties of S. mutans-C. albicans dual-species biofilms in an in vitro model.


Effects of differential infantile handling upon weight gain and mortality in the rat and mouse.
Animals were handled during ages 1 to 10, 11 to 20, or 1 to 20 days, or were nonhandled controls. Animals handled for 20 days weighed the most in adulthood, while the controls weighed the least. Animals handled on days 1 to 10 survived food and water deprivation the longest of any group. Mice handled for 20 days died earlier than controls, while the reverse was true for the rat.


A Multi-Domain Self-Report Measure of Coparenting.
OBJECTIVE: This study reports the psychometric properties of a multi-domain measure of the coparenting relationship in dual-parent families. METHOD: 152 couples participating in a transition to parenthood study completed the Coparenting Relationship Scale and additional measures during home visits at child age 6 months, 1 year, and 3 years. RESULTS: Psychometric and construct validity assessments indicated the measure performed satisfactorily. The 35-item measure demonstrated good reliability and strong stability. Subscales measuring theoretically and empirically important aspects of coparenting (coparenting agreement, coparenting closeness, exposure of child to conflict, coparenting support, coparenting undermining, endorsement of partner's parenting, and division of labor) demonstrated good reliability as well. A 14-item brief overall measure showed very strong associations with the overall measure. Relations of the full scale with a measure of social desirability were weak, and the full scale was positively associated with positive dimensions of the dyadic couple relationship (love, sex/romance, couple efficacy) and inversely associated with negative dimensions (conflict, ineffective arguing)-as expected. CONCLUSIONS: This initial examination of the Coparenting Relationship Scale suggests that it possesses good psychometric properties (reliability, stability, construct validity, and inter-rater agreement), can be flexibly administered in short and long forms, and is positioned to promote further conceptual and methodological progress in the study of coparenting.


K4, K9 and K18 in human histone H3 are targets for biotinylation by biotinidase.
Histones are modified post-translationally, e.g. by methylation of lysine and arginine residues, and by phosphorylation of serine residues. These modifications regulate processes such as gene expression, DNA repair, and mitosis and meiosis. Recently, evidence has been provided that histones are also modified by covalent binding of the vitamin biotin. The aims of this study were to identify biotinylation sites in histone H3, and to investigate the crosstalk among histone biotinylation, methylation and phosphorylation. Synthetic peptides based on the sequence of human histone H3 were used as substrates for enzymatic biotinylation by biotinidase; biotin in peptides was probed using streptavidin peroxidase. These studies provided evidence that K4, K9 and K18 in histone H3 are good targets for biotinylation; K14 and K23 are relatively poor targets. Antibodies were generated to histone H3, biotinylated either at K4, K9 or K18. These antibodies localized to nuclei in human placental cells in immunocytochemistry and immunoblotting experiments, suggesting that lysines in histone H3 are biotinylated in vivo. Dimethylation of R2, R8 and R17 increased biotinylation of K4, K9 and K18, respectively, by biotinidase; phosphorylation of S10 abolished biotinylation of K9. These observations are consistent with crosstalk between biotinylation of histones and other known modifications of histones. We speculate that this crosstalk provides a link to known roles for biotin in gene expression and cell proliferation.


Current trends in the pharmacologic and surgical treatment of Parkinson's disease.
Recently, there has been a surge in the research regarding the pharmacologic and surgical treatment of Parkinson's disease. This article reviews the latest modes of medical and surgical therapy for Parkinson's disease. The latest drug therapy has consisted of levodopa, a combination of levodopa and carbidopa (Sinemet/Sinemet CR), and monoamine oxidase type B (MAO-B) inhibitors (selegiline hydrochloride). The surgical treatment modalities have been stereotaxic implantations of dopamine-producing tissues (such as adrenal medulla and fetal mesencephalon) into the caudate nucleus and ventral pallidotomy of patients with Parkinson's disease. The most recent work has been in the field of gene therapy. The implantation of cells genetically modified to express trophic factors and tyrosine hydroxylase for the synthesis of L-dopa from tyrosine has been proposed as a possible route for the treatment of Parkinson's disease. Although the etiology of the disease is still unknown, two recent theories are discussed.


PacBio sequencing reveals bacterial community diversity in cheeses collected from different regions.
Cheese is a fermented dairy product that is popular for its unique flavor and nutritional value. Recent studies have shown that microorganisms in cheese play an important role in the fermentation process and determine the quality of the cheese. We collected 12 cheese samples from different regions and studied the composition of their bacterial communities using PacBio small-molecule real-time sequencing (Pacific Biosciences, Menlo Park, CA). Our data revealed 144 bacterial genera (including Lactobacillus, Streptococcus, Lactococcus, and Staphylococcus) and 217 bacterial species (including Lactococcus lactis, Streptococcus thermophilus, Staphylococcus equorum, and Streptococcus uberis). We investigated the flavor quality of the cheese samples using an electronic nose system and we found differences in flavor-quality indices among samples from different regions. We found a clustering tendency based on flavor quality using principal component analysis. We found correlations between lactic acid bacteria and the flavor quality of the cheese samples. Biodegradation and metabolism of xenobiotics, and lipid-metabolism-related pathways, were predicted to contribute to differences in cheese flavor using Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt). This preliminary study explored the bacterial communities in cheeses collected from different regions and their potential genome functions from the perspective of flavor quality.


Squamous Cell Carcinoma DNA Detection Using Ultrabright SERS Nanorattles and Magnetic Beads for Head and Neck Cancer Molecular Diagnostics.
A rise in head and neck cancers in low and middle countries over recent years has prompted the need for low-cost, resource-efficient diagnostic technologies. Standard diagnosis with histopathology is often not feasible due to the low number of trained pathologists in these regions, resulting in delayed diagnosis and treatment. This study presents an alternative diagnostic method to standard histopathology. We developed a surface enhanced raman scattering (SERS) based method to distinguish squamous cell carcinoma from other cell lines. Using a "sandwich" method employing ultrabright SERA nanorattles and magnetic beads, we directly targeted specific nucleic acid markers of squamous cells. Our method was able to detect the presence of squamous cells with high sensitivity and specificity, supporting its potential for use as a diagnostic tool in head and neck fine needle aspirations (FNA).


Partial signaling by CD8+ T cells in response to antagonist ligands.
Structural variants of an agonist peptide-major histocompatibility complex (MHC) molecule ligand can show partial agonist and/or antagonist properties. A number of such altered ligands appear to act as pure antagonists. They lack any detectable ability to induce T cell effector function and have been described as unable to induce calcium transients and turnover of inositol phosphates. This has been interpreted as an inability of these ligands to initiate any T cell receptor (TCR)-dependent signal transduction, with their antagonist properties ascribed to competition with offered agonist for TCR occupancy. Yet antagonists for mature CD8+ T cells can induce positive selection of thymocytes, implying active induction of T cell differentiation events, and partial agonists or agonist/antagonist combinations elicit a distinctive pattern of early TCR-associated tyrosine phosphorylation events in CD4+ T cells. We have therefore directly examined proximal TCR signaling in a CD8+ T cell line in response to various related ligands. TCR engagement with natural peptide-MHC class I agonist resulted in the same pattern of early TCR-associated tyrosine phosphorylation events as seen with CD4+ cells, including accumulation of both the p21 and p23 forms of phosphorylated zeta, phosphorylation of CD3 epsilon, and association of phosphorylated ZAP-70 with the TCR. Two antagonists that lacked the ability to induce any detectable CTL effector response (cytolysis, esterase release, gamma interferon secretion, interleukin-2 receptor alpha upregulation) were nevertheless found to also induce TCR-dependent phosphorylation events. In these cases, there was preferential accumulation of the p21 form of phospho-zeta without net phosphorylation of CD3 epsilon, as well as the association of nonphosphorylated ZAP-70 kinase with the receptor. These data show that variant ligands induce similar TCR-dependent phosphorylation events in CD8+ T cells as first observed in CD4+ cells. More importantly, they demonstrate that some putatively pure antagonists are actually a subset of partial agonists able to induce intracellular biochemical changes through the TCR. This delivery of a partial signal by antagonists raises the possibility that antagonism in some cases may result from active interference with stimulation of effector activity by agonist in mature T cells, while the same variant signal could selectively trigger intracellular events that allow positive without negative selection in thymocytes.


