Chronic hepatitis and HIV risks amongst Pakistani migrant men in a French suburb and insights into health promotion interventions: the ANRS Musafir qualitative study.
Seine-Saint-Denis is a deprived departement (French administrative unit) in the North-East of Paris, France, hosting the majority of South Asian migrants in France. In recent years, the number of migrants from Pakistan, which has a high prevalence of hepatitis C globally, increased. As a corollary, this study addressed the high proportion of Pakistani patients in the infectious diseases clinic of a local hospital, diagnosed with hepatitis C, but also hepatitis B and Human Immunodeficiency Virus (HIV). It explored genealogies and beliefs about hepatitis and HIV transmission, including community, sexual and blood risk behaviours. The aim was to understand the ways these risk factors reduce or intensify both en route and once in France, in order to devise specific forms of community health intervention. The study took place at Avicenne University-Hospital in Seine-Saint-Denis, and its environs, between July and September 2018. The design of the study was qualitative, combining semi-structured interviews, a focus group discussion, and ethnographic observations. The sample of Pakistani participants was selected from those followed-up for chronic hepatitis C, B, and/or HIV at Avicenne, and who had arrived after 2010 in Seine-Saint-Denis. Thirteen semi-structured interviews were conducted, until saturation was reached. All participants were men from rural Punjab province. Most took the Eastern Mediterranean human smuggling route. Findings suggest that vulnerabilities to hepatitis and HIV transmission, originating in Pakistan, are intensified along the migration route and perpetuated in France. Taboo towards sexuality, promiscuity in cohabitation conditions, lack of knowledge about transmission were amongst the factors increasing vulnerabilities. Participants suggested a number of culturally-acceptable health promotion interventions in the community, such as outreach awareness and testing campaigns in workplaces, health promotion and education in mosques, as well as web-based sexual health promotion tools to preserve anonymity. Our findings highlight the need to look at specific groups at risk, related to their countries of origin. In-depth understandings of such groups, using interdisciplinary approaches such as were employed here, can allow for culturally adapted, tailored interventions. However, French colour-blind policies do not easily permit such kinds of targeted approach and this limitation requires further debate.


Adverse effects of in vitro GenX exposure on rat thyroid cell viability, DNA integrity and thyroid-related genes expression.
The hexafluoropropylene-oxide-dimer-acid (GenX) is a short-chain perfluoroalkyl substance that was recently introduced following the phase out of PFOA, as an alternative for the process of polymerization. GenX was detected at high concentrations in rivers, drinking water and in sera of exposed workers and recent findings suggested its potential dangerousness for human health. Aim of the study was to assess the consequences of GenX exposure on in vitro thyroid cells with particular attention to the effects on cell-viability, proliferation, DNA-damage and in the thyroid-related genes expression. FRTL-5 rat-thyroid cell line were incubated with increasing concentrations of GenX for 24 h, 48 h and 72 h to assess cell viability by WST-1. DNA-damage was assessed by comet assay and further confirmed by micronucleus assay. The proliferation of survived cells was measured by staining with crystal violet and evaluation of its optical density after incubation with SDS. Changes in TTF-1, Pax8, Tg, TSH-R, NIS and TPO genes expression were evaluated by RT-PCR. GenX exposure reduced FRTL-5 viability in a time and dose-dependent manner (24 h: ANOVA F = 22.286; p < 0.001; 48 h: F = 43.253, p < 0.001; 72 h: F = 49.708, p < 0.001). Moreover, GenX exerted a genotoxic effect, as assessed by comet assay (significant increase in tail-length, olive-tail-moment and percentage of tail-DNA) and micronucleus assay, both at cytotoxic and non-cytotoxic concentrations. Exposure to GenX at concentrations non-cytotoxic exerted a significant lowering of the expression of the regulatory gene TTF-1 (p < 0.05 versus untreated) and higher expression of Pax-8 (p < 0.05 versus untreated) and a down-regulation of NIS (p < 0.05 versus untreated). In addition, cells survived to GenX exposure showed a reduced re-proliferation ability (24 h: ANOVA F = 11,941; p < 0,001; 48 h: F = 93.11; p < 0.001; 72 h F = 21.65; p < 0.001). The exposure to GenX produces several toxic effects on thyroid cells in vitro. GenX is able to promote DNA-damage and to affect the expression of thyroid transcription-factor genes.


Ramadan fasting and newborn's birth weight in pregnant Muslim women in The Netherlands.
Many Muslim women worldwide are pregnant during Ramadan and adhere to Ramadan fasting during pregnancy. In the present study, we determined whether maternal adherence to Ramadan fasting during pregnancy has an impact on the birth weight of the newborn, and whether the effects differed according to trimester in which Ramadan fasting took place. A prospective cohort study was conducted in 130 pregnant Muslim women who attended antenatal care in Amsterdam and Zaanstad, The Netherlands. Data on adherence to Ramadan fasting during pregnancy and demographics were self-reported by pregnant women, and the outcome of the newborn was retrieved from medical records after delivery. The results showed that half of all the women adhered to Ramadan fasting. With strict adherence to Ramadan fasting in pregnancy, the birth weight of newborns tended to be lower than that of newborns of non-fasting mothers, although this was not statistically significant ( - 198 g, 95 % CI - 447, 51, P= 0·12). Children of mothers who fasted in the first trimester of pregnancy were lighter at birth than those whose mothers had not fasted ( - 272 g, 95 % CI - 547, 3, P= 0·05). There were no differences in birth weight between children whose mothers had or had not fasted if Ramadan fasting had taken place later in pregnancy. Ramadan fasting during early pregnancy may lead to lower birth weight of newborns. These findings call for further confirmation in larger studies that should also investigate potential implications for perinatal and long-term morbidity and mortality.


Ewing's Sarcoma (Primitive Neuroectodermal Tumor) of Seminal Vesicles: A Case Report.
Malignant tumors of the seminal vesicles are rare; they may be of epithelial or mesenchymal origin. Carcinomas are the most common and pelvic sarcoma may be confused with a primary tumor of the seminal vesicles. Little is known of the prognosis and best sequence of treatment in such sarcoma. We report a rare case of extra-skeletal Ewing sarcoma/primitive neuroectodermal tumor of the seminal vesicles in a 54-year-old man who presented with chronic lower abdominal pain, urinary retention, and severe constipation. Pelvic CT scan and MRI confirmed the presence of a soft tissue mass lesion centered on seminal vesicles. A trans-gluteal Tru-cut biopsy confirmed the diagnosis. Three cycles of the preoperative chemotherapy VAC/IE (vincristine, Adriamycin and cyclophosphamide, followed by ifosfamide and etoposide) protocol achieved an excellent clinical response.


