Cyclic antidepressants and the risk of hip fracture.
To determine whether cyclic antidepressants increase the risk of hip fracture, we conducted a population-based case-control study in the Canadian province of Saskatchewan. We identified 4501 persons 65 years of age or older with a first hospitalization for hip fracture between 1977 and 1985 and 24,041 comparable controls. Current antidepressant users had a relative risk of hip fracture of 1.6 (95% confidence interval, 1.3 to 1.9). Medical record review for a sample of 164 cases suggested this finding was not due to confounding by body mass, impaired ambulation, functional status, or dementia.


A World at Risk: Aggregating Development Trends to Forecast Global Habitat Conversion.
A growing and more affluent human population is expected to increase the demand for resources and to accelerate habitat modification, but by how much and where remains unknown. Here we project and aggregate global spatial patterns of expected urban and agricultural expansion, conventional and unconventional oil and gas, coal, solar, wind, biofuels and mining development. Cumulatively, these threats place at risk 20% of the remaining global natural lands (19.68 million km2) and could result in half of the world's biomes becoming >50% converted while doubling and tripling the extent of land converted in South America and Africa, respectively. Regionally, substantial shifts in land conversion could occur in Southern and Western South America, Central and Eastern Africa, and the Central Rocky Mountains of North America. With only 5% of the Earth's at-risk natural lands under strict legal protection, estimating and proactively mitigating multi-sector development risk is critical for curtailing the further substantial loss of nature.


Pica and the obsessive-compulsive spectrum disorders.
The concept of a spectrum of obsessive-compulsive related disorders may have clinical and research heuristic value in the approach to disorders similar to obsessive-compulsive disorder (OCD) in respect of phenomenology and psychobiology. Like other repetitive and ritualistic behaviours, pica may be postulated to fall at times on this spectrum. Five cases of pica seen at our clinics are presented here in order to test this hypothesis. Phenomenology, neurobiology (where available) and pharmacotherapy data are provided in order to consider a possible relationship with OCD and OCD spectrum disorders. In 2 of the cases, pica appeared to be a compulsion and patients had additional symptoms which met diagnostic criteria for OCD. In 2 of the cases, the clinical picture and neurobiological data were reminiscent of an impulse control disorder. Four of the 5 patients responded to treatment with a serotonin re-uptake inhibitor (SRI). These results are consistent with a hypothesis that at least some cases of pica may usefully be conceptualised as lying within a compulsive-impulsive spectrum of symptoms and disorders.


Genetic improvement of purslane (Portulaca oleracea L.) and its future prospects.
Common purslane (Portulaca oleracea), also known as pigweed, fatweed, pusle, and little hogweed, is an annual succulent herb in the family Portulacaceae that is found in most corners of the globe. From the ancient ages purslane has been treated as a major weed of vegetables as well as other crops. However, worldwide researchers and nutritionists have studied this plant as a potential vegetable crop for humans as well as animals. Purslane is a nutritious vegetable with high antioxidant properties and recently has been recognized as the richest source of α-linolenic acid, essential omega-3 and 6 fatty acids, ascorbic acid, glutathione, α-tocopherol and β-carotene. The lack of vegetable sources of ω-3 fatty acids has resulted in a growing level of attention to introduce purslane as a new cultivated vegetable. In the rapid-revolutionizing worldwide atmosphere, the ability to produce improved planting material appropriate to diverse and varying rising conditions is a supreme precedence. Though various published reports on morphological, physiological, nutritional and medicinal aspects of purslane are available, research on the genetic improvement of this promising vegetable crop are scant. Now it is necessary to conduct research for the genetic improvement of this plant. Genetic improvement of purslane is also a real scientific challenge. Scientific modernization of conventional breeding with the advent of advance biotechnological and molecular approaches such as tissue culture, protoplast fusion, genetic transformation, somatic hybridization, marker-assisted selection, qualitative trait locus mapping, genomics, informatics and various statistical representation have opened up new opportunities of revising the relationship between genetic diversity, agronomic performance and response to breeding for varietal improvement. This review is an attempt to amalgamate the assorted scientific information on purslane propagation, cultivation, varietal improvement, nutrient analyses, medicinal uses and to describe prospective research especially for genetic improvement of this crop.


Mesenchymal stem cells for sensorineural hearing loss: protocol for a systematic review of preclinical studies.
Sensorineural hearing loss (SNHL) is the most common form of hearing impairment and is characterized by a loss of receptor hair cells and/or spiral ganglion neurons. Regenerative stem cell therapy could potentially restore normal hearing and slow the progression of hearing loss in patients. Preclinical animal studies have demonstrated that mesenchymal stem cells (MSCs) could be a promising new therapy for this condition. These findings have prompted investigators to begin human clinical trials to assess the safety and efficacy of MSCs for the treatment of SNHL. The objective of the proposed systematic review is to examine the efficacy of MSCs as a therapy for SNHL in animal models. We will include preclinical animal studies of SNHL in which MSCs are administered, and outcomes are compared against MSC-naïve controls. The primary outcome will include audiologic tests that are routinely used in experimental studies of hearing loss, such as auditory brainstem response (ABR) and distortion product otoacoustic emissions testing (DPOAE). Secondary outcomes will include histology, microscopy, gene protein expression, and behavioral responses of animals. Electronic searches of MEDLINE via PubMed, Scopus, ScienceDirect, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) will be performed. Search results will be screened independently and in duplicate. Data from eligible studies will be extracted, pooled, and analyzed using random effects models. Risk of bias and publication bias will be assessed using the Systematic Review Center for Laboratory Animal Experimentation (SYRCLE) risk of bias tool and Funnel Plots/Egger's regression tests, respectively. This systematic review will provide a summary of the efficacy of MSC therapy in animal models of SNHL, utilizing functional hearing assessment as a primary outcome. Findings from this review are important because they can elucidate research gaps that should be addressed in future preclinical studies and in turn can be translated into clinical studies. CAMARADES ( http://www.dcn.ed.ac.uk/camarades/ ).


Usability testing, initial implementation, and formative evaluation of an evidence-based intervention: lessons from a demonstration project to reduce long-term foster care.
The field of child welfare faces an undersupply of evidence-based interventions to address long-term foster care. The Permanency Innovations Initiative is a five-year federal demonstration project intended to generate evidence to reduce long stays in foster care for those youth who encounter the most substantial barriers to permanency. This article describes a systematic and staged approach to implementation and evaluation of a PII project that included usability testing as one of its key activities. Usability testing is an industry-derived practice which analyzes early implementation processes and evaluation procedures before they are finalized. This article describes the iterative selection, testing, and analysis of nine usability metrics that were designed to assess three important constructs of the project's initial implementation and evaluation: intervening early, obtaining consent, and engaging parents. Results showed that seven of nine metrics met a predetermined target. This study demonstrates how findings from usability testing influenced the initial implementation and formative evaluation of an evidence-supported intervention. Implications are discussed for usability testing as a quality improvement cycle that may contribute to better operationalized interventions and more reliable, valid, and replicable evidence.


Incidence and risk factors for fatal pulmonary embolism after major trauma: a nested cohort study.
Venous thromboembolism is common after major trauma. Strategies to prevent fatal pulmonary embolism (PE) are widely utilized, but the incidence and risk factors for fatal PE are poorly understood. Using linked data from the intensive care unit, trauma registry, Western Australian Death Registry, and post-mortem reports, the incidence and risk factors for fatal PE in a consecutive cohort of major trauma patients, admitted between 1994 and 2002, were assessed. Non-linear relationships between continuous predictors and risk of fatal PE were modelled by logistic regression. Of the 971 consecutive trauma patients considered in the study, 134 (13.8%) died after their injuries. Fatal PE accounted for 11.9% of all deaths despite unfractionated heparin prophylaxis being used in 44% of these patients. Fatal PE occurred in those who were older (mean age 51- vs 37-yr-old, P=0.01), with more co-morbidities (Charlson's co-morbidity index 1.1 vs 0.2, P=0.01), had a larger BMI (31.8 vs 24.5, P=0.01), and less severe head and systemic injuries when compared with those who died of other causes. Sites of injuries were not significantly related to the risk of fatal PE. Fatal PE occurred much later than deaths from other causes (median 18 vs 2 days, P=0.01), and the estimated attributable mortality of PE was 49% (95% confidence interval 36-62%). Fatal PE appeared to be a potential preventable cause of late mortality after major trauma. Severity of injuries, co-morbidity, and BMI were important risk factors for fatal PE after major trauma.


Narrow-leafed lupin (Lupinus angustifolius L.) seed β-conglutins reverse the induced insulin resistance in pancreatic cells.
Insulin resistance (IR) is the main contributor to the development of type 2 diabetes. In this study, we have purified recombinant β-conglutin proteins (rβ1 to rβ4, and rβ6) from narrow-leafed lupin (NLL) by using affinity chromatography. The objective of this study was to evaluate the capacity of these β-conglutins to improve the IR state using ex vivo and in vitro systems. rβ1, rβ3, and rβ6 produced lower levels of pro-inflammatory mediator nitric oxide (about -7-fold in all cases), up-regulated mRNA expression levels of IRS-1 (+201, +173, +192%) and Glut-4 (+286, +121, +147%), increased levels of p85-PI3K (+188, +187, +137-fold) and Glut-4 (+503, +548, +515-fold) proteins, higher phosphorylation levels of the insulin signalling pathway activator p-IRS-1 and downstream mediators such as p-Akt, p-Cbl, and p-caveolin, and improved glucose uptake in insulin resistant (IR-C) culture cells. β-conglutin proteins were able to suppress the oxidative stress produced by insulin-induced resistance on PANC-1 control (C) cells by strongly reducing the protein oxidative carbonylation induced by ROS and balancing the metabolic homeostasis in IR-C cells through regulation of mRNA expression. At the same time, β-conglutins are able to reduce the levels of the pro-inflammatory mediator nitric oxide and promote the anti-oxidative capacity of cells by increasing the levels of reduced glutathione. These results suggest NLL β-conglutins might play a fundamental role as functional food components, since β-conglutins' nutraceutical properties could enhance the effectiveness of dietary improvement of type 2 diabetes complications.