Chiral multidentate oxazoline ligands based on cyclophosphazene cores: synthesis, characterization and complexation studies.
Chiral oxazoline based bi and hexadentate ligands built on cyclophosphazene cores have been synthesized and characterized. (NPPh2)2[NP(m-OC6H4C(O)OCH3)2] (1) was prepared by the reaction of gem-(NPPh2)2(NPCl2) with methyl-3-hydroxy benzoate in the presence of Cs2CO3. Compound 1 was converted to the dicarboxylic acid (NPPh2)2[NP(m-OC6H4C(O)OH)2] (2) by base promoted hydrolysis with KO(t-Bu). The dicarboxylic acid 2 on reaction with oxalyl chloride followed by (S)-(+)-2-amino-3-methyl-1-butanol, triethylamine and mesyl chloride was converted to the C2-symmetric phosphazene based chiral bisoxazoline ligand (NPPh2)2[NP{m-OC6H4(4-iPr-2-Ox)}2] (3) (Ox = oxazolinyl). A similar C2-symmetric bisoxazoline derivative having an oxazoline group attached to the para position of the phenyl ring was also synthesized starting from (NPPh2)2[NP(p-OC6H4C(O)OCH3)2] (4) which was first converted to the dicarboxylic acid (NPPh2)2[NP(p-OC6H4C(O)OH)2] (5) and finally to (NPPh2)2[NP{p-OC6H4(4-iPr-2-Ox)}2] (6) and (NPPh2)2[NP{p-OC6H4(4-Ph-2-Ox)}2] (7) under similar reaction conditions. Reaction of 6 with Pd(OAc)2 in acetic acid at room temperature and with PdCl2(C6H5CN)2 in refluxing benzene resulted in chiral palladium complexes Pd(OAc)2(NPPh2)2[NP{p-OC6H4(4-iPr-2-Ox)}2] (8) and PdCl2(NPPh2)2[NP{p-OC6H4(4-iPr-2-Ox)}2] (9), respectively. The utility of these palladium complexes as chiral catalysts for the asymmetric rearrangement of trichloroacetimidates to trichloroacetamides has been explored. The hexa(methylbenzoate) derivative of cyclophosphazene [PN(OC6H4COOCH3)2]3 (10) on treatment with KO(t-Bu) and H2O gave the hexacarboxylic acid derivative [PN(OC6H4COOH)2]3 (11), which on treatment with oxalyl chloride followed by (S)-(+)-2-amino-3-methyl-1-butanol/(S)-(+)-2-phenylglycinol, triethylamine and mesyl chloride was converted to the C3-symmetric cyclophosphazene based chiral hexaoxazoline ligands [PN{OC6H4(4-iPr-2-Ox)}2]3 (12) and [PN{OC6H4(4-Ph-2-Ox)}2]3 (13). The bis(phebox) derivative of the cyclophosphazene was prepared starting from (NPPh2)2[NP{OC6H3(COOCH3)2}2] (14), by the reaction of gem-Ph4P3N3Cl2 with dimethyl 5-hydroxyisophthalate in the presence of Cs2CO3. Compound 14 was converted to the tetracarboxylic acid (NPPh2)2[NP{OC6H3(COOH)2}2] (15) by base promoted hydrolysis with KO(t-Bu). The tetracarboxylic acid 15 on reaction with oxalyl chloride followed by (S)-(+)-2-amino-3-methyl-1-butanol/(S)-(+)-2-phenylglycinol, triethylamine and mesyl chloride was converted to the bis(phebox) substituted tetraphenylcyclophosphazene derivatives (NPPh2)2[NP{OC6H3(4-iPr-2-Ox)2}2] (16)/(NPPh2)2[NP{OC6H3(4-Ph-2-Ox)2}2] (17). A similar tetra(phebox) derivative was synthesized from (NPPh2)[NP{OC6H3(COOCH3)2}2]2 (18) which was first converted to (NPPh2)[NP{OC6H3(COOH)2}2]2 (19) and further converted to the tetra(phebox) derivative (NPPh2) [NP{OC6H3(4-Ph-2-Ox)2}2]2 (20). All new compounds were characterized by IR, NMR [(1)H, (13)C{(1)H} and (31)P{(1)H}] and HRMS studies. Compounds 1, 2, 4, 5, 7, 14 and 18 have also been structurally characterized.


Histone deacetylation is required for progression through mitosis in tobacco cells.
Post-translational modifications of core histone proteins play a key role in chromatin structure and function. Here, we study histone post-translational modifications during reentry of protoplasts derived from tobacco mesophyll cells into the cell cycle and evaluate their significance for progression through mitosis. Methylation of histone H3 at lysine residues 4 and 9 persisted in chromosomes during all phases of the cell cycle. However, acetylation of H4 and H3 was dramatically reduced during mitosis in a stage-specific manner; while deacetylation of histone H4 commenced at prophase and persisted up to telophase, histone H3 remained acetylated up to metaphase but was deacetylated at anaphase and telophase. Phosphorylation of histone H3 at serine 10 was initiated at prophase, concomitantly with deacetylation of histone H4, and persisted up to telophase. Preventing histone deacetylation by the histone deacetylase inhibitor trichostatin A (TSA) led to accumulation of protoplasts at metaphase-anaphase, and reduced S10 phosphorylation during anaphase and telophase; in cultured tobacco cells, TSA significantly reduced the frequency of mitotic figures. Our results indicate that deacetylation of histone H4 and H3 in tobacco protoplasts occurs during mitosis in a phase-specific manner, and is important for progression through mitosis.


Ataques de nervios and somatic complaints among island and mainland Puerto Rican children.
Previous research has documented the association between the Latino cultural idiom of distress, ataques de nervios (i.e., "attacks of nerves"), and unexplained neurological symptoms among adults. However, the associations between ataques and somatic complaints in children have not been sufficiently explored. In this study, we assessed the relation between this anxiety-related experience, henceforth ataques, and somatic complaints in a probability sample of Puerto Rican youth, ages 5-13 years, living in San Juan, Puerto Rico (N = 1353) and in the South Bronx, New York (N = 1138). When both sites were combined, children with ataques were significantly more likely to have either a lifetime prevalence of asthma or headaches, and tended to have more stomach aches and a history of epilepsy or seizure than children without ataques. Further within site analyses showed a similar patterning of complaints for the South Bronx sample as for the combined sample. However, children in San Juan with ataques were only slightly more likely to experience headaches, and at risk for injury, than those without ataques. In addition, comparisons between ataque sufferers across sites indicated that children in San Juan with ataques were at elevated risk for serious illness or injury in comparison to those in the South Bronx with ataques. Ataques are significantly associated with a wide range of physical complaints in Puerto Rican youth. However, their pattern of associations differs by context.