In-Vitro Use of 5-ALA for Photodynamic Therapy in Pediatric Brain Tumors.
Light irradiation (635 nm) of cells containing protoporphyrin IX (PPIX) after 5- aminolevulinic acid (5-ALA) pretreatment causes cell death via different pathways including apoptosis and necrosis, as previously demonstrated for malignant glioma cells. To elucidate whether various malignant pediatric brain tumors, which have been shown to accumulate PPIX, would also be susceptible to photodynamic therapy (PDT). Medulloblastoma (DAOY, UW228), pNET (PFSK-1), and rhabdoid tumor (BT16) cell lines were incubated with 5-ALA in variable concentrations for 4 h. Consequently, cells were irradiated by 635 nm diode laser light. After 12 h, cell viability was measured by WST-1 testing and these results were compared to control cells incubated with 5-ALA without irradiation or irradiation only without prior incubation with 5-ALA. We demonstrated significant cell death in malignant pediatric tumor cells after incubation with 5-ALA and laser irradiation in comparison to control groups. In all cell lines, we noticed significant cell death above a 5-ALA concentration of 50 μg/ml (P < .05). Neither 5-ALA incubation alone nor irradiation alone caused cell death. DAOY and PFSK cell lines were more susceptible than UW228 and BT16 cells. We conclude that PDT causes cell death with higher PPIX concentrations after exposure to 5-ALA in vitro in accordance to similar studies with glioma cells. This indicates that PDT might be feasible for eliminating brain tumor cells in malignant pediatric brain tumors. Additionally, we noticed a dependency between fluorescence intensity and death rates.


The Deep Correlation between Energy Metabolism and Reproduction: A View on the Effects of Nutrition for Women Fertility.
In female mammals, mechanisms have been developed, throughout evolution, to integrate environmental, nutritional and hormonal cues in order to guarantee reproduction in favorable energetic conditions and to inhibit it in case of food scarcity. This metabolic strategy could be an advantage in nutritionally poor environments, but nowadays is affecting women's health. The unlimited availability of nutrients, in association with reduced energy expenditure, leads to alterations in many metabolic pathways and to impairments in the finely tuned inter-relation between energy metabolism and reproduction, thereby affecting female fertility. Many energetic states could influence female reproductive health being under- and over-weight, obesity and strenuous physical activity are all conditions that alter the profiles of specific hormones, such as insulin and adipokines, thus impairing women fertility. Furthermore, specific classes of nutrients might affect female fertility by acting on particular signaling pathways. Dietary fatty acids, carbohydrates, proteins and food-associated components (such as endocrine disruptors) have per se physiological activities and their unbalanced intake, both in quantitative and qualitative terms, might impair metabolic homeostasis and fertility in premenopausal women. Even though we are far from identifying a "fertility diet", lifestyle and dietary interventions might represent a promising and invaluable strategy to manage infertility in premenopausal women.


Exercise associated or not to the intake of Eurycoma longifolia improves strength and cardiorespiratory fitness in men with androgen deficiency.
This study aims to analyze the effects of a concurrent training (CT) associated with Eurycoma longifolia (EL) supplementation on the muscle strength, cardiorespiratory fitness, and symptomatology score of men with the androgen deficiency of aging male (ADAM). Forty-five subjects (47.6 ± 5.2 years) were included in the study. The randomized, double-blinded, placebo controlled clinical trial lasted for 6 months. Participants were randomized into four groups, control (C; n = 12); EL (n = 11); CT (n = 11); and CT + EL (n = 11). Along this period, the isokinetic peak torque of the knee extensors increased in the CT (14%) and CT + EL (17%) groups (p = 0.040; p = 0.006, respectively), while the isokinetic peak torque of knee flexion increased in the CT + EL group only (p < 0.05). For all participants, testosterone levels were correlated with isokinetic peak torque of knee extension (r = 0.517, p = 0.001) and flexion (r = 0.362, p = 0.028). Subjects of the CT (27.3%) and CT + EL (36.1%) groups decreased the symptomatology of ADAM (p = 0.005). This study demonstrated the benefits of CT and EL consumption as a non-pharmacological treatment for ADAM.


Disregulated influenza A virus-specific CD8+ T cell homeostasis in the absence of IFN-gamma signaling.
Recent studies indicate that IFN-gamma may influence both the expansion and the trafficking of virus-specific CD8+ CTL, though the effects are not necessarily consistent for different models of viral and bacterial disease. Influenza A virus infection of mice deficient for IFN-gamma (IFN-gamma(-/-)) or deficient for the IFN-gamma receptor 1 (IFNGR1(-/-)) was, when compared with the wild-type (WT) B6 controls, associated with increased Ag-specific CD8+ T cell counts in the spleen and mediastinal lymph nodes. At the same time, fewer of these CTL effectors were found in the bronchoalveolar lavage population recovered from the IFN-gamma(-/-) mice. Comparable effects were observed for WT mice treated with a neutralizing IFN-gamma-specific mAb. Transfer of WT memory Thy1.1(+) CD8+ populations into Thy1.2+ B6 IFN-gamma(-/-) or IFNGR1(-/-) mice followed by intranasal virus challenge demonstrated both that IFN-gamma produced by the host was important for the regulation of Ag-specific CTL numbers and that IFN-gamma was likely to act directly on the T cells themselves. In addition, the prevalence of CTLs undergoing apoptosis in spleen was lower when measured directly ex vivo for IFN-gamma(-/-) vs WT B6 mice. The present analysis is the first comprehensive demonstration that IFN-gamma signaling can differentially regulate both Ag-specific CTL homeostasis in secondary lymphoid organs and trafficking to a site of virus-induced pathology.


Patient characteristics associated with undergoing cancer operations at low-volume hospitals.
Although strong volume-outcome relationships exist for many cancer operations, patients continue to undergo these operations at low-volume hospitals. Patients were identified from the National Cancer Data Base from 2010-2013 who underwent resection for bladder, breast, esophagus, lung, pancreas, rectum, and stomach cancers. Low-volume hospitals were defined as those in the bottom quartile by surgical volume for each cancer type separately. Logistic regression models were constructed to assess patient-level factors associated with undergoing cancer surgery at low-volume hospitals across cancer types while controlling for tumor characteristics. Survival outcomes (30- and 90-day mortality; overall survival) were also assessed. Low volume thresholds were 4, 84, 4, 18, 8, 7, and 4 resections per year for bladder, breast, esophagus, lung, pancreas, rectum, and stomach cancers, respectively, resulting in 772 (74.1%), 828 (57.5%), 664 (77.5%), 830 (64.7%), 716 (79.2%), 898 (65.1%), and 888 (68.5%) hospitals classified as low-volume hospitals, respectively. For all the cancers examined, patients were more likely to undergo operation at low-volume hospitals if they traveled shorter distances (home to surgical facility), resided in rural locations, or had not received neoadjuvant therapy. Other patient and tumor factors were not associated consistently with undergoing operation at low-volume hospitals. Patients who went to low-volume hospitals had poorer outcomes among the studied cancers. Patients continue to undergo operation at low-volume hospitals due to where they live and how far they have to travel. Regionalization policy initiatives will remain challenging in this population. Efforts should therefore continue to emphasize quality improvement locally at each facility caring for patients with cancer.