Discrete cyclic di-GMP-dependent control of bacterial predation versus axenic growth in Bdellovibrio bacteriovorus.
Bdellovibrio bacteriovorus is a Delta-proteobacterium that oscillates between free-living growth and predation on Gram-negative bacteria including important pathogens of man, animals and plants. After entering the prey periplasm, killing the prey and replicating inside the prey bdelloplast, several motile B. bacteriovorus progeny cells emerge. The B. bacteriovorus HD100 genome encodes numerous proteins predicted to be involved in signalling via the secondary messenger cyclic di-GMP (c-di-GMP), which is known to affect bacterial lifestyle choices. We investigated the role of c-di-GMP signalling in B. bacteriovorus, focussing on the five GGDEF domain proteins that are predicted to function as diguanylyl cyclases initiating c-di-GMP signalling cascades. Inactivation of individual GGDEF domain genes resulted in remarkably distinct phenotypes. Deletion of dgcB (Bd0742) resulted in a predation impaired, obligately axenic mutant, while deletion of dgcC (Bd1434) resulted in the opposite, obligately predatory mutant. Deletion of dgcA (Bd0367) abolished gliding motility, producing bacteria capable of predatory invasion but unable to leave the exhausted prey. Complementation was achieved with wild type dgc genes, but not with GGAAF versions. Deletion of cdgA (Bd3125) substantially slowed predation; this was restored by wild type complementation. Deletion of dgcD (Bd3766) had no observable phenotype. In vitro assays showed that DgcA, DgcB, and DgcC were diguanylyl cyclases. CdgA lacks enzymatic activity but functions as a c-di-GMP receptor apparently in the DgcB pathway. Activity of DgcD was not detected. Deletion of DgcA strongly decreased the extractable c-di-GMP content of axenic Bdellovibrio cells. We show that c-di-GMP signalling pathways are essential for both the free-living and predatory lifestyles of B. bacteriovorus and that obligately predatory dgcC- can be made lacking a propensity to survive without predation of bacterial pathogens and thus possibly useful in anti-pathogen applications. In contrast to many studies in other bacteria, Bdellovibrio shows specificity and lack of overlap in c-di-GMP signalling pathways.


Musical mirror-symmetrical movement tasks: comparison of rhythm versus melody-playing.
Bimanual mirror-symmetrical movement (MSM) is relatively easy to control movement. Different MSM tasks may have different activations and interhemispheric interactions. The purpose of this study is to compare anatomo-physiological features such as hemispheric activations and dominance of two different MSMs, namely melody-playing and rhythm. We examined functional MRI (fMRI) recordings in a group of fifteen right-handed pianists performing two separate tasks: bimanual rhythm and bimanual melody-playing on two different keyboards with standard key order for right hand and reversed for left hand, which allows homolog fingers' movements. Activations and laterality indices on fMRI were examined. The results show that significant cerebellar activations (especially in anterior cerebellum) in both groups. Significant primary sensorimotor cortical activations are observed in the melody-playing group. While there are also bilaterally symmetric activations, and laterality indices suggest overall lateralization towards the left hemisphere in both groups. Activations in the left fronto-parietal cortex, left putamen and left thalamus in conjunction with right cerebellar activations suggest that the left cortico-thalamo-cerebellar loop may be a dominant loop. Dynamic causal modeling (DCM) indicates the presence of causal influences from the left to the right cerebral cortex. In conclusion, melody-playing with bimanual MSM is a complex in-phase task and may help activate the bilateral cortical areas, and left hemisphere is dominant according to laterality indices and DCM results. On the other hand, bimanual rhythm is a simpler in-phase task and may help activate subcortical areas, which might be independent of the voluntary cortical task.


History of venereal diseases from antiquity to the renaissance.
Sexually transmitted diseases (STDs), previously known as venereal diseases (VD), were present among the populations of antiquity as well as during the Middle Ages. Clay tablets from Mesopotamia, Egyptian papyri, along with mythology, paintings of erotic scenes, and presence of prostitutes give sufficient information to assume that some form of urethral and vaginal discharge, and also herpes genitalis were present among people at that time, and that these diseases were considered a divine punishment. Some passages of the Bible say much about the sexual behavior of the ancient Hebrews. The writings of the Greek and Roman physicians and of their satiric poets (Martial, Juvenal, Ovid) described diverse genital diseases. Celsus described various diseases of the genitals, that he called the "obscene parts". Galen made a strange description of the female genitals and coined the term gonorrhea - flow of semen. The ancient Chinese and Indian physicians also gave some account on the presence of venereal diseases in their books, and the temple sculptures depict their sexual life. During the Middle Ages, numerous physicians and surgeons from Europe as well as from Arabic countries wrote on local diseases of the genitals, describing chancres, condylomata, erosions, pustules, urethral and vaginal discharge, and their treatment. Some were aware that the alterations were connected with sexual activity. In spite the fact the Christian church propagated abstinence, the spread of venereal diseases was possible because the diffusion of prostitution, communal baths, and wars. During the 19th century, some of the physicians and historians, especially J. Rosenbaum, F. Buret, and E. Lancereaux believed syphilis was as old as mankind, whereas later authors had the opinion the disease appeared at the end of the 15th century.


Determinants of Restoration of CD4 and CD8 Cell Counts and Their Ratio in HIV-1-Positive Individuals With Sustained Virological Suppression on Antiretroviral Therapy.
An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics. We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models. When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm. Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm. Starting ART with a CD4 cell count of ≥500 cells/mm makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation.


Family Model of Diabetes Education With a Pacific Islander Community.
The purpose of the study was to use a community-based participatory research approach to pilot-test a family model of diabetes education conducted in participants' homes with extended family members. The pilot test included 6 families (27 participants) who took part in a family model of diabetes self-management education (DSME) using an intervention-driven pre- and posttest design with the aim of improving glycemic control as measured by A1C. Questionnaires and additional biometric data were also collected. Researchers systematically documented elements of feasibility using participant observations and research field reports. More than three-fourths (78%) of participants were retained in the study. Posttest results indicated a 5% reduction in A1C across all participants and a 7% reduction among those with type 2 diabetes. Feasibility of an in-home model with extended family members was documented, along with observations and recommendations for further DSME adaptations related to blood glucose monitoring, physical activity, nutrition, and medication adherence. The information gained from this pilot helps to bridge the gap between knowledge of an evidence-based intervention and its actual implementation within a unique minority population with especially high rates of type 2 diabetes and significant health disparities. Building on the emerging literature of family models of DSME, this study shows that the family model delivered in the home had high acceptance and that the intervention was more accessible for this hard-to-reach population.


Immunotherapy using anti-PD-1 and anti-PD-L1 in Leishmania amazonensis-infected BALB/c mice reduce parasite load.
Leishmaniasis is a neglected disease, for which current treatment presents numerous issues. Leishmania amazonensis is the etiological agent of cutaneous and diffuse cutaneous leishmaniasis. The roles of the programmed death-1 (PD-1) receptor on lymphocytes and its ligand (PD-L1) on antigen-presenting cells have been well studied in tumor and other infection models; but little is known about their roles in non-healing cutaneous leishmaniasis. In this study, we observed that L. amazonensis induced PD-1 expression on both CD4+ and CD8+ T cells and PD-L1 on dendritic cells on BALB/c mice. We tested the therapeutic potential of anti-PD-1 and anti-PD-L1 monoclonal antibodies (MoAbs) against a non-healing L. amazonensis infection in BALB/c mice, and that anti-PD-1 and anti-PD-L1 treatment significantly increased IFN-γ-producing CD4+ and CD8+ T cells, respectively. Compared with infection controls, mice treated with anti-PD-1 and anti-PD-L1, but not anti-PD-L2, displayed bigger lesions with significantly lower parasite loads. Treatment did not affect anti-Leishmania antibody (IgM, IgG, IgG1 and IgG2a) or IL-10 production, but anti-PD-1 treatment reduced both IL-4 and TGF-β production. Together, our results highlight the therapeutic potential of an anti-PD-1-based treatment in promoting the reinvigoration of T cells for the control of parasite burden.


How can we better help cancer patients quit smoking? The London Regional Cancer Program experience with smoking cessation.
Because continued cigarette smoking after a cancer diagnosis is associated with detrimental outcomes, supporting cancer patients with smoking cessation is imperative. We evaluated the effect of the Smoking Cessation Program at the London Regional Cancer Program (lrcp) over a 2-year period. The Smoking Cessation Program at the lrcp began in March 2014. New patients are screened for tobacco use. Tobacco users are counselled about the benefits of cessation and are offered referral to the program. If a patient accepts, a smoking cessation champion offers additional counselling. Follow-up is provided by interactive voice response (ivr) telephone system. Accrual data were collected monthly from January 2015 to December 2016 and were evaluated. During 2015-2016, 10,341 patients were screened for tobacco use, and 18% identified themselves as current or recent tobacco users. In 2015, 84% of tobacco users were offered referral, but only 13% accepted, and 3% enrolled in ivr follow-up. At the lrcp in 2016, 77% of tobacco users were offered referral to the program, but only 9% of smokers accepted, and only 2% enrolled in ivr follow-up. The Smoking Cessation Program at the lrcp has had modest success, because multiple factors influence a patient's success with cessation. Limitations of the program include challenges in referral and counselling, limited access to nicotine replacement therapy (nrt), and minimal follow-up. To mitigate some of those challenges, a pilot project was launched in January 2017 in which patients receive free nrt and referral to the local health unit.