Biological data and clinical symptoms as predictors of astrogliosis and neurodegeneration in patients with second-stage Trypanosoma brucei gambiense sleeping sickness.
Concentrations of glial fibrillary acidic protein (GFAp) and light subunit neurofilament protein (NFL) in cerebrospinal fluid (CSF) were measured in patients with second-stage Trypanosoma brucei gambiense sleeping sickness. Correlations between GFAp and NFL in CSF as markers for astrogliosis and neurodegeneration, and clinical and biological data were investigated. Abnormal levels of GFAp and NFL were significantly associated with increasing CSF cell number and protein concentration, and with the absence of lymph nodes or the absence of trypanosomes in lymph node aspirate. A significant association was found between abnormal NFL and presence of trypanosomes in CSF, abnormal limb movements, difficulties in gait and coordination, and low Karnofsky index. By multivariate analysis, it was shown that increasing CSF cell number, increasing CSF protein concentration, and the absence of lymph nodes or the absence of trypanosomes in the lymph node aspirate were the best predictors for astrogliosis and neurodegeneration among the variables tested. These results demonstrate the importance of CSF cell count and protein determination in assessment of the severity of central nervous system involvement and reinforces the importance of laboratory diagnosis to assess the stage of the disease. The clinical symptoms studied were less useful in predicting astrogliosis or neurodegeneration.


Combined transplantation of bone marrow stromal cell-derived neural progenitor cells with a collagen sponge and basic fibroblast growth factor releasing microspheres enhances recovery after cerebral ischemia in rats.
Bone marrow stromal cells (MSCs) are a useful source of cells because of their abundant supply and few associated ethical problems. We have previously reported that neural progenitor cells (NS-MSCs) can be effectively induced from MSCs and differentiate into neurons to contribute to functional recovery when transplanted into the rat stroke model. In this study, we attempted to enhance the therapeutic effects of NS-MSCs with a collagen sponge and basic fibroblast growth factor (bFGF) releasing microspheres. NS-MSCs were generated from MSCs by transfection of Notch-1 intracellular domain followed by culturing the cells in a free-floating culture system. The resulting NS-MSCs were transplanted into the rats with induced brain ischemia by using collagen sponges as scaffolds for transplanted cells, and with bFGF incorporated into gelatin microspheres to aid neovascularization around the transplanted region and proliferation of neural stem cells/neural progenitor cells. In culture, NS-MSCs successfully formed spheres containing cells highly expressing neural progenitor markers. Cell survival, neovascularization, and proliferation of host neural stem cells/neural progenitor cells were improved in animals that received NS-MSCs together with these biomaterials. Behavioral analysis also revealed significant functional recovery. These observations demonstrate that transplantation of NS-MSCs in combination with a collagen sponge and bFGF releasing microspheres significantly improves histological and functional recovery in the rat stroke model. When used with these biomaterials, NS-MSCs would be a promising cell source for treating stroke and neurodegenerative diseases.


How are medical students trained to locate biomedical information to practice evidence-based medicine? A review of the 2007-2012 literature.
This study describes how information retrieval skills are taught in evidence-based medicine (EBM) at the undergraduate medical education (UGME) level. The authors systematically searched MEDLINE, Scopus, Educational Resource Information Center, Web of Science, and Evidence-Based Medicine Reviews for English-language articles published between 2007 and 2012 describing information retrieval training to support EBM. Data on learning environment, frequency of training, learner characteristics, resources and information skills taught, teaching modalities, and instructor roles were compiled and analyzed. Twelve studies were identified for analysis. Studies were set in the United States (9), Australia (1), the Czech Republic (1), and Iran (1). Most trainings (7) featured multiple sessions with trainings offered to preclinical students (5) and clinical students (6). A single study described a longitudinal training experience. A variety of information resources were introduced, including PubMed, DynaMed, UpToDate, and AccessMedicine. The majority of the interventions (10) were classified as interactive teaching sessions in classroom settings. Librarians played major and collaborative roles with physicians in teaching and designing training. Unfortunately, few studies provided details of information skills activities or evaluations, making them difficult to evaluate and replicate. This study reviewed the literature and characterized how EBM search skills are taught in UGME. Details are provided on learning environment, frequency of training, level of learners, resources and skills trained, and instructor roles. The results suggest a number of steps that librarians can take to improve information skills training including using a longitudinal approach, integrating consumer health resources, and developing robust assessments.


Is there an advantage to including the nucleoprotein in a rabies glycoprotein subunit vaccine?
The PV rabies (genotype 1) G and N proteins were produced by recombinant baculoviruses in insect cells. We tested the ability of recombinant antigens to synergistically induce an immune response and, particularly, to broaden the spectrum of Lyssavirus-neutralizing antibodies produced. Cell-free preparations of recombinant proteins caused an immune response. Recombinant rabies G protein (RRG) from infected cell extract or supernatant induced virus neutralizing antibodies (VNAb) against rabies (CVS virus (genotype 1) and in a less extent against European Bat Lyssavirus-1 (EBL-1:genotype 5) Recombinant rabies N protein (RRN) induced antibodies that reacted with the rabies virus ribonucleoprotein (RNP) and primed mice for both the production of VNAb induced by inactivated and purified rabies virus and the protection conferred by RNP. RRN also had an adjuvant effect on VNAb production induced by RRG when the two recombinant proteins were physically associated either encapsulated in liposomes or subjected to ultrasound treatment. However, there was no increase in production of VNAb directed against EBL-1 although classical vaccines (genotype 1) induce partial protection against this virus. thus, beside its adjuvant effect there is some doubt as to whether including rabies N protein in a rabies subunit vaccine containing the recombinant G protein would be advantageous.


Odontogenic Keratocyst in Children: A Review.
Is to highlight the characteristics and management of odontogenic keratocyst in children only. Computerized search in pubmed between (2005-2015) using specific words such as odontogenic keratocyst in children, odontogenic keratocyst association with Gorlin-Goltz syndrome with abstract written in English only. During computerized literature search 77 articles in the years (2005-2015) were found. All these publications were miscellaneous studies including case series and case reports. Only 35 papers were selected which conform to our criteria. Most of the papers indicate that the histological type of keratocyst prevalent in children was parakeratinized variant, and most of the cases occurred in maxilla rather than mandible. We recommend that the surgeons who treat keratocysts in children take into consideration the late presentation in addition to the destructive nature and high recurrence rate. General practitioners face difficulty in early detection and referral of children with keratocysts or Gorlin syndrome. Treatment by multidiscplinary team is important if associated with Gorlin's syndrome Postoperative follow up is advised every 6 months.


Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics.
We have observed rapid and extensive depletion of cellular energy stores by Delta(9)-tetrahydrocannabinol (THC) in the pulmonary transformed cell line A549. ATP levels declined dose dependently with an IC(50) of 7.5 microg/ml of THC after 24-h exposure. Cell death was observed only at concentrations >10 microg/ml. Studies using JC-1, a fluorescent probe for mitochondrial membrane potential, revealed diminished mitochondrial function at THC concentrations as low as 0.5 microg/ml. At concentrations of 2.5 or 10 microg/ml of THC, a decrease in mitochondrial membrane potential was observed as early as 1 h after THC exposure. Mitochondrial function remained diminished for at least 30 h after THC exposure. Flow cytometry studies on cells exposed to particulate smoke extracts indicate that JC-1 red fluorescence was fivefold lower in cells exposed to marijuana smoke extract relative to cells exposed to tobacco smoke extract. Comparison with a variety of mitochondrial inhibitors demonstrates that THC produced effects similar to that of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, suggesting uncoupling of electron transport. Loss of red JC-1 fluorescence by THC was suppressed by cyclosporin A, suggesting mediation by the mitochondrial permeability transition pore. This disruption of mitochondrial function was sustained for at least 24 h after removal of THC by extensive washing. These results suggest that exposure of the bronchopulmonary epithelium to THC may have important health and physiological consequences.