MR findings in lipoma arborescens of the knee: our experience.
This paper describes the role of MR imaging in the identification of the different macroscopic patterns of lipoma arborescens. Between June 1995 and January 2004, a total of 6387 MR examinations of the knee were retrospectively assessed for the presence of lipoma arborescens. The MR examinations were performed using a superconductive 0.5 T MR unit with a transmitting/ receiving coil dedicated for the extremities. The MR images were acquired with SE T1-weighted, GE T2-weighted and STIR sequences in sagittal, coronal and axial planes with 3-mm thickness and 1-mm gap. Lipoma arborescens was identified in 9 patients (mean age: 36 years). In 2/9 cases a localized lipoma arborescens was detected as a well-marginated single nodule on the suprapatellar bursa without irregularity or synovial hyperplasia. In the remaining 7 cases diffuse lipoma arborescens was identified on the wall of the suprapatellar bursa. In one case of diffuse lipoma arborescens there was involvement of both knees. In all cases the MR findings were verified at surgery and the final diagnosis was made by histological examination. MR imaging shows a high accuracy in the identification and characterization of lipoma arborescens, due to its multiplanar capabilities and high contrast resolution. MRI allows correct evaluation of size and grade, accurate treatment planning and effective follow-up, avoiding the need for synovial biopsy.


Short-Range Graphitic Nanodomains in Hypocrystalline Carbon Nanotubes Realize Fast Potassium Ion Migration and Multidirection Stress Release.
Defect-rich carbon materials are considered as one of the most promising anodes for potassium-ion batteries due to their enormous adsorption sites of K+ , while the realization of both rate capability and cycling stability is still greatly limited by unstable electrochemical kinetics and inevitable structure degradation. Herein, an Fe3+ -induced hydrothermal-pyrolysis strategy is reported to construct well-tailored hybrid carbon nanotubes network architecture (PP-CNT), in which the short-range graphitic nanodomains are in-situ localized in the pea pod shape hypocrystalline carbon. The N,O codoped hypocrystalline carbon region contributes to abundant defect sites for potassium ion storage, ensuring high reversible capacity. Meanwhile, the short-range graphitic nanodomains with expanded interlayer spacing facilitate stable K+ migration and fast electron transfer. Furthermore, the finite element analysis confirms the volume expansion caused by K+ intercalation can be availably buffered due to the multidirection stress release effect of the unique porous pea pod shape, endowing carbon nanotubes with superior structural integrity. Consequently, the PP-CNT anode exhibits superior potassium-storage performance, including high reversible capacity, exceptional rate capability, and ultralong cycling stability. This work opens a new avenue for the fabrication of advanced carbon materials for achieving durable and fast potassium storage.


Guideline recommended treatment to targets of cardiovascular risk is inadequate in patients with inflammatory joint diseases.
Patients with inflammatory joint diseases (IJD) have an increased risk of cardiovascular disease (CVD). Our goal was to examine indications for, and use of, lipid-lowering therapy (LLT) and antihypertensive treatment (AntiHT) in patients with IJD. Furthermore, to investigate the frequency of low-density lipoprotein cholesterol (LDL-c) and blood pressure (BP) goal attainment among IJD patients. The cohort was derived from the NOrwegian Collaboration on Atherosclerosis in patients with Rheumatic joint diseases (NOCAR). Indications for AntiHT were: systolic/diastolic BP ≥ 140/90 mm Hg, self-reported hypertension or AntiHT. CVD risk was estimated by the systematic coronary risk evaluation (SCORE) algorithm. LDL-c goals were <2.6 mmol/L in case of diabetes, total cholesterol > 8 mmol/L or a SCORE estimate ≥ 5%, and <1.8 mmol/L for those with established CVD or SCORE ≥ 10%. Comparisons across IJD entities were performed using age and sex adjusted logistic regression. In total, 2277 patients (rheumatoid arthritis: 1376, axial spondyloarthritis: 474, psoriatic arthritis: 427) were included. LLT and AntiHT were indicated in 36.1% and 52.6% of the patients, of whom 37.6% and 47.0% were untreated, respectively. LDL-c and BP targets were obtained in 26.2% and 26.3%, respectively. Guideline recommended treatment and/or corresponding treatment targets were not initiated or obtained in approximately 50%. Rheumatoid arthritis patients were particularly likely to be undertreated with LLT, whereas hypertension undertreatment was most common in psoriatic arthritis. Inadequate CVD prevention encompasses all the three major IJD entities. The unmet need for CVD preventive measures is not only prevalent in RA, but exists across all the major IJD entities.


Enzyme ultracytochemical demonstration of Ca(++)-ATPase in the rat cerebral cortex.
The localization of Ca(++)-ATPase activity was investigated in the rat cerebral cortex using an ultracytochemical method. Our cytochemical procedure for the detection of enzyme activity is based on an incubation medium consisting of tricine buffer, ATP-disodium salt as substrate, cerium chloride as capturing agent, CaCl2, and levamisole as a nonspecific alkaline phosphatase inhibitor. Final pH was 7.4. Reaction products showing Ca(++)-ATPase activity were localised on the pre- and postsynaptic plasma membrane in association with synaptic vesicles, postsynaptic dendrites and on the axolemma in myelinated nerve fibres. The verification of the main enzymatic properties of Ca(++)-ATPase localization activity is the subject of the following report.


Metabolite profiling of Calvin cycle intermediates by HPLC-MS using mixed-mode stationary phases.
A sensitive and robust mixed-mode high performance liquid chromatography-tandem mass spectrometry method was developed for the qualitative and quantitative determination of sugar phosphates, which are notoriously difficult to separate using reversed-phase materials. Sugar phosphates were separated on a Primesep SB column by gradient elution using aqueous ammonium formate and acetonitrile as mobile phases. Target analytes were identified by their precursor/product ions and retention times. Quantitative analysis was performed in negative ionization/multiple reaction monitoring mode with five different time segments. The method was validated by spiking authentic sugar phosphate standards into complex plant tissue extracts. Standard curves of neat authentic standards and spiked extracts were generated for concentrations in the low picomole to nanomole range, with correlation coefficients of R(2) > 0.991, and the degree of ion suppression in the presence of a plant matrix was calculated for each analyte. Analyte recoveries, which were determined by including known quantities of authentic standards in the sugar phosphate extraction protocol, ranged from 40.0% to 57.4%. The analytical reproducibility was assessed by determining the coefficient of variance based on repeated extractions/measurements (<20%). The utility of our method is demonstrated with two types of applications: profiling of Calvin cycle intermediates in (i) dark-adapted and light-treated tobacco leaves, and in (ii) antisense plants expressing reduced levels of the Calvin cycle enzymes glyceraldehyde-3-phosphate dehydrogenase or ribulose-1,5-bisphosphate carboxylase/oxygenase (comparison with wild-type controls). The broader applicability of our method is illustrated by profiling sugar phosphates extracted from the leaves of five taxonomically diverse plants.


Treatment of anxiety in the cognitively impaired elderly: can cognitive-behavior therapy help?
Anxiety is commonly reported in patients with dementia, resulting in a further decline in functioning. An overview of the clinical application of cognitive-behavioral techniques in treating anxiety in elderly patients with brain damage is presented. Two cases are described with a focus on clinical anxiety management techniques that have been modified to suit cognitively impaired elderly patients. These modifications include simplifying material, using more structured techniques, and recognizing the critical role of the patient's caregiver in therapy. It is concluded that cognitive-behavior therapy can help in reducing anxiety in the demented population; the potential benefits of this therapy are an increase in patients' self-esteem and independence and the prevention of hospitalization.