Decomposition of protonated noradrenaline and normetanephrine assisted by NH2 migration studied by electrospray tandem mass spectrometry and molecular orbital calculations.
As part of a research program on neurotransmitters in a biological fluid, the fragmentations characterising catecholamines protonated under electrospray ionisation (ESI) conditions, under low collision energy in a triple-quadrupole mass spectrometer, were investigated. The decompositions of protonated noradrenaline (VH) and normetanephrine (VIH) were studied. Both precursor ions eliminate first H2O at very low collision energy, and the fragmentations of [MH-H2O]+ occur at higher collision energy. The breakdown graphs of [MH-H2O]+ ions, with collision energy varying from 0-40 eV in the laboratory frame, are presented. [VIH-H2O]+ ions lose competitively NH3 and CH3OH. For [VH-H2O]+ the loss of NH3 is dominant while H2O is eliminated at very low abundance at all collision energies. All of these secondary fragmentations are followed at higher collision energies by elimination of CO. These fragmentations are interpreted by means of ab initio calculations up to the B3LYP/6-311+G(2d,2p) level of theory. The elimination of H2O requires first the isomerisation of N-protonated forms, chosen as energy references, to O-protonated forms. The isomerisation barriers are calculated to be lower than 81 kJ/mol above the N-protonated forms. The elimination of NH3 from [MH-H2O]+ requires first the migration, via a cyclisation, of the amine function from the linear chain to the aromatic ring in order to prevent the formation of unstable disubstituted carbocations in the ring. The barriers associated with the loss of NH3 are located 220 and 233 kJ/mol above VH and 219 kJ/mol above VIH. The energy barrier for the loss of ROH is located 236 and 228 kJ/mol above VH and VIH, respectively. The absence of ions corresponding to [VH-2H2O]+ is due to a parasitic mechanism with an activation barrier lower than 236 kJ/mol that leads to a stable species unable to fragment, thus preventing the second loss of H2O. Losses of CO following the secondary fragmentations involve activation barriers higher than 330 kJ/mol.


Surgical necrotizing enterocolitis in extremely premature neonates is associated with genetic variations in an intergenic region of chromosome 8.
BackgroundTwin studies suggest that genetic factors may account for up to 50% increased risk for necrotizing enterocolitis (NEC), but genome-wide association studies for NEC are lacking.MethodsGenotyping was done on Illumina BeadChip, followed by analysis using PLINK with logistic regression under an additive model.ResultsAmong 751 extremely-low-birth-weight (<1,000 g, >401 g) neonates, 30 had surgical NEC. Two hundred and sixty-one single-nucleotide polymorphisms (SNPs) showed association with NEC at P<0.05, of which 35 were significant at P<10-7. Minor allele(s) in a cluster of SNPs spanning a 43-kb region of chromosome 8 (8q23.3) conferred an odds ratio of 4.72 (95% confidence interval (CI): 2.51-8.88) for elevated risk of NEC. Two smaller clusters on chromosome 14 and chromosome 11 exhibited P values of 10-7-10-8. The chromosome 8 cluster is in an intergenic region between CUB and Sushi multiple domains 3 (-1.43 Mb) and trichorhinophalangeal syndrome I (+542 kb). RNA sequencing in this region identified a potential novel open-reading frame corresponding to a long interspersed element-1 retrotransposable element.ConclusionGenetic variation in an intergenic region of chromosome 8 is associated with increased risk for NEC with a mechanism that is yet to be identified.


[Diagnosis and clinical presentations of celiac disease: a multicenter study].
Ample use of serological markers of high sensitivity and specificity led to relevant changes in the epidemiology of celiac disease. The impact of these changes in our country is poorly known. To assess the diagnostic procedures, clinical presentations and follow up of celiac disease as conducted in current pediatric practice. A multicentric retrospective study of patients diagnosed between 2000 and 2005 in five pediatric hospitals in Santiago, Chile. Data was obtained from clinical records, recorded in electronic spreadsheets and analyzed by descriptive statistics. Seventy four of 83 identified patients fulfilled the inclusion criteria and were analyzed. Mean time to reach the diagnosis was 2.1 years. Cases younger than 10 years presented digestive manifestations such as chronic diarrhea and abdominal distension. Twenty one percent of older patients had atypical presentations (mainly short stature, refractory anaemia). Ten percent of cases were screened because a first degree relative had celiac disease. All patients had significant duodenal/jejunal lesion. IgA-antiendomysial antibodies (n =65) and IgA-antigliadin antibodies (n =23) were the most commonly used screening tests used but often, they were not available for follow up. A second biopsy was planned in all patients but only 26 had it due to repeated dietary transgressions, often due to unnoticed consumption of gluten in poorly labeled products. Digestive manifestations were the main presentation form for celiac disease among patients under 10 years of age. Atypical symptoms become relevant in patients older than 10 years. Antiendomysial and antitransglutaminase antibody measurement should be incorporated for routine screening and follow up of celiac disease in public hospitals. To improve food labeling about their gluten content is needed.


The Physical Activity and Redesigned Community Spaces (PARCS) Study: Protocol of a natural experiment to investigate the impact of citywide park redesign and renovation.
The built environment plays a critical role in promoting physical activity and health. The association between parks, as a key attribute of the built environment, and physical activity, however, remains inconclusive. This project leverages a natural experiment opportunity to assess the impact of the Community Parks Initiative (CPI), a citywide park redesign and renovation effort in New York City, on physical activity, park usage, psychosocial and mental health, and community wellbeing. The project will use a longitudinal design with matched controls. Thirty intervention park neighborhoods are socio-demographically matched to 20 control park neighborhoods. The study will investigate whether improvements in physical activity, park usage, psychosocial and mental health, and community wellbeing are observed from baseline to 3 years post-renovation among residents in intervention vs. control neighborhoods. This study represents a rare opportunity to provide robust evidence to further our understanding of the complex relationship between parks and health. Findings will inform future investments in health-oriented urban design policies and offer evidence for addressing health disparities through built environment strategies.


In Vitro Effect of Cinnamomum zeylanicum Blume Essential Oil on Candida spp. Involved in Oral Infections.
The present study demonstrates the antifungal potential of chemically characterized essential oil (EO) of Cinnamomum zeylanicum Blume on Candida spp. biofilm and establishes its mode of action, effect on fungal growth kinetics, and cytotoxicity to human cells. The minimal inhibitory concentration (MIC) and minimal fungicidal concentration (MFC) values varied from 62.5 to 1,000 μg/mL, and the effect seems to be due to interference with cell wall biosynthesis. The kinetics assay showed that EO at MICx2 (500 μg/mL) induced a significant (p < 0.05) reduction of the fungal growth after exposure for 8 h. At this concentration, the EO was also able to hinder biofilm formation and reduce Candida spp. monospecies and multispecies in mature biofilm at 24 h and 48 h (p < 0.05). A protective effect on human red blood cells was detected with the EO at concentrations up to 750 μg/mL, as well as an absence of a significant reduction (p > 0.05) in the viability of human red blood cells at concentrations up to 1,000 μg/mL. Phytochemical analysis identified eugenol as the main component (68.96%) of the EO. C. zeylanicum Blume EO shows antifungal activity, action on the yeast cell wall, and a deleterious effect on Candida spp. biofilms. This natural product did not show evidence of cytotoxicity toward human cells.


Reducing perineal trauma through perineal massage with vaseline in second stage of labor.
Maintaining an intact perineum is a highly regarded aim in delivery procedures today. Since perineal massage is a common practice during delivery, the present study aims to investigate the effect of perineal massage with Vaseline on perineal trauma (rate of episiotomy procedures and perineal tears). Ninety primiparous women (aged between 18 and 30 years with gestational age of 38-42 weeks) were selected sequentially in Tehran in 2009. Once participants' characteristics were registered, they were randomly assigned to the intervention (perineal massage with Vaseline) or control groups. In the massage group, perineal massage was performed in the second stage of delivery once the genitalia were treated with sterilized Vaseline. The perineum was examined after the delivery in terms of episiotomy or tear and its severity degree. The two groups were homogeneous in terms of demographic data, weight gain during pregnancy, gestational age, abortion history and fetal weight. The second stage of delivery was significantly shorter in the massage group than the control group and the massage group had significantly more intact perineum (P = 0.004). In addition, lower episiotomy and higher first- and second-degree perineal tears were seen in the massage group in comparison with the control one (P < 0.001). Neither of the groups suffered from third- and fourth-degree tears. The findings showed that the perineal massage with Vaseline in the second stage of labor increases perineal integrity and decreases perineal traumas (episiotomy and tears). So, it seems that the perineal massage could be an effective way to preserve an intact perineum in labor.


Biochemical characterization and crystal structures of a fungal family 3 β-glucosidase, Cel3A from Hypocrea jecorina.
Cellulase mixtures from Hypocrea jecorina are commonly used for the saccharification of cellulose in biotechnical applications. The most abundant β-glucosidase in the mesophilic fungus Hypocrea jecorina is HjCel3A, which hydrolyzes the β-linkage between two adjacent molecules in dimers and short oligomers of glucose. It has been shown that enhanced levels of HjCel3A in H. jecorina cellulase mixtures benefit the conversion of cellulose to glucose. Biochemical characterization of HjCel3A shows that the enzyme efficiently hydrolyzes (1,4)- as well as (1,2)-, (1,3)-, and (1,6)-β-D-linked disaccharides. For crystallization studies, HjCel3A was produced in both H. jecorina (HjCel3A) and Pichia pastoris (Pp-HjCel3A). Whereas the thermostabilities of HjCel3A and Pp-HjCel3A are the same, Pp-HjCel3A has a higher degree of N-linked glycosylation. Here, we present x-ray structures of HjCel3A with and without glucose bound in the active site. The structures have a three-domain architecture as observed previously for other glycoside hydrolase family 3 β-glucosidases. Both production hosts resulted in HjCel3A structures that have N-linked glycosylations at Asn(208) and Asn(310). In H. jecorina-produced HjCel3A, a single N-acetylglucosamine is present at both sites, whereas in Pp-HjCel3A, the P. pastoris-produced HjCel3A enzyme, the glycan chains consist of 8 or 4 saccharides. The glycosylations are involved in intermolecular contacts in the structures derived from either host. Due to the different sizes of the glycosylations, the interactions result in different crystal forms for the two protein forms.