Effects of isolation-rearing on voluntary consumption of ethanol, sucrose and saccharin solutions in Fawn Hooded and Wistar rats.
These experiments examined the hypothesis that isolation-rearing and strain influence hedonic mechanisms. In experiment 1, voluntary consumption of ethanol and water was monitored in the home cage of Fawn Hooded (FH) and Wistar rats. FH rats were found to consume more ethanol at low concentrations than Wistar rats, independent of rearing condition, and isolation-reared rats were found to consume more of high ethanol concentrations, independent of strain. In experiment 2, isolation-reared rats were found to consume more sucrose, independent of concentration, than socially reared rats. In experiment 3, Fawn Hooded rats were found to be more sensitive to low concentration solutions of saccharin, and to consume less of the high concentration solutions, while isolation-rearing was found to enhance consumption of high concentrations. Thus, hedonic processes are independently modulated by strain and rearing conditions, although the effects of isolation-rearing appear to be exacerbated in Fawn Hooded rats.


Lutein intake at the age of 1 year and cardiometabolic health at the age of 6 years: the Generation R Study.
Lutein is a carotenoid with strong antioxidant properties. Previous studies in adults suggest a beneficial role of lutein on cardiometabolic health. However, it is unknown whether this relation also exists in children; therefore, we aimed to assess the relation between lutein intake at 13 months of age and cardiometabolic outcomes at the age of 6 years. We included 2044 Dutch children participating in a population-based prospective cohort study. Diet was measured at 13 months of age with an FFQ. Lutein intake was standardised for energy and β-carotene intake. Blood pressure, anthropometrics, serum lipids and insulin were measured at the age of 6 years. Dual-energy X-ray absorptiometry was performed to measure total and regional fat and lean mass. A continuous cardiometabolic risk factor score was created, including the components body fat percentage, blood pressure, insulin, HDL-cholesterol and TAG. Age- and sex-specific standard deviation scores were created for all outcomes. Multivariable linear regression was performed, including socio-demographic and lifestyle variables. Median (energy-standardised) lutein intake was 1317 mcg/d (95% range 87, 6069 mcg/d). There were no consistent associations between lutein intake at 13 months and anthropometrics and body composition measures at 6 years of age. In addition, lutein intake was not associated with a continuous cardiometabolic risk factor score, nor was it associated with any of the individual components of the cardiometabolic risk factor score. Results from this large population-based prospective cohort study do not support the hypothesis that lutein intake early in life has a beneficial role for later cardiometabolic health.


A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis.
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by selective death of motor neurons. In 5-10% of the familial cases, the disease is inherited because of mutations. One such mutation, P56S, was identified in human VAPB that behaves in a dominant negative manner, sequestering wild type protein into cytoplasmic inclusions. We have conducted a reverse genetic screen to identify interactors of Drosophila VAPB. We screened 2635 genes and identified 103 interactors, of which 45 were enhancers and 58 were suppressors of VAPB function. Interestingly, the screen identified known ALS loci - TBPH, alsin2 and SOD1. Also identified were genes involved in cellular energetics and homeostasis which were used to build a gene regulatory network of VAPB modifiers. One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S) expression in neurons. A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2) that negatively regulates TOR signaling as also by reduction of S6K activity. In comparison, the small bouton phenotype associated with VAP(wt) expression was reversed with Tsc1 knock down as well as S6K-CA expression. Tor therefore interacts with both VAP(wt) and VAP(P58S), but in a contrasting manner. Reversal of VAP(P58S) bouton phenotypes in larvae fed with the TOR inhibitor Rapamycin suggests upregulation of TOR signaling in response to VAP(P58S) expression. The VAPB network and further mechanistic understanding of interactions with key pathways, such as the TOR cassette, will pave the way for a better understanding of the mechanisms of onset and progression of motor neuron disease.


Designs of two randomized, community-based trials to assess the impact of alternative cookstove installation on respiratory illness among young children and reproductive outcomes in rural Nepal.
Acute lower respiratory infections (ALRI) are a leading cause of death among children. Low birthweight is prevalent in South Asia and associated with increased risks of mortality, and morbidity, high levels of indoor household air pollution caused by open burning of biomass fuels are common and associated with high rates of ALRI and low birthweight. Alternative stove designs that burn biomass fuel more efficiently have been proposed as one method for reducing these high exposures and lowering rates of these disorders. We designed two randomized trials to test this hypothesis. We conducted a pair of community-based, randomized trials of alternative cookstove installation in a rural district in southern Nepal. Phase one was a cluster randomized, modified step-wedge design using an alternative biomass stove with a chimney. A pre-installation period of morbidity assessment and household environmental assessment was conducted for six months in all households. This was followed by a one year step-wedge phase with 12 monthly steps for clusters of households to receive the alternative stove. The timing of alternative stove introduction was randomized. This step-wedge phase was followed in all households by another six month follow-up phase. Eligibility criteria for phase one included household informed consent, the presence of a married woman of reproductive age (15-30 yrs) or a child < 36 months. Children were followed until 36 months of age or the end of the trial. Pregnancies were identified and followed until completion or end of the trial. Phase two was an individually randomized trial of the same alternative biomass stove versus liquid propane gas stove in a subset of households that participated in phase one. Follow-up for phase two was 12 months following stove installation. Eligibility criteria included the same components as phase one except children were only enrolled for morbidity follow-up if they were less than 24 months.The primary outcomes included: incidence of ALRI in children and birthweight. We presented the design and methods of two randomized trials of alternative cookstoves on rates of ALRI and birthweight. Clinicaltrials.gov (NCT00786877, Nov. 5, 2008).


Muslim patients and cross-gender interactions in medicine: an Islamic bioethical perspective.
As physicians encounter an increasingly diverse patient population, socioeconomic circumstances, religious values and cultural practices may present barriers to the delivery of quality care. Increasing cultural competence is often cited as a way to reduce healthcare disparities arising from value and cultural differences between patients and providers. Cultural competence entails not only a knowledge base of cultural practices of disparate patient populations, but also an attitude of adapting one's practice style to meet patient needs and values. Gender roles, relationship dynamics and boundaries are culture specific, and are frequently shaped by religious teachings. Consequently, religion may be conceptualised as a cultural repertoire, or dynamic tool-kit, by which members of a faith adapt and negotiate their identity in multicultural societies. The manner in which Islamic beliefs and values inform Muslim healthcare behaviours is relatively under-investigated. In an effort to explore the impact of Islam on the relationship between patients and providers, we present an Islamic bioethical perspective on cross-gender relations in the patient-doctor relationship. We will begin with a clinical scenario highlighting three areas of gender interaction that bear clinical relevance: dress code, seclusion of members of the opposite sex and physical contact. Next, we provide a brief overview of the foundations of Islamic law and ethical deliberation and then proceed to develop ethicolegal guidelines pertaining to gender relations within the medical context. At the end of this reflection, we offer some practice recommendations that are attuned to the cultural sensitivities of Muslim patient populations.