Prevalence of Children's Mental Health Problems and the Effectiveness of Population-Level Family Interventions.
The prevalence of mental health problems among children and adolescents is of growing importance. Intervening in children's mental health early in life has been shown to be more effective than trying to resolve these problems when children are older. With respect to prevention activities in community settings, the prevalence of problems should be estimated, and the required level of services should be delivered. The prevalence of children's mental health disorders has been reported for many countries. Preventive intervention has emphasized optimizing the environment. Because parents are the primary influence on their children's development, considerable attention has been placed on the development of parent training to strengthen parenting skills. However, a public-health approach is necessary to confirm that the benefits of parent-training interventions lead to an impact at the societal level. This literature review clarifies that the prevalence of mental health problems is measured at the national level in many countries and that population-level parenting interventions can lower the prevalence of mental health problems among children in the community.


Therapeutic Development Based on the Immunopathogenic Mechanisms of Psoriasis.
Psoriasis, a complex inflammatory autoimmune skin disorder that affects 2-3% of the global population, is thought to be genetically predetermined and induced by environmental and immunological factors. In the past decades, basic and clinical studies have significantly expanded knowledge on the molecular, cellular, and immunological mechanisms underlying the pathogenesis of psoriasis. Based on these pathogenic mechanisms, the current disease model emphasizes the role of aberrant Th1 and Th17 responses. Th1 and Th17 immune responses are regulated by a complex network of different cytokines, including TNF-α, IL-17, and IL-23; signal transduction pathways downstream to the cytokine receptors; and various activated transcription factors, including NF-κB, interferon regulatory factors (IRFs), and signal transducer and activator of transcriptions (STATs). The biologics developed to specifically target the cytokines have achieved a better efficacy and safety for the systemic management of psoriasis compared with traditional treatments. Nevertheless, the current therapeutics can only alleviate the symptoms; there is still no cure for psoriasis. Therefore, the development of more effective, safe, and affordable therapeutics for psoriasis is important. In this review, we discussed the current trend of therapeutic development for psoriasis based on the recent discoveries in the immune modulation of the inflammatory response in psoriasis.


Regulation of renal hemodynamics by plasma amino acid and hormone concentrations.
Our results as well as those in the literature suggest that some hormone or combination of hormones, that are inhibited by somatostatin, is responsible for the hyperfiltration response following amino acid infusion/protein ingestion. Recently, we have infused amino acids with somatostatin and replaced the stimulated levels of insulin/glucagon/growth hormone observed during amino acid infusion alone (Castellino and DeFronzo, preliminary results). This combined hormone replacement was able to overcome the inhibitory effect of somatostatin and return the increase in RPF and GFR to the elevated levels observed following amino acid infusion. These results suggest that some combination of these hormones is involved in the hyperfiltration response to hyperaminoacidemia. However, several comments are worthy of emphasis. First, somatostatin is known to inhibit a number of hormones (Table 1), and a contributory role for any of these should not be excluded. Second, a large body of evidence has accumulated to indicate that neither insulin, glucagon, nor growth hormone alone are capable of augmenting either RPF or GFR. The possibility that infusion of the three hormones together will increase RPF and GFR, when neither hormone alone will do so, has not been examined. More likely, some interaction between the elevated plasma amino acid concentrations and the elevated hormone levels is responsible for the hyperfiltration response. It is interesting to speculate that such an interaction might be exerted at the level of the kidney by an effect on renal amino acid metabolism.


Acute effects of alcohol on auditory brainstem potentials in humans.
Auditory brainstem potentials were recorded from human subjects before and after an intoxicating dose of alcohol. Following alcohol ingestion there were significant, progressive increases in the latencies of brainstem potential peaks III through VII. No changes in peak amplitudes were found. The results indicate that alcohol has a depressive effect on neural transmission within the primary auditory brainstem pathway.


Influence of reporting error on the relation between blood folate concentrations and reported folic acid-containing dietary supplement use among reproductive-aged women in the United States.
Folic acid intake is the most important predictor of blood folate concentrations among nonpregnant women, but the reporting of folic acid-containing supplement use is subject to error. We assessed the effect of reporting error of supplement use on blood folate concentrations. Data from the third National Health and Nutrition Examination Survey were analyzed. Respondents to that survey were asked twice about supplement use: ie, during the household interview, to recall use in the previous month, and during the physical examination, to recall use in the previous 24 h. To examine the effect of error reporting, we classified women (aged 15-44 y) into 5 groups according to supplement use in the previous month (nonusers, those ingesting < 400 micro g/d, and those ingesting >or= 400 micro g/d) and in the 24 h before the physical examination (yes or no). We expected nonappreciable differences in red blood cell (RBC) folate concentration by status of 24-h recall within the same category of previous-month use because RBC folate reflects long-term average consumption. We calculated covariate-adjusted means of serum and RBC folate concentrations. Among women who reported average daily use of >or= 400 micro g folic acid in the previous month, the adjusted mean RBC folate was 436.5 nmol/L (95% CI: 406.7, 466.3 nmol/L) in those who did not take the supplement in the previous 24 h and 519.7 nmol/L (95% CI: 496.2, 543.2 nmol/L) in those who did do so (P < 0.01). This significant difference indicates apparently erroneous reporting of supplement use in the previous month by some participants. The effect of reporting error on blood folate concentrations is important in interpreting survey results, evaluating health education campaigns, and identifying populations needing special education programs.


Comparison of individual characteristics and death rates of disabled-worker beneficiaries entitled in 1972 and 1985.
The many changes to the Disability Insurance (DI) program that took place during the early 1980's suggest that there may be significant differences in the characteristics of newly awarded beneficiaries over time. This study compares two cohorts of newly entitled beneficiaries--one from 1972 and the other from 1985--in order to assess changes in individual characteristics and death rates between the pre-1980's and the late 1980's. The 1985 cohort had a greater percentage of beneficiaries with mental impairments and a lower percentage with diseases of the circulatory system. The 1985 cohort was also younger, more educated, had higher primary insurance amount levels, and had greater percentages of women and black beneficiaries. Although the death rates and survival curves for both cohorts were very similar, differences in the curves occurred for some covariate subgroups. When the populations were standardized, the estimated percentages of beneficiaries who survived 5 years after entitlement were 78 percent for the 1972 cohort and 77 percent for the 1985 cohort.