Negative regulation of the stability and tumor suppressor function of Fbw7 by the Pin1 prolyl isomerase.
Fbw7 is the substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex and a well-characterized tumor suppressor that targets numerous oncoproteins for destruction. Genomic deletion or mutation of FBW7 has been frequently found in various types of human cancers; however, little is known about the upstream signaling pathway(s) governing Fbw7 stability and cellular functions. Here we report that Fbw7 protein destruction and tumor suppressor function are negatively regulated by the prolyl isomerase Pin1. Pin1 interacts with Fbw7 in a phoshorylation-dependent manner and promotes Fbw7 self-ubiquitination and protein degradation by disrupting Fbw7 dimerization. Consequently, overexpressing Pin1 reduces Fbw7 abundance and suppresses Fbw7's ability to inhibit proliferation and transformation. By contrast, depletion of Pin1 in cancer cells leads to elevated Fbw7 expression, which subsequently reduces Mcl-1 abundance, sensitizing cancer cells to Taxol. Thus, Pin1-mediated inhibition of Fbw7 contributes to oncogenesis, and Pin1 may be a promising drug target for anticancer therapy.


The effect of vitamin E and L-carnitine against methotrexate-induced injury in rat testis.
Methotrexate (MTX), used commonly as an antimetabolite drug in cancer therapy, leads to acute toxic side effects in tissues or organs containing rapidly dividing cells, such as bone marrow, gastrointestinal mucosa, and seminiferous tubules. In this study, we investigated the protective effects of vitamin E and L-carnitine against MTX-induced injury in rat testis. Rats were divided into 4 groups, including the control group. The study took 17 days and the animals received daily doses of 0.5 mL/kg saline, 250 mg/kg vitamin E, or 500 mg/kg L-carnitine intraperitoneally. The experimental groups received 20 mg/kg methotrexate intraperitoneally on days 3 and 10. Weight loss, testicular weight loss and marked histological injuries, increased malondialdehyde levels, and decreased superoxide dismutase levels were only observed in the MTX-treated groups. Vitamin E and L-carnitine treatments did not affect MTX-induced weight loss or testicular weight loss, but they inhibited MTX-induced testicular histological injuries. Vitamin E and L-carnitine treatments suppressed the increases in malondialdehyde levels and the decreases in superoxide dismutase levels. Vitamin E and L-carnitine treatments decreased MTX-induced testicular histological injuries, and these results were supported by biochemical measurements.


Conservation of complete trimethylation of lysine-43 in the rotor ring of c-subunits of metazoan adenosine triphosphate (ATP) synthases.
The rotors of ATP synthases turn about 100 times every second. One essential component of the rotor is a ring of hydrophobic c-subunits in the membrane domain of the enzyme. The rotation of these c-rings is driven by a transmembrane proton-motive force, and they turn against a surface provided by another membrane protein, known as subunit a. Together, the rotating c-ring and the static subunit a provide a pathway for protons through the membrane in which the c-ring and subunit a are embedded. Vertebrate and invertebrate c-subunits are well conserved. In the structure of the bovine F1-ATPase-c-ring subcomplex, the 75 amino acid c-subunit is folded into two transmembrane α-helices linked by a short loop. Each bovine rotor-ring consists of eight c-subunits with the N- and C-terminal α-helices forming concentric inner and outer rings, with the loop regions exposed to the phospholipid head-group region on the matrix side of the inner membrane. Lysine-43 is in the loop region and its ε-amino group is completely trimethylated. The role of this modification is unknown. If the trimethylated lysine-43 plays some important role in the functioning, assembly or degradation of the c-ring, it would be expected to persist throughout vertebrates and possibly invertebrates also. Therefore, we have carried out a proteomic analysis of c-subunits across representative species from different classes of vertebrates and from invertebrate phyla. In the twenty-nine metazoan species that have been examined, the complete methylation of lysine-43 is conserved, and it is likely to be conserved throughout the more than two million extant metazoan species. In unicellular eukaryotes and prokaryotes, when the lysine is conserved it is unmethylated, and the stoichiometries of c-subunits vary from 9-15. One possible role for the trimethylated residue is to provide a site for the specific binding of cardiolipin, an essential component of ATP synthases in mitochondria.


Pharmacological manipulation of gastric juice: thrombelastographic assessment and implications for treatment of gastrointestinal haemorrhage.
The impairment of formation and maintenance of a formed fibrin clot contributes to the prolonged bleeding and high incidence of rebleeding in upper gastrointestinal haemorrhage. To investigate the basis for the use of drug therapy in gastric bleeding, this study used thrombelastography to determine the effects of pharmacological manipulation of gastric juice on coagulation and fibrinolysis. The thrombelastograph is a mechanical device that provides a visual assessment of all stages of coagulation and fibrinolysis. The effects of fresh and pharmacologically changed gastric juice was assessed after its addition to fresh whole blood in the thrombelastograph cuvette. Pharmacological manipulation was achieved through alkalisation or through addition of tranexamic acid, aprotinin, or sucralfate. Fresh gastric juice delayed clot formation, decreased maximum clot amplitude, and stimulated clot lysis. Alkalisation inhibited the lytic effects of fresh gastric juice and improved the induced abnormalities in coagulation. Tranexamic acid partially inhibited gastric juice induced clot lysis but did not exhibit a beneficial effect on coagulation. Sucralfate, and to a lesser extent aprotinin significantly inhibited fibrinolysis but exacerbated the detrimental effect of gastric juice on the parameters of coagulation. Alkalisation of gastric juice reduces the adverse effect on coagulation and fibrinolysis. Tranexamic acid, aprotinin, and sucralfate can all reduce or inhibit clot lysis, but the adverse effects on clot formation may outweigh any potential benefit in the treatment of gastrointestinal bleeding.


Accelerated endothelial wound healing on microstructured substrates under flow.
Understanding and accelerating the mechanisms of endothelial wound healing is of fundamental interest for biotechnology and of significant medical utility in repairing pathologic changes to the vasculature induced by invasive medical interventions. We report the fundamental mechanisms that determine the influence of substrate topography and flow on the efficiency of endothelial regeneration. We exposed endothelial monolayers, grown on topographically engineered substrates (gratings), to controlled levels of flow-induced shear stress. The wound healing dynamics were recorded and analyzed in various configurations, defined by the relative orientation of an inflicted wound, the topography and the flow direction. Under flow perpendicular to the wound, the speed of endothelial regeneration was significantly increased on substrates with gratings oriented in the direction of the flow when compared to flat substrates. This behavior is linked to the dynamic state of cell-to-cell adhesions in the monolayer. In particular, interactions with the substrate topography counteract Vascular Endothelial Cadherin phosphorylation induced by the flow and the wounding. This effect contributes to modulating the mechanical connection between migrating cells to an optimal level, increasing their coordination and resulting in coherent cell motility and preservation of the monolayer integrity, thus accelerating wound healing. We further demonstrate that the reduction of vascular endothelial cadherin phosphorylation, through specific inhibition of Src activity, enhances endothelial wound healing in flows over flat substrates.


Symptoms predictive for the later development of retinal breaks.
To identify symptoms in patients with isolated posterior vitreous detachment predictive for the later development of retinal breaks. Two hundred eighty consecutive patients seen with symptoms of posterior vitreous detachment were prospectively asked to complete a questionnaire detailing their symptoms. At the time of presentation and follow-up, all patients had a full ophthalmologic examination including slitlamp biomicroscopy with Goldmann 3-mirror contact lens after maximal pupil dilatation. Two hundred fifty patients with an isolated posterior vitreous detachment were included and reexamined 6 weeks after the onset of symptoms. If small retinal or vitreous hemorrhages were detected, patients were reexamined after 2 weeks. In 13 patients (5.2%) a retinal break was detected at reexamination. Logistic regression analysis with backward elimination revealed that symptoms of flashes in combination with clouds or multiple (>10) small dots at the time of the initial examination or an increase of floaters after the initial examination were statistically significantly (P<.001) related to the development of new breaks. These symptoms had a predictive value for the presence or absence of a new retinal break of 75.0% and 99.6%, respectively. Specific symptoms can identify patients at risk for the development of new retinal breaks after an initial examination in which no abnormalities were found and may obviate the need for follow-up appointments of patients not at risk.


Visualizing electronic interactions between iron and carbon by X-ray chemical imaging and spectroscopy.
The electronic interaction of a catalyst and its support is of vital importance to its catalytic performance. However, it is still a great challenge to directly probe the interaction due to the lack of well-defined models and efficient technical means. In this study, we report that pod-like carbon nanotubes with encapsulated iron particles (Pod-Fe) and scanning transmission X-ray microscopy (STXM) can be used as an ideal model and technique to study the electronic interaction between carbon shells and iron particles. The chemical imaging and spectroscopy of Pod-Fe by STXM show that the local electronic structures at C K-edge near edge (π*) of carbon shells can be significantly modified by the encapsulated iron particles, which promotes the adsorption of oxygen-containing species, and thereby further modifies the electronic structure (π* and σ*) of the carbon shells. Moreover, computed X-ray absorption near edge structure spectra (XANES) confirmed the electronic modifications of carbon shells by the encapsulated iron particles. The present study provides a direct evidence of electronic interactions with simultaneously collected images and spectra, which can promote the understanding towards the nature of active sites and supports.