Grass-air exchange of polychlorinated biphenyls.
Three field experiments were performed to assess the clearance, uptake, and exchange kinetics of polychlorinated biphenyls (PCBs) between grass and the atmosphere using mixed- and single-species grass (Holcus lanatus). In the clearance experiment, the grass was artificially contaminated by equilibration with diluted Aroclor vapor then exposed to field air, and the rates of depletion were monitored by sampling at regular intervals to determine clearance rate constants. In the uptake experiment, the uptake of PCBs from the ambient atmosphere was followed in growing grass at ambient concentrations for 3 and 6 weeks by analysis of segmented samples along the length of the sward. In the third experiment, diurnal temperature-driven changes in grass concentrations were measured. The results indicate that the grass is behaving as a two-compartment system: (1) a fast-exchanging surface adsorption site with a response time of hours and a capacity essentially independent of K(OA), the octanol-air partition coefficient and (2) a slow responding site with a response time of weeks, the capacity of which is related to K(OA). The kinetic and equilibrium phenomena involved in grass-air exchange are thus complex and are not adequately described by simple first-order rate constants and equilibrium partitioning coefficients.


D3R Grand Challenge 4: ligand similarity and MM-GBSA-based pose prediction and affinity ranking for BACE-1 inhibitors.
The Drug Design Data Resource (D3R) Grand Challenges present an opportunity to assess, in the context of a blind predictive challenge, the accuracy and the limits of tools and methodologies designed to help guide pharmaceutical drug discovery projects. Here, we report the results of our participation in the D3R Grand Challenge 4 (GC4), which focused on predicting the binding poses and affinity ranking for compounds targeting the [Formula: see text]-amyloid precursor protein (BACE-1). Our ligand similarity-based protocol using HYBRID (OpenEye Scientific Software) successfully identified poses close to the native binding mode for most of the ligands with less than 2 Å RMSD accuracy. Furthermore, we compared the performance of our HYBRID-based approach to that of AutoDock Vina and DOCK 6 and found that using a reference ligand to guide the docking process is a better strategy for pose prediction and helped HYBRID to perform better here. We also conducted end-point free energy estimates on molecules dynamics based ensembles of protein-ligand complexes using molecular mechanics combined with generalized Born surface area method (MM-GBSA). We found that the binding affinity ranking based on MM-GBSA scores have poor correlation with the experimental values. Finally, the main lessons from our participation in D3R GC4 are: (i) the generation of the macrocyclic conformers is a key step for successful pose prediction, (ii) the protonation states of the BACE-1 binding site should be treated carefully, (iii) the MM-GBSA method could not discriminate well between different predicted binding poses, and (iv) the MM-GBSA method does not perform well at predicting protein-ligand binding affinities here.


Identifying differential alternative splicing events from RNA sequencing data using RNASeq-MATS.
RNA sequencing (RNA-Seq) has emerged as a powerful and increasingly cost-effective technology for analysis of transcriptomes. RNA-Seq has several significant advantages over gene expression microarrays, including its high sensitivity and accuracy, broad dynamic range, nucleotide-level resolution, ability to detect novel mRNA transcripts, and ability to analyze pre-mRNA alternative splicing. A major application of RNA-Seq is to detect differential alternative splicing, i.e., differences in exon splicing patterns among different biological conditions. We recently developed a statistical method multivariate analysis of transcript splicing (MATS) for detecting differential alternative splicing events from RNA-Seq data. Here, we describe a computational pipeline RNASeq-MATS based on the MATS algorithm. This pipeline automatically detects and analyzes differential alternative splicing events corresponding to all major types of alternative splicing patterns from RNA-Seq data.


Milestone achievements in a national sample of pediatric emergency medicine fellows: impact of primary residency training.
Pediatric emergency medicine (PEM) fellowships recruit trainees from both pediatric and emergency medicine (EM) residencies. The Accreditation Council for Graduate Medical Education (ACGME) defines separate training pathways for each. The 2015 PEM milestones reflect a combination of subcompetencies from the two residencies. This project aims to compare the milestone achievement of PEM fellows based on their primary residency training. We hypothesize that fellows trained in pediatrics achieve PEM milestones at different rates than EM-trained fellows in the ACGME domains of patient care, medical knowledge, systems-based practice, practice-based learning, professionalism, and interpersonal and communication skills. This is a multicenter, retrospective cohort study of fellows from a national sample of U.S. PEM fellowship programs. Basic demographic information and deidentified, biannual milestone scores for 23 competencies were collected for fellows training between 2015 and 2018. Subcompetencies are scored on a 5-point milestone scale. Descriptive and multivariable analyses for longitudinal data were performed to compare milestone assessments by primary residency training. Complete data were obtained for 600 fellows; 95% (570) and 5% (30) completed pediatric and EM residency, respectively. In both year 1 and year 2 of fellowship, the mean milestone scores of EM-trained fellows were statistically higher than pediatrics-trained fellows across the majority of subcompetencies. By the final year of training, there were no statistically significant differences in milestone scores for any of the subcompetencies. Fellow milestone achievement between groups was not significantly different by graduation. However, fellows entering PEM training from an EM background attained higher scores on the milestones than fellows from a pediatric background in the first year of fellowship.


A density functional theory study of the carbon-coating effects on lithium iron borate battery electrodes.
Lithium iron borate (LiFeBO3) is a promising cathode material due to its high theoretical specific capacity, inexpensive components and small volume change during operation. Yet, challenges related to severe air- and moisture-induced degradation have prompted the utilization of a protective coating on the electrode which also improves the electronic conductivity. However, not much is known about the preferential geometries of the coating as well as how these coating-electrode interfaces influence the lithium diffusion between the coating and the electrode. Here, we therefore present a density functional theory (DFT) study of the anchoring configurations of carbon coating on the LiFeBO3 electrode and its implications on the interfacial lithium diffusion. Due to large barriers associated with Li-ion diffusion through a parallel-oriented pristine graphene coating on the FeBO3 and LiFeBO3 electrode surfaces, large structural defects in the graphene coating are required for fast Li-ion diffusion. However, such defects are expected to exist only in small concentrations due to their high formation energies. Alternative coating geometries were therefore investigated, and the configuration in which the coating layers were anchored normal to the electrode surface at B and O atoms was found to be most stable. Nudged elastic band (NEB) calculations of the lithium diffusion barriers across the interface between the optimally oriented coating layers and the electrode show no kinetic limitations for lithium extraction and insertion. Additionally, this graphite-coating configuration showed partial blocking of electrode-degrading species.


Dexamethasone (DEX) induces Osmotic stress transcription factor 1 (Ostf1) through the Akt-GSK3β pathway in freshwater Japanese eel gill cell cultures.
Osmosensing and osmoregulatory processes undertaken in gills of euryhaline fish are coordinated by integrative actions of various signaling molecules/transcriptional factors. Considerable numbers of studies report the hyper- and hypo-osmoregulatory functions of fish gills, by illustrating the process of gill cell remodeling and the modulation of the expression of ion channels/transporters. Comparatively mechanistic information relayed from signal integration to transcriptional regulation in mediating gill cell functions has not yet been elucidated. In this study we demonstrate the functional links from cortisol stimulation, to Akt activation, to the expression of the transcriptional factor, Ostf1. Using the synthetic glucocorticoid receptor agonist, dexamethasone (DEX), Ostf1 expression is found to be activated via glucocorticoid receptor (GR) and mediated by the Akt-GSK3β signaling pathway. Pharmacological experiments using kinase inhibitors reveal that the expression of Ostf1 is negatively regulated by Akt activation. The inhibition of PI3K or Akt activities, by the specific kinase inhibitors (wortmannin, LY294002 or SH6), stimulates Ostf1 expression, while a reduction of GSK3β activity by LiCl reduces Ostf1 expression. Collectively, our report for the first time indicates that DEX can induce Ostf1 via GR, with the involvement of the Akt-GSK3β signaling pathway in primary eel gill cell cultures. The data also suggest that Ostf1 may play different roles in gill cell survival during seawater acclimation.