Limited variation in visual sensitivity among bowerbird species suggests that there is no link between spectral tuning and variation in display colouration.
Variation in visual spectral tuning has evolved in concert with signal colour in some taxa, but there is limited evidence of this pattern in birds. To further investigate this possibility, we compared spectral sensitivity among bowerbird species that occupy different visual habitats and are highly diverged in plumage and decoration colour displays, which are important in mate choice and possibly reproductive isolation. Microspectrophotometry of violet-, short-, medium- and long-wavelength-sensitive cones revealed no significant interspecific variation in visual pigment peak spectral absorbance values that ranged between 404-410, 454, 503-511 and 558-568 nm, respectively. Mean cut-off wavelength values for C-, Y-, R- and P-type coloured oil droplets were 418-441, 508-523, 558-573 and 412-503 nm, respectively, with values at longer wavelengths in ventral compared with dorsal retina cones. Low ocular media mid-wavelength transmission values (340-352 nm) suggest that bowerbirds may represent a transitional stage in the evolution from the ancestral violet-sensitive- to the derived ultraviolet-sensitive-type short-wavelength-sensitive-1-based visual system found in younger passerine lineages. Sequence data obtained for rod opsin and four cone opsin genes were identical at key tuning sites, except for an interspecific leucine-52-alanine polymorphism in the short-wavelength-sensitive 2 opsin. There was no obvious relationship between relative proportions of cone classes and either visual habitat or display colour. Overall, we detected little interspecific variation in bowerbird spectral sensitivity and no association between sensitivity and display diversity, which is consistent with the general trend among avian taxa.


Obstructive sleep apnea as a risk factor for stroke and death.
Previous studies have suggested that the obstructive sleep apnea syndrome may be an important risk factor for stroke. It has not been determined, however, whether the syndrome is independently related to the risk of stroke or death from any cause after adjustment for other risk factors, including hypertension. In this observational cohort study, consecutive patients underwent polysomnography, and subsequent events (strokes and deaths) were verified. The diagnosis of the obstructive sleep apnea syndrome was based on an apnea-hypopnea index of 5 or higher (five or more events per hour); patients with an apnea-hypopnea index of less than 5 served as the comparison group. Proportional-hazards analysis was used to determine the independent effect of the obstructive sleep apnea syndrome on the composite outcome of stroke or death from any cause. Among 1022 enrolled patients, 697 (68 percent) had the obstructive sleep apnea syndrome. At baseline, the mean apnea-hypopnea index in the patients with the syndrome was 35, as compared with a mean apnea-hypopnea index of 2 in the comparison group. In an unadjusted analysis, the obstructive sleep apnea syndrome was associated with stroke or death from any cause (hazard ratio, 2.24; 95 percent confidence interval, 1.30 to 3.86; P=0.004). After adjustment for age, sex, race, smoking status, alcohol-consumption status, body-mass index, and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension, the obstructive sleep apnea syndrome retained a statistically significant association with stroke or death (hazard ratio, 1.97; 95 percent confidence interval, 1.12 to 3.48; P=0.01). In a trend analysis, increased severity of sleep apnea at baseline was associated with an increased risk of the development of the composite end point (P=0.005). The obstructive sleep apnea syndrome significantly increases the risk of stroke or death from any cause, and the increase is independent of other risk factors, including hypertension.


Recent advances in coronal heating.
The solar corona, the tenuous outer atmosphere of the Sun, is orders of magnitude hotter than the solar surface. This 'coronal heating problem' requires the identification of a heat source to balance losses due to thermal conduction, radiation and (in some locations) convection. The review papers in this Theo Murphy meeting issue present an overview of recent observational findings, large- and small-scale numerical modelling of physical processes occurring in the solar atmosphere and other aspects which may affect our understanding of the proposed heating mechanisms. At the same time, they also set out the directions and challenges which must be tackled by future research. In this brief introduction, we summarize some of the issues and themes which reoccur throughout this issue.


Pre-rheumatoid arthritis and its prevention.
Pre-rheumatoid arthritis (pre-RA) is the preclinical period of the disease that precedes the onset of clinically apparent RA. It includes the interaction between genetic and environmental risk factors and development of disease-related autoantibodies and joint symptoms and signs, which may be considered nonspecific or unclassified for RA. A better understanding of the pre-RA stage will be useful in developing screening programs for early detection of RA. Identifying and modifying risk factors such as smoking, periodontitis, obesity, viral infections, and hormonal or dietary factors will be useful in preventing RA in susceptible population.


Clinical Effectiveness of Statin Therapy After Ischemic Stroke: Primary Results From the Statin Therapeutic Area of the Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) Study.
In patients with ischemic stroke, data on the real-world effectiveness of statin therapy for clinical and patient-centered outcomes are needed to better inform shared decision making. Patient-Centered Research Into Outcomes Stroke Patients Prefer and Effectiveness Research (PROSPER) is a Patient-Centered Outcomes Research Institute-funded research program designed with stroke survivors to evaluate the effectiveness of poststroke therapies. We linked data on patients ≥65 years of age enrolled in the Get With The Guidelines-Stroke Registry to Medicare claims. Two-year to postdischarge outcomes of those discharged on a statin versus not on a statin were adjusted through inverse probability weighting. Our coprimary outcomes were major adverse cardiovascular events and home time (days alive and out of a hospital or skilled nursing facility). Secondary outcomes included all-cause mortality, all-cause readmission, cardiovascular readmission, and hemorrhagic stroke. From 2007 to 2011, 77 468 patients who were not taking statins at the time of admission were hospitalized with ischemic stroke; of these, 71% were discharged on statin therapy. After adjustment, statin therapy at discharge was associated with a lower hazard of major adverse cardiovascular events (hazard ratio, 0.91; 95% confidence interval, 0.87-0.94), 28 more home-time days after discharge (P<0.001), and lower all-cause mortality and readmission. Statin therapy at discharge was not associated with increased risk of hemorrhagic stroke (hazard ratio, 0.94; 95% confidence interval, 0.72-1.23). Among statin-treated patients, 31% received a high-intensity dose; after risk adjustment, these patients had outcomes similar to those of recipients of moderate-intensity statin. In older ischemic stroke patients who were not taking statins at the time of admission, discharge statin therapy was associated with lower risk of major adverse cardiovascular events and nearly 1 month more home time during the 2-year period after hospitalization.


A synthesis of mercury research in the Southern Hemisphere, part 2: Anthropogenic perturbations.
Environmental mercury (Hg) contamination is a global concern requiring action at national scales. Scientific understanding and regulatory policies are underpinned by global extrapolation of Northern Hemisphere Hg data, despite historical, political, and socioeconomic differences between the hemispheres that impact Hg sources and sinks. In this paper, we explore the primary anthropogenic perturbations to Hg emission and mobilization processes that differ between hemispheres and synthesize current understanding of the implications for Hg cycling. In the Southern Hemisphere (SH), lower historical production of Hg and other metals implies lower present-day legacy emissions, but the extent of the difference remains uncertain. More use of fire and higher deforestation rates drive re-mobilization of terrestrial Hg, while also removing vegetation that would otherwise provide a sink for atmospheric Hg. Prevalent Hg use in artisanal and small-scale gold mining is a dominant source of Hg inputs to the environment in tropical regions. Meanwhile, coal-fired power stations continue to be a significant Hg emission source and industrial production of non-ferrous metals is a large and growing contributor. Major uncertainties remain, hindering scientific understanding and effective policy formulation, and we argue for an urgent need to prioritize research activities in under-sampled regions of the SH.