Autophagy modulator scoring system: a user-friendly tool for quantitative analysis of methodological integrity of chemical autophagy modulator studies.
Over the past 20 years (1999-2019), we have witnessed a rapid increase in publications involving chemical macroautophagy/autophagy modulators. However, an overview of the methodologies used in these studies is still lacking, and methodology flaws are frequently observed in some reports. To provide an objective and quantitative analysis of studies involving autophagy modulators, we present an Autophagy Modulator Scoring System (AMSS), which is designed to evaluate methodological integrity. AMSS-A includes the autophagy characterization by 4 aspects, namely, autophagosome quantification, autophagy-related biochemical changes, autophagy substrate degradation, and autophagic flux. AMSS-B contains the pharmacological and functional characteristics of chemical autophagy modulators, including lysosomal function, drug targets, autophagy-dependent pharmacological effects, and validation in multiple cell lines and in vivo models. Our analysis shows that of the 385 studies reporting chemical autophagy modulators, only 142 single studies had examined all 4 aspects of autophagy characterization in AMSS-A, and only 10 out of 142 studies had fulfilled all the AMSS criteria in a single study. A comprehensive analysis of the methodologies used in all the studies was made, along with a summary of studies that demonstrated the highest methodological integrity based on AMSS ranking. To test the reliability of the AMSS, a co-efficiency analysis of scores and co-citation values in the co-citation network was performed, and a significant co-efficiency was obtained. Collectively, AMSS provides insight into the methodological integrity of autophagy modulators studies and also offers a user-friendly toolkit to help choose appropriate assays to characterize autophagy modulators.Abbreviations: 3-MA: 3-methyladenine; AMSS: Autophagy Modulator Scoring System; ATG: autophagy-related; BAF: bafilomycin A1; BECN1: beclin 1; CQ: chloroquine; GFP: green fluorescent protein; LC3: microtubule associated protein 1 light chain 3; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate.


Active viral genes in transformed cells lie close to the nuclear cage.
Nuclear DNA is looped by attachment to a matrix or cage. Using nine different lines transformed by polyoma or avian sarcoma virus, we have mapped viral sequences integrated within these loops. In all lines that contain high concentrations of viral transcripts and express the transformed phenotype, the integrated viral genes lie close to the points of attachment to the cage. Integration of polyoma DNA induces outlying cellular sequences to become closely associated with the cage. The strength of this correlation between gene activity and proximity to the cage was examined using sub-clones of one avian sarcoma virus transformant. Proviral sequences are closely associated with the cage in this transformant, much less so in two untransformed 'flat revertants' which contain no detectable viral transcripts but regain their close association with the cage in two retransformed derivatives.


Repeat head computed tomography in anticoagulated traumatic brain injury patients: still warranted.
Anticoagulation agents are proven risk factors for intracranial hemorrhage (ICH) in traumatic brain injury (TBI). The aim of our study is to describe the epidemiology of prehospital coumadin, aspirin, and Plavix (CAP) patients with ICH and evaluate the use of repeat head computed tomography (CT) in this group. We performed a retrospective study from our trauma registry. All patients with intracranial hemorrhage on initial CT with prehospital CAP therapy were included. Demographics, CT scan findings, number of repeat CT scans, progressive findings, and neurosurgical intervention were abstracted. A comparison between prehospital CAP and no-CAP patients was done using χ(2) and Mann-Whitney U test. A total of 1606 patients with blunt TBI charts were reviewed of whom 508 patients had intracranial bleeding on initial CT scan and 72 were on prehospital CAP therapy. CAP patients were older (P < 0.001), had higher Injury Severity Score and head Abbreviated Injury Scores on admission (P < 0.001), were more likely to present with an abnormal neurologic examination (P = 0.004), and had higher hospital and intensive care unit lengths of stay (P < 0.005). Eighty-four per cent of patients were on antiplatelet therapy and 27 per cent were on warfarin. The CAP patients have a threefold increase in the rate of worsening repeat head CT (26 vs 9%, P < 0.05). Prehospital CAP therapy is high risk for progression of bleeding on repeat head CT. Routine repeat head CT remains an important component in this patient population and can provide useful information.


Caffeine Gum Does Not Improve Marksmanship, Bound Duration, Susceptibility to Enemy Fire, or Cognitive Performance During Tactical Combat Movement Simulation.
Military personnel supplement caffeine as a countermeasure during unavoidable sustained wakefulness. However, its utility in combat-relevant tasks is unknown. This study examined the effects of caffeinated gum on performance in a tactical combat movement simulation. Healthy men (n = 30) and women (n = 9) (age = 25.3 ± 6.8 years; mass 75.1 ± 13.1 kg) completed a marksmanship with a cognitive workload (CWL) assessment and a fire-andmove simulation (16 6-m bounds) in experimental conditions (placebo versus caffeinated gum, 4mg/kg). Susceptibility to enemy fire was modeled on bound duration during the fireand- move simulation. Across both conditions, bound duration and susceptibility to enemy fire increased by 9.3% and 7.8%, respectively (p = .001). Cognitive performance decreased after the fire-and-move simulation across both conditions (p < .05). However, bound duration, susceptibility to enemy fire, marksmanship, and cognitive performance did not differ between the caffeine and placebo conditions. These data do not support a benefit of using caffeinated gum to improve simulated tactical combat movements.


Neurofibromatosis 2.
Recent clinical and molecular research on neurofibromatosis 2 (NF2) is reviewed, and the implications for clinical practice and research are discussed. NF2 patients who are treated in specialty centers have a significantly lower risk of mortality than those who are treated in non-specialty centers. Vestibular schwannoma growth rates in NF2 are generally higher in younger people but are highly variable, even among multiple NF2 patients of similar ages in the same family. Radiation therapy is best reserved for NF2 patients who have particularly aggressive tumors, those who are poor surgical risks, those who refuse surgery, or those who are elderly. In-vivo studies have demonstrated that leptomeningeal cell activation of in mice results in leptomeningeal hyperplasia and meningioma formation. In-vitro studies have identified molecules that interact with the product (merlin or schwannomin), some of which (e.g., CD44 and paxillin) may play critical roles in merlin growth regulation. NF2 patients should be referred to specialty treatment centers for optimal care. Clinical management of multiple patients in NF2 families cannot be based on the expectation of similar vestibular schwannoma growth rates, even when other clinical aspects of disease severity are similar. The availability of accurate mouse models of human NF2-associated tumors and the identification of molecules involved in merlin growth regulation now provide an opportunity to design targeted treatments for schwannomas and meningiomas.


Genome-wide identification of polycomb target genes reveals a functional association of Pho with Scm in Bombyx mori.
Polycomb group (PcG) proteins are evolutionarily conserved chromatin modifiers and act together in three multimeric complexes, Polycomb repressive complex 1 (PRC1), Polycomb repressive complex 2 (PRC2), and Pleiohomeotic repressive complex (PhoRC), to repress transcription of the target genes. Here, we identified Polycomb target genes in Bombyx mori with holocentric centromere using genome-wide expression screening based on the knockdown of BmSCE, BmESC, BmPHO, or BmSCM gene, which represent the distinct complexes. As a result, the expressions of 29 genes were up-regulated after knocking down 4 PcG genes. Particularly, there is a significant overlap between targets of BmPho (331 out of 524) and BmScm (331 out of 532), and among these, 190 genes function as regulator factors playing important roles in development. We also found that BmPho, as well as BmScm, can interact with other Polycomb components examined in this study. Further detailed analysis revealed that the C-terminus of BmPho containing zinc finger domain is involved in the interaction between BmPho and BmScm. Moreover, the zinc finger domain in BmPho contributes to its inhibitory function and ectopic overexpression of BmScm is able to promote transcriptional repression by Gal4-Pho fusions including BmScm-interacting domain. Loss of BmPho expression causes relocalization of BmScm into the cytoplasm. Collectively, we provide evidence of a functional link between BmPho and BmScm, and propose two Polycomb-related repression mechanisms requiring only BmPho associated with BmScm or a whole set of PcG complexes.


Recent advances in the biosynthesis of modified tetrapyrroles: the discovery of an alternative pathway for the formation of heme and heme d 1.
Hemes (a, b, c, and o) and heme d 1 belong to the group of modified tetrapyrroles, which also includes chlorophylls, cobalamins, coenzyme F430, and siroheme. These compounds are found throughout all domains of life and are involved in a variety of essential biological processes ranging from photosynthesis to methanogenesis. The biosynthesis of heme b has been well studied in many organisms, but in sulfate-reducing bacteria and archaea, the pathway has remained a mystery, as many of the enzymes involved in these characterized steps are absent. The heme pathway in most organisms proceeds from the cyclic precursor of all modified tetrapyrroles uroporphyrinogen III, to coproporphyrinogen III, which is followed by oxidation of the ring and finally iron insertion. Sulfate-reducing bacteria and some archaea lack the genetic information necessary to convert uroporphyrinogen III to heme along the "classical" route and instead use an "alternative" pathway. Biosynthesis of the isobacteriochlorin heme d 1, a cofactor of the dissimilatory nitrite reductase cytochrome cd 1, has also been a subject of much research, although the biosynthetic pathway and its intermediates have evaded discovery for quite some time. This review focuses on the recent advances in the understanding of these two pathways and their surprisingly close relationship via the unlikely intermediate siroheme, which is also a cofactor of sulfite and nitrite reductases in many organisms. The evolutionary questions raised by this discovery will also be discussed along with the potential regulation required by organisms with overlapping tetrapyrrole biosynthesis pathways.


Solution Structure and Dynamics of LptE from Pseudomonas aeruginosa.
LptE is an outer membrane (OM) lipoprotein found in Gram-negative bacteria, where it forms a complex with the β-barrel lipopolysaccharide (LPS) transporter LptD. The LptD/E complex plays a key role in OM biogenesis, by translocating newly synthesized LPS molecules from the periplasm into the external leaflet of the asymmetric OM during cell growth. The LptD/E complex in Pseudomonas aeruginosa (Pa) is a target for macrocyclic β-hairpin-shaped peptidomimetic antibiotics, which inhibit the transport of LPS to the cell surface. So far, the three-dimensional structure of the Pa LptD/E complex and the mode of interaction with these antibiotics are unknown. Here, we report the solution structure of a Pa LptE derivative lacking the N-terminal lipid membrane anchor, determined by multidimensional solution nuclear magnetic resonance (NMR) spectroscopy. The structure reveals a central five-stranded β-sheet against which pack a long C-terminal and a short N-terminal α-helix, as found in homologues of LptE from other Gram-negative bacteria. One unique feature is an extended C-terminal helix in Pa LptE, which in a model of the Pa LptD/E complex appears to be long enough to contact the periplasmic domain of LptD. Chemical shift mapping experiments suggest only weak interactions occur between LptE and the oligosaccharide chains of LPS. The NMR structure of Pa LptE will be valuable for more detailed structural studies of the LptD/E complex from P. aeruginosa.