Tobacco carcinogen induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation.
Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carcinoma (HCC). In the present study, we investigated whether the tobacco carcinogen 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces lesions in both lungs and livers of ferrets with or without lycopene intervention. Male ferrets (6 groups, n = 8-10) were treated either with NNK (50 mg/kg BW, i.p., once a month for four consecutive months) or saline with or without dietary lycopene supplementation (2.2 and 6.6 mg/kg BW/day, respectively) for 26 weeks. Results demonstrate that NNK exposure results in higher incidences of lung tumors, HCC and steatohepatitis (which is characterized by severe inflammatory cell infiltration with concurrent fat accumulation in liver, hepatocellular ballooning degeneration and increased NF-κB expression), as well as elevations in bilirubin and AST levels in ferrets. Lycopene supplementation at two doses prevented NNK-induced expressions of α7 nicotinic acetylcholine receptor in the lung and NF-κB and CYP2E1 in the liver and attenuated the NNK-induced mortality and pathological lesions in both the lungs and livers of ferrets. The present study provided strong experimental evidence that the tobacco carcinogen NNK can induce both HCC and steatohepatitis in the ferrets and can be a useful model for studying tobacco carcinogen-associated NAFLD and liver cancer. Furthermore, lycopene could provide potential benefits against smoke carcinogen-induced pulmonary and hepatic injury.


Linear pharmacokinetics of micafungin and its active metabolites in Japanese pediatric patients with fungal infections.
The objective of this study was to propose the appropriate dosage regimen of micafungin for pediatric use, considering the effects of dose-linearity, age and other cofactors on the pharmacokinetics. Pharmacokinetic analysis of micafungin and its active metabolites (M1 and M2) after intravenous infusion at doses of 1 to 3 mg/kg was conducted for 19 Japanese pediatric patients (3 infants, 7 toddlers, and 9 pupils) with deep mycosis caused by either Aspergillus or Candida species. One patient was given the maximum dose of 6 mg/kg. The Cmax of micafungin increased in proportion to the dose. The mean values (S.D.) were 5.03 (2.33), 10.25 (4.45), 14.8 (5.52) and 21.1 microg/ml at 1, 2 , 3 and 6 mg/kg, respectively. These parameters were comparable to those seen in adults when the parameter was normalized by body weight. The elimination half life (t1/2) of micafungin over the dose range was apparently constant with the value of 13.1 h. There was no difference between the age groups observed. In fact, the metabolite concentrations were almost the same as those obtained for non-pediatric patients. Thus, micafungin showed the same dose-proportional pharmacokinetics in pediatric patients as it did in adults. No age dependent pharmacokinetics were observed in this study. It was concluded that the body weight adjustment was adequate for the treatment of micafungin in pediatric patients.


A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy.
Engineered nanoparticles that respond to pathophysiological parameters, such as pH or redox potential, have been developed as contrast agents for the magnetic resonance imaging (MRI) of tumours. However, beyond anatomic assessment, contrast agents that can sense these pathological parameters and rapidly amplify their magnetic resonance signals are desirable because they could potentially be used to monitor the biological processes of tumours and improve cancer diagnosis. Here, we report an MRI contrast agent that rapidly amplifies magnetic resonance signals in response to pH. We confined Mn(2+) within pH-sensitive calcium phosphate (CaP) nanoparticles comprising a poly(ethylene glycol) shell. At a low pH, such as in solid tumours, the CaP disintegrates and releases Mn(2+) ions. Binding to proteins increases the relaxivity of Mn(2+) and enhances the contrast. We show that these nanoparticles could rapidly and selectively brighten solid tumours, identify hypoxic regions within the tumour mass and detect invisible millimetre-sized metastatic tumours in the liver.


Accelerometer and self-reported measures of sedentary behaviour and associations with adiposity in UK youth.
This study used accelerometer and self-report measures of overall sedentary time (ST) and screen time behaviours to examine their respective associations with adiposity among UK youth. Participants (Year groups 5, 8, and 10; n=292, 148 girls) wore the SenseWear Armband Mini accelerometer for eight days and completed the Youth Activity Profile, an online report tool designed to estimate physical activity and ST.Stature, body mass and waist circumference were measured to classify adiposity outcomes (overweight/obese and central obesity). One-way between groups ANOVA and adjusted linear, logistic and multinomial logistic regression analyses were conducted. There was a significant main effect of age on total ST across the whole week (F(2, 289)=41.64, p≤0.001). ST increased monotonically across Year 5 (581.09±107.81 min·d-¹), 8 (671.96±112.59 min·d-¹) and 10 (725.80±115.20 min·d-¹), and all pairwise comparisons were significant at p≤0.001. A steep age-related gradient to mobile phone use was present (p≤0.001). ST was positively associated with adiposity outcomes independent of moderate-to-vigorous intensity physical activity (MVPA; p≤0.001). Engaging in >3 hours of video gaming daily was positively associated with central obesity (OR=2.12, p≤0.05) but not after adjustment for MVPA. Results further demonstrate the importance of reducing overall ST to maintain healthy weight status among UK youth.


Metastatic Breast Cancer in Kenya: Presentation, Pathologic Characteristics, and Patterns-Findings From a Tertiary Cancer Center.
The purpose of this research was to describe the sociodemographic and clinical characteristics of Kenyan women with metastatic breast cancer diagnosed and treated at Aga Khan University Hospital in Nairobi, Kenya from 2012 to 2018. We reviewed charts of Kenyan women with metastatic breast cancer and analyzed sociodemographic data, breast cancer risk factors, and tumor characteristics associated with stage at diagnosis, receptor status (ie, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 [HER2]), and site of metastasis using χ2, analysis of variance, two-sample t tests, and logistic regressions. A total of 125 cases with complete medical records were included in the analysis. Forty women (32%) had metastases at diagnosis. Of the others, those diagnosed in stage III developed metastases sooner than those diagnosed in stage II (P < .001). Fifty-eight percent of patients had metastases to bone, 14% to brain, 57% to lungs, and 50% to liver. Seventy-four percent of patients presented with more than one metastatic site. Metastases to bone were associated with greater age at diagnosis (P = .02) and higher parity (P = .04), and metastases to the brain were associated with early menopause (P = .04), lower parity (P = .04), and lack of breastfeeding (P = .01). Patients whose tumors were triple negative (estrogen receptor-negative, progesterone receptor-negative, and HER2 negative) were more likely to develop brain metastases (P = .01), and those whose tumors were HER2 positive were more likely to develop liver metastases (P = .04). Although our data on patterns of metastases and pathologic subtypes are similar to those in published literature, some unique findings concerning hormonal risk factors of women with metastatic breast cancer and specific metastatic sites need additional exploration in larger patient populations.