How lipids affect the activities of integral membrane proteins.
The activities of integral membrane proteins are often affected by the structures of the lipid molecules that surround them in the membrane. One important parameter is the hydrophobic thickness of the lipid bilayer, defined by the lengths of the lipid fatty acyl chains. Membrane proteins are not rigid entities, and deform to ensure good hydrophobic matching to the surrounding lipid bilayer. The structure of the lipid headgroup region is likely to be important in defining the structures of those parts of a membrane protein that are located in the lipid headgroup region. A number of examples are given where the conformation of the headgroup-embedded region of a membrane protein changes during the reaction cycle of the protein; activities of such proteins might be expected to be particularly sensitive to lipid headgroup structure. Differences in hydrogen bonding potential and hydration between the headgroups of phosphatidycholines and phosphatidylethanolamines could be important factors in determining the effects of these lipids on protein activities, as well as any effects related to the tendency of the phosphatidylethanolamines to form a curved, hexagonal H(II) phase. Effects of lipid structure on protein aggregation and helix-helix interactions are also discussed, as well as the effects of charged lipids on ion concentrations close to the surface of the bilayer. Interpretations of lipid effects in terms of changes in protein volume, lipid free volume, and curvature frustration are also described. Finally, the role of non-annular, or 'co-factor' lipids, tightly bound to membrane proteins, is described.


Identifying factors for optimal development of health-related websites: a delphi study among experts and potential future users.
The Internet has become a popular medium for offering tailored and targeted health promotion programs to the general public. However, suboptimal levels of program use in the target population limit the public health impact of these programs. Optimizing program development is considered as one of the main processes to increase usage rates. To distinguish factors potentially related to optimal development of health-related websites by involving both experts and potential users. By considering and incorporating the opinions of experts and potential users in the development process, involvement in the program is expected to increase, consequently resulting in increased appreciation, lower levels of attrition, and higher levels of sustained use. We conducted a systematic three-round Delphi study through the Internet. Both national and international experts (from the fields of health promotion, health psychology, e-communication, and technical Web design) and potential users were invited via email to participate. During this study an extensive list of factors potentially related to optimal development of health-related websites was identified, by focusing on factors related to layout, general and risk information provision, questionnaire use, additional services, and ease of use. Furthermore, we assessed the extent to which experts and potential users agreed on the importance of these factors. Differences as well as similarities among experts and potentials users were deduced. In total, 20 of 62 contacted experts participated in the first round (32% response rate); 60 of 200 contacted experts (30% response rate) and 210 potential users (95% response rate) completed the second-round questionnaire, and 32 of 60 contacted experts completed the third round (53% response rate). Results revealed important factors consented upon by experts and potential users (eg, ease of use, clear structure, and detailed health information provision), as well as differences regarding important factors consented upon by experts (eg, visual aids, self-monitoring tool, and iterative health feedback) or by potential users only (eg, bread crumb navigation and prevention of receiving spam). This study is an important first step in determining the agreed-upon factors that should be taken into account when developing online health promotion programs. The public health impact of these programs will be improved by optimizing the development process in line with these factors.


From circadians of the fifties to chronomes in vitro as in vivo.
In a recent review of cellular mechanisms of entrainment, an ocular circadian rhythm of Bulla was reported (1). The isolated retina of this marine mollusk is described to contain a circadian oscillator. A glance at the spontaneous impulse frequency from eyes recorded in darkness at 15 degrees C suggests lower-frequency modulations of the about 24-h rhythm and prompts the quantitative assessment of the broader time structure, the chronome, in this extensively used model of a budding neurochronophysiology. The cultured retina of mollusks is interpreted by the original authors as descriptive of similar cellular mechanisms that may underlie mammalian as well as molluscan physiology. We report here the rhythmometric analysis of the original data by Block et al. (2), taken from Figure 2 of the article by Colwell et al. (1), resolved by computer just as the microscope resolves cellular structure. The results are further compared with those obtained on data kindly provided by Stephan Michel on another retina of Bulla. The findings of multiple chronome components (beyond the circadian system) are placed into the broader context of cell biophysics and its implications for biomedicine within the scope of an international chronome endeavor.


[Mercury technogenic pollution of the environment--a priority ecological hygiene problem (a review of the literature)].
The authors analyze distribution of mercury in the contaminated zone depending on the chemical formula of mercury and routes of entry, enumerate the norm rating and indices to be used in ecologo-hygienic evaluation of the hazards degrees of the actual level of mercury in the water, atmospheric air and soil, describe numerous sources of technical solutions of reducing mercury entry to environment from technogenous sources. Modern achievements of science and technology make it possible to exclude entry of mercury and its compounds into the environment.


Isotopic ratio and vertical distribution of radionuclides in soil affected by the accident of Fukushima Dai-ichi nuclear power plants.
The results of γ analyses of soil samples obtained from 50 locations in Fukushima prefecture on April 20, 2011, revealed the presence of a spectrum of radionuclides resulted from the accident of the Fukushima Dai-ichi nuclear power plant (FDNPP). The sum γ radioactivity concentration ranged in more than 3 orders of magnitude, depending on the sampling locations. The contamination of soils in the northwest of the FDNPP was considerable. The (131)I/(137)Cs activity ratios of the soil samples plotted as a function of the distance from the F1 NPPs exhibited three distinctive patterns. Such patterns would reflect not only the different deposition behaviors of these radionuclides, but also on the conditions of associated release events such as temperature and compositions and physicochemical forms of released radionuclides. The (136)Cs/(137)Cs activity ratio, on the other hand, was considered to only reflect the difference in isotopic compositions of source materials. Two locations close to the NPP in the northwest direction were found to be depleted in short-lived (136)Cs. This likely suggested the presence of distinct sources with different (136)Cs/(137)Cs isotopic ratios, although their details were unknown at present. Vertical γ activity profiles of (131)I and (137)Cs were also investigated, using 20-30 cm soil cores in several locations. About 70% or more of the radionuclides were present in the uppermost 2-cm regions. It was found that the profiles of (131)I/(137)Cs activity ratios showed maxima in the 2-4 cm regions, suggesting slightly larger migration of the former nuclide.


Photoaffinity labeling of the nuclear Ah receptor from mouse Hepa 1c1c7 cells using 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin.
The photoinduced formation of the covalently labeled cytosolic and nuclear aryl hydrocarbon (Ah) receptors was studied using 2,3,7,8-[3H]tetrachlorodibenzo-p-dioxin (TCDD) as the photoaffinity label. Irradiation of TCDD alone at wavelengths of greater than 300 nm resulted in rapid degradation of this compound (t 1/2 = 8 min). In a separate experiment, the unliganded cytosolic Ah receptor was only slowly inactivated (t 1/2 = 48 min) using the greater than 300 nm light source. Preliminary experiments with rat hepatic cytosol did not result in significant formation of specifically bound [3H]TCDD-protein covalent adducts which could be visualized by autoradiography. Irradiation of [3H]TCDD-nuclear Ah receptor complexes isolated from mouse Hepa 1c1c7 cells for 15 min gave approximately a 40% overall yield of the radiolabeled Ah receptor protein adduct. Denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the [3H]TCDD-nuclear Ah receptor photoadduct gave a single major radiolabeled protein with an apparent molecular size of 91 kDa. The chromatographic properties of the control (dark) and photolabeled nuclear Ah receptor complexes were comparable using Sephacryl S-300 and DNA-Sepharose columns. Velocity sedimentation of both the control (dark) and irradiated nuclear Ah receptor complexes gave specifically bound peaks which sedimented at 6.5 S. However, the trichloroacetic acid-precipitable (buffer-reconstituted) [3H]TCDD-nuclear Ah receptor photo-covalent adduct was eluted from the Sephacryl S-300 column in the void volume and did not exhibit a specifically bound peak after velocity sedimentation analysis due to protein aggregate formation. In contrast, the elution profile of the aggregate on a DNA-Sepharose column was similar to that observed for the control (dark) and photolabeled complexes, which were eluted from the column with salt concentrations between 0.24 and 0.28 M. These photolabeling studies show that [3H] TCDD can act as a photoaffinity label for the Ah receptor and can be utilized as photoligand to probe further the structure and function of this protein.