N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation.
Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma. Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation. The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cad-herin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis. Taken together, our data show that myeloma cells frequently display aberrant expression of N-cadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.


Augmentation of Pap smear screening of high risk aboriginal women. Use of a computerised process tool within the Broome Aboriginal Medical Service.
The Broome Regional Aboriginal Medical Service (BRAMS) in Broome, Western Australia, conducted a 4 month program to augment the Pap smear screening of Aboriginal women. The emphasis was on those with a past history of abnormal smears, aged greater than 40 years, living in remote communities and very (more than 5 years) overdue. Continuation of existing opportunistic recall processes supplemented by three components: the development of an Aboriginal Health Worker (AHW) run Pap smear clinic; the provision of Aboriginal outstation screening; and active recruitment of targeted women (by AHW staff) using worklists. All components used Healthplanner, a computerised process tool to facilitate targeting and recall. The number of Pap smears taken from the target groups before and after intervention and the proportion screened from the women eligible in each target group at the start of the program. There was statistically significant increase in the coverage of Aboriginal women overall, those over the age of 40 years, and those from remote communities when compared with the same period the previous years. In 4 months, 21-30% of Aboriginal women eligible for Pap smears in these high risk categories including those with past abnormal smears were screened. Over-screening of women did not occur as only 4% of smears taken were from women screened less than 12 months previously. Smears taken by AHW staff were of high quality. Use of a computerised process tool in a remote setting can facilitate selective recruitment of high risk women overdue for Pap smears.


Climate Change and Genetic Structure of Leading Edge and Rear End Populations in a Northwards Shifting Marine Fish Species, the Corkwing Wrasse (Symphodus melops).
One mechanism by which marine organisms may respond to climate shifts is range shifts. The corkwing wrasse (Symphodus melops) is a temperate fish species, inhabiting the coasts of Europe, that show strong indications of current as well as historical (ice-age) range shifts towards the north. Nine neutral microsatellite DNA markers were screened to study genetic signatures and spatial population structure over the entire geographic and thermal gradient of the species from Portugal to Norway. A major genetic break (F ST = 0.159 average among pairs) was identified between Scandinavian and more southern populations, with a marked reduction (30% or more) in levels of genetic variability in Scandinavia. The break is probably related to bottleneck(s) associated with post-glacial colonization of the Scandinavian coasts, and indicates a lack of present gene flow across the North Sea. The lack of gene flow can most likely be attributed to the species' need for rocky substrate for nesting and a relatively short pelagic larval phase, limiting dispersal by ocean currents. These findings demonstrate that long-distance dispersal may be severely limited in the corkwing wrasse, and that successful range-shifts following present climate change may be problematic for this and other species with limited dispersal abilities, even in the seemingly continuous marine environment.


Pediatric neurosurgery training during residency in the United States: a program director survey.
Pediatric neurosurgery is a core component of neurosurgical residency training. Pediatric case minimums are established by the Neurosurgery Residency Review Committee of the Accreditation Council for Graduate Medical Education (ACGME). Case minimums, by themselves, allow for great variability in training between programs. There are no prior data on how the residency programs meet these requirements. The authors' objective was to gather information on pediatric neurosurgical education among the ACGME-accredited neurosurgery training programs in order to shape further pediatric neurosurgical educational efforts. A 25-question survey about pediatric neurosurgical education was created by the Education Committee of the Section on Pediatric Neurological Surgery of the American Association of Neurological Surgeons/Congress of Neurological Surgeons and distributed to program directors of all 111 ACGME-accredited neurosurgery training programs. The response rate was 77% (86/111). In 55% of programs the residents are rotated to a responder-designated "freestanding" children's hospital, and 39% of programs rotate residents to a children's hospital within a larger adult hospital or a general hospital. There are 4 or fewer pediatric neurosurgical faculty in 91% of programs. In 12% of programs less than 100 cases are performed per year, and in 45% more than 500 are performed. In 31% of responding neurosurgery residency programs there is also a pediatric neurosurgery fellowship program supported by the same sponsoring institution. Seventy-seven percent of programs have at least one specific pediatric neurosurgery rotation, with 71% of those rotations occurring during postgraduate year 3 and 50% occurring during postgraduate year 4. The duration of pediatric rotation varies from no specific rotation to more than 1 year, with 48% of residents spending 4-6 months on a pediatric rotation and 12% spending 7-11 months. Last, 17% of programs send their residents to external sites sponsoring other residency programs for their pediatric rotation. There is great variety between neurosurgery training programs with regard to resident education in pediatric neurosurgery. This study's data will serve as a baseline for future studies, and the authors hope the findings will guide further efforts in pediatric neurosurgical education in residency training programs.


Contralateral prophylactic mastectomy for patients with unilateral breast cancer.
Patients with unilateral breast cancer are at increased risk of developing a second cancer in the contralateral breast. Some women choose contralateral prophylactic mastectomy (CPM) to prevent cancer in the contralateral breast. Several studies have demonstrated that CPM significantly decreases the occurrence of contralateral breast cancer. However, the effectiveness of CPM at reducing breast cancer mortality is not as clear. Moreover, CPM is not risk free and patients may need to undergo additional surgical procedures, especially if reconstruction is performed. Nevertheless, most patients are satisfied with their decision to undergo CPM. Alternatives to CPM include close surveillance with clinical breast examination, mammography and possibly breast magnetic resonance imaging. Endocrine therapy with tamoxifen or aromatase inhibitors significantly reduces the risk of contralateral breast cancer and may be more acceptable than CPM for some patients. The decision to undergo CPM is complex and many factors likely contribute to its use. Future prospective studies are critically needed to evaluate the decision-making processes leading to CPM.


Motor-stimulating properties of cisapride on isolated gastrointestinal preparations of the guinea pig.
The effects of cisapride (R 51619), a new non-dopamine-blocking gastrokinetic drug, on gastrointestinal contractility have been determined on isolated preparations of the guinea pig. On the intact gastroduodenal preparation, cisapride enhanced contractile amplitude (3.4 X 10(-7) M), improved antroduodenal coordination (EC50 = 1.9 X 10(-7) M) and antagonized gastric relaxation induced by phenylephrine, dopamine, isoproterenol, 5-hydroxytryptamine (in the presence of atropine) and periarterial nerve stimulation (IC50 range, 9.1 X 10(-7)-2.4 X 10(-6) M). Experiments with metoclopramide yielded similar results on amplitude, coordination and dopamine-induced relaxation at 5 X 10(-5), 2.2 X 10(-5) and 1.7 X 10(-5) M, respectively. On the ileum, cisapride enhanced the contractile response to electrical stimulation at low concentrations (EC50 = 9.2 X 10(-9) M) as compared with metoclopramide (EC50 = 3.3 X 10(-6) M). On this preparation, cisapride showed no direct cholinergic or nicotine-like effects and did not enhance the response to methacholine (indicative of a lack of inhibition of acetylcholinesterase-activity and of sensitization of the muscarine receptor). On the colon ascendens, cisapride induced contractions (EC50 = 3.5 X 10(-8) M) (metoclopramide, 3.5 X 10(-6) M), insensitive to atropine and only marginally inhibited by tetrodotoxin. In conclusion, cisapride effectively improves spontaneous or electrically evoked contractions of isolated preparations of the guinea pig, most likely via facilitation of the release of acetylcholine. However, the inhibition of gastric relaxation and the induction of colonic contractions in the presence of atropine indicate that, besides cholinergic neuronal pathways, other mechanisms are involved in the motor-stimulating properties of cisapride.


A case study for teaching information literacy skills.
The Internet has changed contemporary workplace skills, resulting in a need for proficiency with specific digital, online and web-based technologies within the fields of medicine, dentistry and public health. Although younger students, generally under 30 years of age, may appear inherently comfortable with the use of technology-intensive environments and digital or online search methods, competence in information literacy among these students may be lacking. This project involved the design and assessment of a research-based assignment to help first-year, graduate-level health science students to develop and integrate information literacy skills with clinical relevance. One cohort of dental students (n = 78) was evaluated for this project and the results demonstrate that although all students were able to provide the correct response from the content-specific, or technology-independent, portion of the assignment, more than half (54%) were unable to demonstrate competence with a web-based, technology-dependent section of this assignment. No correlation was found between any demographic variable measured (gender, age, or race). More evidence is emerging that demonstrates the need for developing curricula that integrates new knowledge and current evidence-based practices and technologies, traditionally isolated from graduate and health-care curricula, that can enhance biomedical and clinical training for students. This study provides evidence, critical for the evaluation of new practices, which can promote and facilitate the integration of information literacy into the curriculum.


Fe3O4/γ-Fe2O3 nanoparticle multilayers deposited by the Langmuir-Blodgett technique for gas sensors application.
Fe3O4/γ-Fe2O3 nanoparticles (NPs) based thin films were used as active layers in solid state resistive chemical sensors. NPs were synthesized by high temperature solution phase reaction. Sensing NP monolayers (ML) were deposited by Langmuir-Blodgett (LB) techniques onto chemoresistive transduction platforms. The sensing ML were UV treated to remove NP insulating capping. Sensors surface was characterized by scanning electron microscopy (SEM). Systematic gas sensing tests in controlled atmosphere were carried out toward NO2, CO, and acetone at different concentrations and working temperatures of the sensing layers. The best sensing performance results were obtained for sensors with higher NPs coverage (10 ML), mainly for NO2 gas showing interesting selectivity toward nitrogen oxides. Electrical properties and conduction mechanisms are discussed.