The Stroke Oxygen Study (SO2S) - a multi-center, study to assess whether routine oxygen treatment in the first 72 hours after a stroke improves long-term outcome: study protocol for a randomized controlled trial.
Mild hypoxia is common in stroke patients and may have significant adverse effects on the ischemic brain after stroke. The use of oxygen treatment is rapidly increasing in European stroke units but is not without side effects. It impedes early mobilization, could pose an infection risk, and may encourage the formation of toxic free radicals, leading to further damage to the ischemic brain. In the Stroke Oxygen Pilot Study (2 or 3 L/min for 72 hours) neurological recovery at one week was better in the oxygen group than in controls, and after correction for difference in baseline stroke severity and prognostic factors, there was a trend to better outcome with oxygen at six months. Oxygen was as effective in mild as in severe strokes.Oxygen saturation is lower at night than during the day, and episodes of oxygen desaturation are common during sleep. Nocturnal oxygen supplementation is likely to reduce the burden of hypoxia without interfering with daytime mobilization and rehabilitation.Before wider use of oxygen supplementation becomes established it is important to obtain better evidence on which patients benefit from such treatment. Participants will be randomized to one of three groups: the first will receive continuous oxygen for 72 hours (at a rate of 2 or 3 L/min depending on baseline oxygen saturation), the second group will receive nocturnal oxygen only (at a rate of 2 or 3 L/min depending on baseline oxygen saturation) and the third group will not receive any oxygen (control). A baseline assessment is performed at randomization and a one-week follow-up completed. Outcome data at three, six and twelve months will be obtained via a questionnaire sent to the patient by the trial center. This study will provide evidence on the effectiveness of oxygen supplementation for the treatment of stroke and whether nocturnal oxygen is a potentially beneficial therapy regimen. This trial is registered with the ISRCTN register ID number ISRCTN52416964.


Use of Transcutaneous Bilirubin to Determine the Need for Phototherapy in Resource-Limited Settings.
Routine and timely determination of total serum bilirubin (TSB) remains a challenge in many resource-limited countries with substantial burden of severe neonatal hyperbilirubinemia. Limited evidence exists on the potential usefulness of transcutaneous bilirubin (TcB) to identify infants who may require phototherapy based on possible treatment criteria in such settings. To compare the number of infants requiring phototherapy across different TSB criteria and determine the predictive performance of TcB under each criterion. Infants with paired TcB and TSB measurements in a maternity hospital in Lagos, Nigeria, were assessed for phototherapy based on TSB criteria by the American Academy of Pediatrics (AAP), National Institute for Health and Clinical Excellence (NICE) UK, and World Health Organization (WHO), and an absolute threshold of ≥12 mg/dL. The predictive performance of TcB across treatment criteria was evaluated with receiver operating curve analysis. A total of 1,011 infants with a mean TcB of 10.54 ± 3.19 (range: 2.7-19.9) mg/dL and TSB of 9.63 ± 2.61 (range: 0.3-19.5) mg/dL were assessed. Some 60 (5.9%) infants required phototherapy by 1 or more TSB criteria, with TSB ≥12 mg/dL identifying 55 (91.7%) and AAP 27 (45%) of these infants. All infants identified by the NICE and WHO criteria were equally detected by the AAP criterion. TcB showed negative predictive values of 99.0-99.9%, and positive predictive values of 7.7-15.5% across all criteria. The number of infants requiring phototherapy varies significantly across treatment criteria. TcB may be useful in identifying infants who do not require phototherapy, but may also identify a high proportion of false positives that is burdensome in resource-limited settings.


Magnetic resonance imaging-based versus computed tomography-based thrombolysis in acute ischemic stroke: comparison of safety and efficacy within a cohort study.
In acute ischemic stroke, brain imaging is mandatory in the decision whether to perform intravenous thrombolysis with recombinant tissue plasminogen activator. The most widespread used imaging modality to exclude intracranial hemorrhage is plain computed tomography (CT). However, there is an ongoing debate whether the information provided by magnetic resonance imaging (MRI) could improve the selection of patients for thrombolysis. We investigated whether the choice of imaging modality (MRI vs. CT) affects therapy safety and the patients' outcome. Analyses are based on data from a prospective, single-center observational study that included all patients with acute ischemic stroke who received intravenous thrombolysis within 4.5 h. Stroke severity was assessed by the National Institutes of Health Stroke Scale. Safety was assessed by rates of symptomatic intracranial hemorrhage (SICH), brain edema with mass effect and 7-day mortality. Outcome was assessed at 3 months as mortality and proportion of independent patients (modified Rankin Scale score between 0 and 2). We analyzed 345 patients of whom 141 received multimodal MRI and 204 received plain CT prior to treatment. Groups did not differ significantly in terms of age, neurological deficit, rate of elevated glucose level or rate of very high blood pressure. However, patients with CT-based thrombolysis had significantly higher rates of cardiac comorbidities (coronary artery disease, heart failure). In the MRI group, we observed a lower rate of 7-day mortality (1 vs. 10%; p = 0.001), a lower rate of SICH (1 vs. 6%; p = 0.010) and a nonsignificantly lower rate of brain edema with mass effect (2 vs. 6%; n.s.). In multivariable analysis, 7-day mortality was independently associated with MRI-based thrombolysis, even if cardiac comorbidities were taken into account. For mortality at 3 months, there was a nonsignificant difference in favor of the MRI group (16 vs. 23%; n.s.). In multivariable analyses, mortality at 3 months was independently associated with older age, higher stroke severity, brain edema with mass effect, SICH, pneumonia and coronary artery disease. Neither mortality nor independent outcome was influenced by initial imaging modality. Thrombolysis based on multimodal MRI is associated with reduced rates of SICH and early death. Our results suggest that these complications affect survival principally in the acute phase after thrombolysis. However, nonneurological and especially cardiac comorbidities also influence survival after stroke and are underrepresented in stroke patients undergoing MRI. Selection bias has to be considered.


Pneumonic tularemia in rabbits resembles the human disease as illustrated by radiographic and hematological changes after infection.
Pneumonic tularemia is caused by inhalation of the gram negative bacterium, Francisella tularensis. Because of concerns that tularemia could be used as a bioterrorism agent, vaccines and therapeutics are urgently needed. Animal models of pneumonic tularemia with a pathophysiology similar to the human disease are needed to evaluate the efficacy of these potential medical countermeasures. Rabbits exposed to aerosols containing Francisella tularensis strain SCHU S4 developed a rapidly progressive fatal pneumonic disease. Clinical signs became evident on the third day after exposure with development of a fever (>40.5°C) and a sharp decline in both food and water intake. Blood samples collected on day 4 found lymphopenia and a decrease in platelet counts coupled with elevations in erythrocyte sedimentation rate, alanine aminotransferase, cholesterol, granulocytes and monocytes. Radiographs demonstrated the development of pneumonia and abnormalities of intestinal gas consistent with ileus. On average, rabbits were moribund 5.1 days after exposure; no rabbits survived exposure at any dose (190-54,000 cfu). Gross evaluation of tissues taken at necropsy showed evidence of pathology in the lungs, spleen, liver, kidney and intestines. Bacterial counts confirmed bacterial dissemination from the lungs to the liver and spleen. The pathophysiology of pneumonic tularemia in rabbits resembles what has been reported for humans. Rabbits therefore are a relevant model of the human disease caused by type A strains of F. tularensis.