Prognostic implications of BCL6 rearrangement in uniformly treated patients with diffuse large B-cell lymphoma--a Nordic Lymphoma Group study.
The purpose of this study was to investigate the prognostic implications of BCL6 rearrangement in a uniformly treated population of patients with diffuse large B-cell lymphoma (DLBCL) and to characterise the relationship between BCL6 rearrangement and prognostic factors. A total of 269 patients with DLBCL entered a randomised trial comparing the chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) to the MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin) regimen. In 44 cases, frozen tissue was available for assessment of BCL6 status by Southern blot analysis. BCL6 was rearranged in six of 43 evaluable cases (14%), and was associated with elevated lactate dehydrogenase (LDH), and a higher patient age. No association between BCL6 status and expression of BCL2, Ki-67 or TP53 was found. Patients presenting with BCL6 rearrangement displayed a weak trend towards better overall and failure-free survival (67 and 67% at 5 years), compared to patients with germline BCL6 (63 and 52%), but the difference was not statistically significant. In accordance with previously published series, the presence of BCL6 rearrangement does not define a prognostically distinct subgroup of DLBCL. Assessment of BCL6 status may, however, be of clinical interest when related to other prognostic variables.


Experimental Models of Liquid Biopsy in Hepatocellular Carcinoma Reveal Clone-Dependent Release of Circulating Tumor DNA.
Liquid biopsy, the molecular analysis of tumor components released into the bloodstream, has emerged as a noninvasive and resourceful means to access genomic information from cancers. Most data derived from translational studies showcase its numerous potential clinical applications. However, data from experimental models are scarce, and little is known about the underlying mechanisms and factors controlling the release of circulating tumor DNA (ctDNA) and cells (CTCs). This study aimed to model liquid biopsy in hepatocellular carcinoma xenografts and to study the dynamics of release of ctDNA and CTCs; this included models of intratumoral heterogeneity (ITH) and metastatic disease. We quantified ctDNA by quantitative polymerase chain reaction (PCR) targeting human long interspersed nuclear element group 1; targeted mutation analysis was performed with digital droplet PCR. CTCs were traced by flow cytometry. Results demonstrated the feasibility of detecting ctDNA, including clone-specific mutations, as well as CTCs in blood samples of mice. In addition, the concentration of ctDNA and presence of tumor-specific mutations reflected tumor progression, and detection of CTCs was associated with metastases. Our ITH model suggested differences in the release of DNA fragments impacted by the cell-clone origin and the treatment. Conclusion: These data present new models to study liquid biopsy and its underlying mechanisms and highlighted a clone-dependent release of ctDNA into the bloodstream.


Tribological Performance of Porous Ti-Nb-Ta-Fe-Mn Alloy in Dry Condition.
The tribological properties of a novel porous Ti-Nb-Ta-Fe-Mn alloy with 0%, 30%, and 60% porosity were evaluated for biomedical applications. The tribotesting was performed using a ball-on-disc under dry conditions, using an alumina ball and 1 N of a load. The coefficient of friction at the early stage of the porous samples was lower than that of the bulk, 0.2 and 0.7, respectively, but the samples with 30% porosity shift toward the bulk value after a variable number of cycles, while the samples with 60% remained stable after 100,000 cycles. The wear rate of the specimen with 60% porosity was twice as low as that of the bulk. The results are explained by shift in wear mechanism associated with the modified bearing ratio of the porous surface and by the accumulation of wear debris inside the pores, which prevented the development of three-body abrasion.


Pivotal Roles for pH, Lactate, and Lactate-Utilizing Bacteria in the Stability of a Human Colonic Microbial Ecosystem.
Lactate can be produced by many gut bacteria, but in adults its accumulation in the colon is often an indicator of microbiota perturbation. Using continuous culture anaerobic fermentor systems, we found that lactate concentrations remained low in communities of human colonic bacteria maintained at pH 6.5, even when dl-lactate was infused at 10 or 20 mM. In contrast, lower pH (5.5) led to periodic lactate accumulation following lactate infusion in three fecal microbial communities examined. Lactate accumulation was concomitant with greatly reduced butyrate and propionate production and major shifts in microbiota composition, with Bacteroidetes and anaerobic Firmicutes being replaced by Actinobacteria, lactobacilli, and Proteobacteria Pure-culture experiments confirmed that Bacteroides and Firmicutes isolates were susceptible to growth inhibition by relevant concentrations of lactate and acetate, whereas the lactate-producer Bifidobacterium adolescentis was resistant. To investigate system behavior further, we used a mathematical model (microPop) based on 10 microbial functional groups. By incorporating differential growth inhibition, our model reproduced the chaotic behavior of the system, including the potential for lactate infusion both to promote and to rescue the perturbed system. The modeling revealed that system behavior is critically dependent on the proportion of the community able to convert lactate into butyrate or propionate. Communities with low numbers of lactate-utilizing bacteria are inherently less stable and more prone to lactate-induced perturbations. These findings can help us to understand the consequences of interindividual microbiota variation for dietary responses and microbiota changes associated with disease states.IMPORTANCE Lactate is formed by many species of colonic bacteria, and can accumulate to high levels in the colons of inflammatory bowel disease subjects. Conversely, in healthy colons lactate is metabolized by lactate-utilizing species to the short-chain fatty acids butyrate and propionate, which are beneficial for the host. Here, we investigated the impact of continuous lactate infusions (up to 20 mM) at two pH values (6.5 and 5.5) on human colonic microbiota responsiveness and metabolic outputs. At pH 5.5 in particular, lactate tended to accumulate in tandem with decreases in butyrate and propionate and with corresponding changes in microbial composition. Moreover, microbial communities with low numbers of lactate-utilizing bacteria were inherently less stable and therefore more prone to lactate-induced perturbations. These investigations provide clear evidence of the important role these lactate utilizers may play in health maintenance. These should therefore be considered as potential new therapeutic probiotics to combat microbiota perturbations.