Finding a fox: an evaluation of survey methods to estimate abundance of a small desert carnivore.
The status of many carnivore species is a growing concern for wildlife agencies, conservation organizations, and the general public. Historically, kit foxes (Vulpes macrotis) were classified as abundant and distributed in the desert and semi-arid regions of southwestern North America, but is now considered rare throughout its range. Survey methods have been evaluated for kit foxes, but often in populations where abundance is high and there is little consensus on which technique is best to monitor abundance. We conducted a 2-year study to evaluate four survey methods (scat deposition surveys, scent station surveys, spotlight survey, and trapping) for detecting kit foxes and measuring fox abundance. We determined the probability of detection for each method, and examined the correlation between the relative abundance as estimated by each survey method and the known minimum kit fox abundance as determined by radio-collared animals. All surveys were conducted on 15 5-km transects during the 3 biological seasons of the kit fox. Scat deposition surveys had both the highest detection probabilities (p = 0.88) and were most closely related to minimum known fox abundance (r2 = 0.50, P = 0.001). The next best method for kit fox detection was the scent station survey (p = 0.73), which had the second highest correlation to fox abundance (r2 = 0.46, P<0.001). For detecting kit foxes in a low density population we suggest using scat deposition transects during the breeding season. Scat deposition surveys have low costs, resilience to weather, low labor requirements, and pose no risk to the study animals. The breeding season was ideal for monitoring kit fox population size, as detections consisted of the resident population and had the highest detection probabilities. Using appropriate monitoring techniques will be critical for future conservation actions for this rare desert carnivore.


Strengthening emergency preparedness and response systems: experience from Indonesia.
Indonesia has made excellent progress on emergency preparedness in compliance with the International Health Regulations, 2005, including a joint external evaluation (JEE) of IHR core capacities in 2017. Development of the National action plan for health security (NAPHS) began soon after the JEE, through multisectoral coordination and collaboration and with the support of a presidential instruction. The logic model approach was used to develop the NAPHS, and provided a robust framework to ensure that activities were linked to indicators at the various capacity levels delineated in the JEE. The NAPHS includes a comprehensive tool within which monitoring and evaluation are completely separated and different indicators applied. Furthermore, development of the NAPHS was done in parallel and in line with that of the National medium-term development plan 2020-2024, which included a focus on health system strengthening based on the primary health-care approach. An innovative approach taken in 2018 was the inclusion of emergency preparedness in the mandatory minimum service standards for provincial and district governments. These standards clearly articulate the importance of local emergency preparedness in Indonesia's decentralized governance through the development of contingency plans and simulation exercises for natural disasters and potential disease outbreaks. Development of the NAPHS has benefited from Indonesia's extensive experience in pandemic influenza preparedness planning and exercises, integrated with a national disaster management system. By signing the Delhi Declaration on Emergency Preparedness in the South-East Asia Region, Indonesia has signalled its commitment to implementing the NAPHS in full, focusing on enhanced emergency preparedness at all administrative levels.


MR derived volumetric flow rate waveforms of internal carotid artery in patients treated for unruptured intracranial aneurysms by flow diversion technique.
Little is known about the hemodynamic disturbances induced by the cerebral aneurysms in the parent artery and the effect of flow diverter stents (FDS) on these latter. A better understanding of the aneurysm-parent vessel complex relationship may aid our understanding of this disease and to optimize its treatment. The ability of volumetric flow rate (VFR) waveform to reflect the arterial compliance modifications is well known. By analyzing the VFR waveform and the pulsatility in the parent vessel, this study aimed to test the hypotheses that (1) intracranial aneurysms might disrupt the blood flow of the parent vessel and (2) the treatment by FDS might have measurable corrective effect on these changes. Ten patients followed for unruptured intracranial aneurysms treated by FDS and ten healthy volunteers as control group were included in this study. Two-dimensional quantitative phase-contrast magnetic resonance imaging (MRI) was performed on each patient on the ICA artery upstream and downstream to the aneurysm, and on each volunteer at similar locations. The aneurysms altered significantly the parent vessel pulsatility and this effect was correlated to their volume. The aneurysms treatment by FDS allowed for the restoration of a normally modulated flow and pulsatility correction in the parent vessel.


Total pelvic exenteration for primary and recurrent malignancies.
Complete resection is the most important prognostic factor in surgery for pelvic tumors. In locally advanced and recurrent pelvic malignancies, radical margins are sometimes difficult to obtain because of close relation to or growth in adjacent organs/structures. Total pelvic exenteration (TPE) is an exenterative operation for these advanced tumors and involves en bloc resection of the rectum, bladder, and internal genital organs (prostate/seminal vesicles or uterus, ovaries and/or vagina). Between 1994 and 2008, a TPE was performed in 69 patients with pelvic cancer; 48 with rectal cancer (32 primary and 16 recurrent), 14 with cervical cancer (1 primary and 13 recurrent), 5 with sarcoma (3 primary and 2 recurrent), 1 with primary vaginal, and 1 with recurrent endometrial carcinoma. Ten patients were treated with neoadjuvant chemotherapy and 66 patients with preoperative radiotherapy to induce down-staging. Eighteen patients received IORT because of an incomplete or marginal complete resection. The median follow-up was 43 (range, 1-196) months. Median duration of surgery was 448 (range, 300-670) minutes, median blood loss was 6,300 (range, 750-21,000) ml, and hospitalization was 17 (range, 4-65) days. Overall major and minor complication rates were 34% and 57%, respectively. The in-hospital mortality rate was 1%. A complete resection was possible in 75% of all patients, a microscopically incomplete resection (R1) in 16%, and a macroscopically incomplete resection (R2) in 9%. Five-year local control for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 89%, 38%, and 64%, respectively. Overall survival after 5 years for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 66%, 8%, and 45%. Total pelvic exenteration is accompanied with considerable morbidity, but good local control and acceptable overall survival justifies the use of this extensive surgical technique in most patients, especially patients with primary locally advanced rectal cancer and recurrent cervical cancer.


Dynamic control of auxin distribution imposes a bilateral-to-radial symmetry switch during gynoecium development.
Symmetry formation is a remarkable feature of biological life forms associated with evolutionary advantages and often with great beauty. Several examples exist in which organisms undergo a transition in symmetry during development. Such transitions are almost exclusively in the direction from radial to bilateral symmetry. Here, we describe the dynamics of symmetry establishment during development of the Arabidopsis gynoecium. We show that the apical style region undergoes an unusual transition from a bilaterally symmetric stage ingrained in the gynoecium due to its evolutionary origin to a radially symmetric structure. We also identify two transcription factors, INDEHISCENT and SPATULA, that are both necessary and sufficient for the radialization process. Our work furthermore shows that these two transcription factors control style symmetry by directly regulating auxin distribution. Establishment of specific auxin-signaling foci and the subsequent development of a radially symmetric auxin ring at the style are required for the transition to radial symmetry, because genetic manipulations of auxin transport can either cause loss of radialization in a wild-type background or rescue mutants with radialization defects. Whereas many examples have described how auxin provides polarity and specific identity to cells in a range of developmental contexts, our data presented here demonstrate that auxin can also be recruited to impose uniform identity to a group of cells that are otherwise differentially programmed.


A comparison of high frequency chest wall oscillation and intrapulmonary percussive ventilation for airway clearance in pediatric patients with tracheostomy.
The aim of this study was to compare two modes of airway clearance, the intrapulmonary percussive ventilation system (IPV) to high frequency chest wall oscillation system (HFCWO) in medically complex pediatric patients with tracheostomy requiring long term care. This was a single center, retrospective study comparing the number of respiratory illnesses, lower respiratory tract infections (LRTI), utilization of bronchodilator and systemic steroids, and respiratory illnesses requiring acute care hospitalizations. A total of 8 tracheostomy dependent patients between the ages of 1-22 years were included for a 2-year study period. Each patient was used as their own control. During the period studied, the only variable in the medical regimen was the modality used for airway clearance. A Poisson regression model and generalized estimating equations were used to compare pre and post rates and to account for the correlation of count data from the same individual. Additionally, the paired differences (post-pre) for each event count were computed to provide the median and range of reductions in event rates while using intrapulmonary percussive ventilation system device. The non-parametric wilcoxon signed-rank test employed to determine whether the results from the Poisson model were consistently observed regardless of method of analysis. The total number of respiratory illnesses were reduced from 32 per year on HFCWO therapy to 15 per year on IPV system therapy (p < 0.001). The total number of LRTI requiring antibiotic use were decreased from 15 per year to 6 per year (p = 0.01), use of bronchodilator treatments were reduced from 53 to 21 (p < 0.001) and utilization of systemic steroids were reduced from 12 to 4 on IPV (p = 0.003). Numbers of hospitalizations to acute care facilities were reduced from 8 to 3 hospitalizations during the period of IPV use for airway clearance (p = 0.003). This study suggests that airway clearance by IPV therapy could be more effective and beneficial in providing airway clearance in specific subsets of the medically complex pediatric population.


A Founder Mutation in MYO7A Underlies a Significant Proportion of Usher Syndrome in Indigenous South Africans: Implications for the African Diaspora.
Research over the past 25 years at the University of Cape Town has led to the identification of causative mutations in 17% of the 1416 families in the Retinal Degenerative Diseases (RDD) biorepository in South Africa. A low rate of mutation detection has been observed in patients of indigenous African origin, hinting at novel genes and mutations in this population. Recently, however, data from our translational research program showed two unrelated indigenous African families with Usher syndrome (USH), with the same homozygous MYO7A mutation. Therefore, the extent to which this mutation contributes toward the disease burden in South Africa was investigated. Cohorts of unrelated indigenous South African probands with different RDD diagnoses were tested for the MYO7A c.6377delC mutation. Familial cosegregation analysis was performed for homozygous probands, clinical data were evaluated, and SNP haplotypes were analyzed. This homozygous MYO7A mutation underlies a remarkable 43% of indigenous African USH cases investigated in this study, the majority of which (60%) were diagnosed clinically with Type 2 USH. All homozygotes shared a common haplotype. This mutation does not appear to cause nonsyndromic vision loss. Of interest is the origin of this common mutation relevant to the Bantu population migration into southern Africa. Further investigation of the phenotype may elucidate the disease biology, and perhaps reveal a larger cohort with the same mutation, with which to assess the impact of environmental and genetic modifiers and evaluate therapeutic trials.