Ethnic disparities in stroke: epidemiology, acute care, and postacute outcomes.
Evidence for ethnic disparities in stroke incidence, severity, and mortality has continued to mount in recent years. However, the picture for disparities in acute management and rehabilitation remains more ambiguous. The objective of this report is to summarize current evidence from stroke epidemiology and studies focusing on disparities in stroke care and disability, suggesting courses for action. A comprehensive search of current literature on ethnic/racial variation in stroke incidence, mortality, and severity, as well as acute and postacute patient care was performed. Recent evidence unambiguously reaffirms a greater burden of disease in stroke, greater mortality, and greater severity of strokes for blacks. Evidence for disparities in acute and postacute care is less conclusive, as is the evidence for disparities among other ethnic groups. Evidence for health disparities in stroke care across settings, regions, and the continuum of care varies considerably. Minority ethnic groups have higher rates or more severe stroke, but variations in prognosis for clinical outcomes other than mortality remain less certain. There is considerable need for more studies that take into account regional ethnic variations in treatment and outcomes, and for better documentation of stroke outcomes among groups in addition to blacks. Dealing with ethnic disparities in stroke will be served by sustained attention to quality improvement in high-impact areas in stroke care, complemented by initiatives that promote cultural competence.


Image processing algorithms for the analysis of phase-shifted speckle interference patterns.
A sequence of image processing algorithms for the analysis of interference patterns generated by a phaseshifting speckle interferometer is discussed. The goal is the accurate determination of displacement and strain components at the surface of an object. The phase change related to the displacement is accurately calculated from eight digitized interference patterns using a phase-shifting algorithm. Digital image processing algorithms have been developed for phase unwrapping, phase restoration, and phase fitting. During the processing steps a binary mask is used to solve the problem of invalid areas. Experimental results for the strain components at the surface of a simple object demonstrate a repeatability of 0.3-microstrain rms.


Effect of systemic glucocorticoids on exacerbations of chronic obstructive pulmonary disease. Department of Veterans Affairs Cooperative Study Group.
Although their clinical efficacy is unclear and they may cause serious adverse effects, systemic glucocorticoids are a standard treatment for patients hospitalized with exacerbations of chronic obstructive pulmonary disease (COPD). We conducted a double-blind, randomized trial of systemic glucocorticoids (given for two or eight weeks) or placebo in addition to other therapies, for exacerbations of COPD. Most other care was standardized over the six-month period of follow-up. The primary end point was treatment failure, defined as death from any cause or the need for intubation and mechanical ventilation, readmission to the hospital for COPD, or intensification of drug therapy. Of 1840 potential study participants at 25 Veterans Affairs medical centers, 271 were eligible for participation and were enrolled; 80 received an eight-week course of glucocorticoid therapy, 80 received a two-week course, and 111 received placebo. About half the potential participants were ineligible because they had received systemic glucocorticoids in the previous 30 days. Rates of treatment failure were significantly higher in the placebo group than in the two glucocorticoid groups combined at 30 days (33 percent vs. 23 percent, P=0.04) and at 90 days (48 percent vs. 37 percent, P=0.04). Systemic glucocorticoids (in both groups combined) were associated with a shorter initial hospital stay (8.5 days, vs. 9.7 days for placebo, P=0.03) and with a forced expiratory volume in one second that was about 0.10 liter higher than that in the placebo group by the first day after enrollment. Significant treatment benefits were no longer evident at six months. The eight-week regimen of therapy was not superior to the two-week regimen. The patients who received glucocorticoid therapy were more likely to have hyperglycemia requiring therapy than those who received placebo (15 percent vs. 4 percent, P=0.002). Treatment with systemic glucocorticoids results in moderate improvement in clinical outcomes among patients hospitalized for exacerbations of COPD. The maximal benefit is obtained during the first two weeks of therapy. Hyperglycemia of sufficient severity to warrant treatment is the most frequent complication.


GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment.
Ovarian cancer remains the most lethal gynecologic malignancy, and is primarily diagnosed at late stage when considerable metastasis has occurred in the peritoneal cavity. At late stage abdominal cavity ascites accumulation provides a tumor-supporting medium in which cancer cells gain access to growth factors and cytokines that promote survival and metastasis. However, little is known about the redox status of ascites, or whether antioxidant enzymes are required to support ovarian cancer survival during transcoelomic metastasis in this medium. Gene expression cluster analysis of antioxidant enzymes identified two distinct populations of high-grade serous adenocarcinomas (HGSA), the most common ovarian cancer subtype, which specifically separated into clusters based on glutathione peroxidase 3 (GPx3) expression. High GPx3 expression was associated with poorer overall patient survival and increased tumor stage. GPx3 is an extracellular glutathione peroxidase with reported dichotomous roles in cancer. To further examine a potential pro-tumorigenic role of GPx3 in HGSA, stable OVCAR3 GPx3 knock-down cell lines were generated using lentiviral shRNA constructs. Decreased GPx3 expression inhibited clonogenicity and anchorage-independent cell survival. Moreover, GPx3 was necessary for protecting cells from exogenous oxidant insult, as demonstrated by treatment with high dose ascorbate. This cytoprotective effect was shown to be due to GPx3-dependent removal of extracellular H2O2. Importantly, GPx3 was necessary for clonogenic survival when cells were cultured in patient-derived ascites fluid. While oxidation reduction potential (ORP) of malignant ascites was heterogeneous in our patient cohort, and correlated positively with ascites iron content, GPx3 was required for optimal survival regardless of ORP or iron content. Collectively, our data suggest that HGSA ovarian cancers cluster into distinct groups of high and low GPx3 expression. GPx3 is necessary for HGSA ovarian cancer cellular survival in the ascites tumor environment and protects against extracellular sources of oxidative stress, implicating GPx3 as an important adaptation for transcoelomic metastasis.


Performing purity: reproductive decision-making and implications for a community under threat of zika in iquitos, Peru.
The long-term management and prevention of Zika virus requires understanding of reproductive and sexual health behaviours, including mechanisms of partnered decision-making. In this article, we report on a qualitative study conducted before the arrival of Zika in Iquitos, Peru. We assessed existing patterns of reproductive decision-making among partnered men and women in a community under threat of Zika and discuss how these may impact Zika prevention in the long-term. We used a rapid qualitative assessment methodology, including in-depth semi-structured interviews with partnered women (28) and men (21). Deeply unequal gender role expectations limit discussion of reproductive decisions until after a first child is born. Women needed to perform a domestic 'of-the-house' role to be considered suitable partners, leading them to hide their knowledge of sexual and reproductive health. Condoms symbolise risk and are unused with partners in committed relationships. A shared perception that men must take care of female partner's sexual health, translates into male sexual and reproductive preferences overcoming female desires. Existing decision-making patterns lead to an increased risk of Zika exposure. Long-term response should expand Zika virus information and preventive messages to men and young people, in addition to engaging with broader societal challenges to gender inequity.


Reactions to genetically modified food crops and how perception of risks and benefits influences consumers' information gathering.
Previous research has reported strong consumer perception that genetically modified (GM) food crops may lead to adverse outcomes in a number of different areas. This is despite the widespread promulgation of the potential benefits and opportunities ascribed to the same technology by many scientists and other experts. A computer-based information gathering and evaluation task was completed by 198 adults to assess the extent to which their initial focus on the dangers or opportunities of genetic modification, or both, could be ascribed to the manner in which they gathered information on the topic (heuristically vs. systematically). Results did not confirm the hypothesis that initial focus (risks, benefits, or both) predicted ongoing information gathering and evaluation behavior. Moreover, also contrary to prediction, most participants primarily used systematic strategies when deriving their initial position, regardless of that opinion. Participants found it difficult to achieve a balanced perspective on GM food crop, even though balanced argument, as measured by order of story selection and time spent reading, was preferred as the source of information. Perceived importance is probably the most influential variable determining information gathering about issues or events to which a level of risk is attached.