Synergistic antitumor effects of tanshinone IIA and sorafenib or its derivative SC-1 in hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is the most common form of hepatic malignancy in the world. We aimed to determine the effect of tanshinone IIA (Tan-IIA) in combination with sorafenib or its derivative SC-1 on cytotoxicity, apoptosis, and metastasis in human HCC cells. Cytotoxicity was detected by MTT assay. Apoptosis and sub-G1 populations were analyzed by flow cytometry. Cell migration and invasion were evaluated by Transwell assay. Protein expression was detected by Western blot. Tan-IIA combined with sorafenib or SC-1 exerted synergistic cytotoxicity in HCC cells. Elevated proportions of sub-G1 and caspase activation were observed in the combinative treatments; in addition, marked inhibition of cell migration and invasion, which could be mediated by the modulation of epithelial-mesenchymal transition was observed. pSTAT3 levels were significantly reduced as well. A combination therapy using Tan-IIA and sorafenib or SC-1 could be a promising approach to target HCC, and further preclinical investigations are warranted to establish their synergetic advantage.


Ataxia-telangiectasia-mutated (ATM) protein can enhance human immunodeficiency virus type 1 replication by stimulating Rev function.
The ataxia-telangiectasia-mutated (ATM) kinase plays a central role in responses to various forms of DNA damage and has been suggested to facilitate human immunodeficiency virus type 1 (HIV-1) integration. Here, we describe a series of experiences that indicate that ATM can enhance HIV-1 replication by stimulating the action of the Rev viral posttranscriptional regulator. The Rev-dependent stimulation of viral late gene expression was observed with ATM-overexpressing cells, a result confirmed with a Rev-dependent reporter construct. Both parameters were also enhanced upon treatment of HeLa cells with caffeine, a xanthine that, in this cellular context, stimulates ATM activity. As well, decreased levels of virions with reduced infectivity were released by ATM knockdown cells. Notably, ATM overexpression did not stimulate the HIV-1 late gene expression within the context of Rev-independent constructs or the Rex-dependent production of capsid from human T-cell leukemia virus type 1 proviral constructs. Altogether, these results indicate that ATM can positively influence HIV-1 Rev function.


The Relationship Between Education and Health: Reducing Disparities Through a Contextual Approach.
Adults with higher educational attainment live healthier and longer lives compared with their less educated peers. The disparities are large and widening. We posit that understanding the educational and macrolevel contexts in which this association occurs is key to reducing health disparities and improving population health. In this article, we briefly review and critically assess the current state of research on the relationship between education and health in the United States. We then outline three directions for further research: We extend the conceptualization of education beyond attainment and demonstrate the centrality of the schooling process to health; we highlight the dual role of education as a driver of opportunity but also as a reproducer of inequality; and we explain the central role of specific historical sociopolitical contexts in which the education-health association is embedded. Findings from this research agenda can inform policies and effective interventions to reduce health disparities and improve health for all Americans.


Adherence to osteoporosis pharmacotherapy is underestimated using days supply values in electronic pharmacy claims data.
Days supply (prescription duration) values are commonly used to estimate drug exposure and quantify adherence to therapy, yet accuracy is not routinely assessed, and potential inaccurate reporting has been previously identified. We examined the impact of cleaning days supply values on the measurement of adherence to oral bisphosphonates. We identified new users of oral bisphosphonates among Ontario seniors (April 2001-March 2011). Days supply values were examined by dose, and we identified misclassification by comparing observed values to dose-specific expected values. Days supply values not matching expected values were cleaned using dose-specific algorithms. One-year adherence to therapy was defined using measures of compliance (mean proportion of days covered [PDC], and categorized into high [PDC ≥ 80%], medium [50% < PDC < 80%], low [PDC ≤ 50%]) and persistence (30-day permissible gap). Estimates were compared using the observed and cleaned days supply values, stratified by site of patient residence (community or long-term care [LTC]). We identified 337 729 (5% LTC) eligible new users. Among LTC patients, adherence estimates increased significantly following data cleaning: mean PDC (59 to 83%), proportion with high compliance (47 to 76%), and proportion persisting with therapy (62 to 78%). Modest increases were identified among community-dwelling patients following data cleaning (mean PDC, 71 to 74%; high compliance, 54 to 58%; and persistence, 56 to 61%). Data cleaning to correct for exposure misclassification can influence estimates of adherence with oral bisphosphonate therapy, particularly in LTC. Results highlight the importance of developing data cleaning strategies to correct for exposure misclassification and improve transparency in pharmacoepidemiologic studies.


Sexual differentiation of arachidonate toxicity in mice.
Mature male and female mice 50 days of age were challenged with i.v. sodium arachidonate at doses of 12.5, 25, 50 and 100 mg/kg. A dose-dependent response in terms of mortality was observed. Males were significantly more susceptible to arachidonate-induced mortality than females at the 25 and 50 mg/kg doses (P less than .05). The 100 mg/kg dose produced 100% mortality in both sexes. When mice aged 23, 29, 35 and 50 days were challenged with 50 mg/kg of arachidonate, no gender difference was observed until mice were 35 days of age, at which time the male mortality was 80%, compared to 57% for female mice (P less than .05). Mice gonadectomized at 23 days and intact mice 23 days of age were treated with s.c. estradiol, testosterone or vehicle for 7 days before arachidonate challenge. Among these groups, the gonadectomized females and intact males were significantly protected by estradiol when compared to the appropriate controls (P less than .05). In contrast, testosterone pretreatment had no significant effect on mortality. These results demonstrate that the development of the gender difference in arachidonate-induced mortality in mice is dependent upon the presence of gonadal hormones in the immature stages.


The bright side of being blue: depression as an adaptation for analyzing complex problems.
Depression is the primary emotional condition for which help is sought. Depressed people often report persistent rumination, which involves analysis, and complex social problems in their lives. Analysis is often a useful approach for solving complex problems, but it requires slow, sustained processing, so disruption would interfere with problem solving. The analytical rumination hypothesis proposes that depression is an evolved response to complex problems, whose function is to minimize disruption and sustain analysis of those problems by (a) giving the triggering problem prioritized access to processing resources, (b) reducing the desire to engage in distracting activities (anhedonia), and (c) producing psychomotor changes that reduce exposure to distracting stimuli. As processing resources are limited, sustained analysis of the triggering problem reduces the ability to concentrate on other things. The hypothesis is supported by evidence from many levels-genes, neurotransmitters and their receptors, neurophysiology, neuroanatomy, neuroenergetics, pharmacology, cognition, behavior, and efficacy of treatments. In addition, the hypothesis provides explanations for puzzling findings in the depression literature, challenges the belief that serotonin transmission is low in depression, and has implications for treatment.


Correction of phase extraction error in phase-shifting interferometry based on Lissajous figure and ellipse fitting technology.
The accuracy of phase-shifting interferometers (PSI) is crippled by nonlinearity of the phase shifter and instability of the environment such as vibration and air turbulence. A general algorithm, utilizing Lissajous figures and ellipse fitting, of correcting the phase extraction error in the phase shifting interferometry is described in this paper. By plotting N against D, where N and D represent the numerator and denominator terms of the phase extraction function (i.e. an arctangent function) respectively, a Lissajous ellipse is created. Once the parameters of the ellipse are determined by ellipse fitting, one can transform the ellipse to a unit circle (ETC). Through this process the phase extraction error caused by random phase shift errors can be corrected successfully. Proposed method is non-iterated, adapts to all phase shifting algorithms (PSAs), and has high accuracy. Some factors that may affect the performance of proposed method are discussed in numerical simulations. Optical experiments are implemented to validate the effectiveness of proposed algorithm.


Consequences of chromsome18q deletions.
Providing clinically relevant prognoses and treatment information for people with a chromsome18q deletion is particularly challenging because every unrelated person has a unique region of hemizygosity. The hemizygous region can involve almost any region of 18q including between 1 and 101 genes (30 Mb of DNA). Most individuals have terminal deletions, but in our cohort of over 350 individuals 23% have interstitial deletions. Because of this heterogeneity, we take a gene by gene approach to understanding the clinical consequences. There are 196 genes on 18q. We classified 133 of them as dosage insensitive, 15 (8%) as dosage sensitive leading to haploinsufficiency while another 10 (5%) have effects that are conditionally haploinsufficient and are dependent on another factor, genetic or environmental in order to cause an abnormal phenotype. Thirty-seven genes (19%) have insufficient information to classify their dosage effect. Phenotypes attributed to single genes include: congenital heart disease, minor bone morphology changes, central nervous system dysmyelination, expressive speech delay, vesicouretreral reflux, polyposis, Pitt-Hopkins syndrome, intellectual disability, executive function impairment, male infertility, aural atresia, and high frequency sensorineural hearing loss. Additionally, identified critical regions for other phenotypes include: adolescent idiopathic scoliosis and pectus excavatum, Virchow-Robin perivascular spaces, small corpus callosum, strabismus, atopic disorders, mood disorder, IgA deficiency, nystagmus, congenital heart disease, kidney malformation, vertical talus, CNS dysmyelination growth hormone deficiency and cleft palate. Together these findings make it increasingly feasible to compile an individualized syndrome description based on each person's individuated genotype. Future work will focus on understanding molecular mechanisms leading to treatment.