Crowder titrations enable the quantification of driving forces for macromolecular phase separation.
Macromolecular solubility is an important contributor to the driving forces for phase separation. Formally, the driving forces in a binary mixture comprising a macromolecule dissolved in a solvent can be quantified in terms of the saturation concentration, which is the threshold macromolecular concentration above which the mixture separates into coexisting dense and dilute phases. Additionally, the second virial coefficient, which measures the effective strength of solvent-mediated intermolecular interactions provides direct assessments of solvent quality. The sign and magnitude of second virial coefficients will be governed by a combination of solution conditions and the nature of the macromolecule of interest. Here, we show, using a combination of theory, simulation, and in vitro experiments, that titrations of crowders, providing they are true depletants, can be used to extract the intrinsic driving forces for macromolecular phase separation. This refers to saturation concentrations in the absence of crowders and the second virial coefficients that quantify the magnitude of the incompatibility between macromolecules and the solvent. Our results show how the depletion-mediated attractions afforded by crowders can be leveraged to obtain comparative assessments of macromolecule-specific, intrinsic driving forces for phase separation. Phase separation has emerged as a process of significant relevance to sorting macromolecules into distinct compartments, thereby enabling spatial and temporal control over cellular matter. Considerable effort is being invested into uncovering the driving forces that enable the separation of macromolecular solutions into coexisting phases. At its heart, this process is governed by the balance of macromolecule-solvent, inter-macromolecule, and solvent-solvent interactions. We show that the driving forces for phase separation, including the coefficients that measure interaction strengths between macromolecules, can be extracted by titrating the concentrations of crowders that enable macromolecules to phase separate at lower concentrations. Our work paves the way to leverage specific categories of measurements for quantitative characterizations of driving forces for phase separation.


Timing of pregnancy, postpartum risk of virologic failure and loss to follow-up among HIV-positive women.
We assessed the association between the timing of pregnancy with the risk of postpartum virologic failure and loss from HIV care in South Africa. This is a retrospective cohort study of 6306 HIV-positive women aged 15-49 at antiretroviral therapy (ART) initiation, initiated on ART between January 2004 and December 2013 in Johannesburg, South Africa. The incidence of virologic failure (two consecutive viral load measurements of >1000 copies/ml) and loss to follow-up (>3 months late for a visit) during 24 months postpartum were assessed using Cox proportional hazards modelling. The rate of postpartum virologic failure was higher following an incident pregnancy on ART [adjusted hazard ratio 1.8, 95% confidence interval (CI): 1.1-2.7] than among women who initiated ART during pregnancy. This difference was sustained among women with CD4 cell count less than 350 cells/μl at delivery (adjusted hazard ratio 1.8, 95% CI: 1.1-3.0). Predictors of postpartum virologic failure were being viremic, longer time on ART, being 25 or less years old and low CD4 cell count and anaemia at delivery, as well as initiating ART on stavudine-containing or abacavir-containing regimen. There was no difference postpartum loss to follow-up rates between the incident pregnancies group (hazard ratio 0.9, 95% CI: 0.7-1.1) and those who initiated ART in pregnancy. The risk of virologic failure remains high among postpartum women, particularly those who conceive on ART. The results highlight the need to provide adequate support for HIV-positive women with fertility intention after ART initiation and to strengthen monitoring and retention efforts for postpartum women to sustain the benefits of ART.


Gastric emptying of a solid meal is accelerated by the removal of dietary fibre naturally present in food.
Exogenous fibre added to liquid meals delays gastric emptying. Its effect on solid meals is uncertain, and nothing is known of the effect on gastric emptying of fibre naturally present in food. This study therefore looked at gastric emptying of two different solid meals in eight healthy subjects and their blood glucose responses. The meals were exactly equivalent except for the total dietary fibre content (high fibre 20 g, low fibre 4 g of dietary fibre per 1000 kcal) and supplied 870 kcal (700 kcal women), 47% of which was from carbohydrates, 36% from fats, and 17% from proteins. Ultrasonography was used to measure antral diameters before the meal (basal), immediately after it (time 0), and at 30, 60, 120, 180, 240, and 300 minutes. In addition, subjects filled in a questionnaire on their feelings of hunger, epigastric fullness, and satiety before the meal and at hourly intervals after it. Basal and maximal postprandial antral sections were similar for the two meals (basal section: 283.9 (29.5) v 340.9 (44.7) mm2 for the low and the high fibre meal, NS; maximal postprandial section: 1726 (101.9) v 1593 (120.4) mm2, NS). Total gastric emptying time was significantly reduced by fibre removal (186.0 (15.6) v 231.7 (17.3) minutes after the low and the high fibre meal, p < 0.05). Blood glucose was higher after the low fibre meal, and the area under the glycaemic curve significantly greater (226 (23.1) v 160 (20.0) mmol/min/dl-1, p < 0.05). No difference was found in satiety or fullness feelings, but hunger returned more rapidly after the low fibre meal. In conclusion, fibre naturally present in food delays gastric emptying of a solid meal, reduces the glycaemic response, and delays the return of hunger.


In-silico design of peptides for inhibition of HLA-A*03-KLIETYFSK complex as a new drug design for treatment of multiples sclerosis disease.
Multiple sclerosis is recognized as a chronic inflammatory disease. Human leukocyte antigen (HLA) plays an important role in initiating adaptive immune responses. HLA class I is present in almost all nucleated cells and presents the cleaved endogenous peptide antigens to cytotoxic T cells. HLA-A*03 is one of the HLA class I alleles, which is reported as substantially related HLA to MS disease. In 2011, the structure of the HLA-A*03 in complex was identified with an immunodominant proteolipid protein (PLP) epitope (KLIETYFSK). This complex has been reported as an important autoantigen-presenting complex in MS pathogenesis. In this study, new peptides were designed to bind to this complex that may prevent specific pathogenic cytotoxic T cell binding to this autoantigen-presenting complex and CNS demyelination. Herein, 14 new helical peptides containing 19 amino acids were designed and their structures were predicted using the PEP-FOLD server. The binding of each designed peptide to the mentioned complex was then performed. A mutation approach was used by the BeAtMuSiC server to improve the binding affinity of the designed peptide. In each position, amino acid substitutions leading to an increase in the binding affinity of the peptide to the mentioned complex were determined. Finally, the resulting complexes were simulated for 40 ns using AMBER18 software. The results revealed that out of 14 designed peptides, "WRYWWKDWAKQFRQFYRWF" peptide exhibited the highest affinity for binding to the mentioned complex. This peptide can be considered as a potential drug to control multiple sclerosis disease in patients carrying the HLA-A*03 allele.


Successful adherence to observed prophylaxis and treatment of tuberculosis among drug users in a methadone program.
Incomplete antituberculous chemoprophylaxis and treatment are major causes of the resurgence of tuberculosis, often drug-resistant, among drug users. We offered directly observed antituberculous chemoprophylaxis (n = 102) or treatment (n = 12) to tuberculous chemoprophylaxis (n = 102) or treatment (n = 12) to eligible methadone maintenance treatment patients. Methadone dosing was not contingent upon ingestion of antituberculous medication(s). No material incentives were provided. Ninety (88%) prophylaxis and 9 (75%) treatment patients were administered > or = 5 weekly doses of antituberculous medications during > or = 80% of 4740 patient-weeks. The majority of patients were HIV-seropositive. Active substance abuse was not associated with diminished adherence. Over 80% of patients completed or were still receiving therapy at the end of the study. Adherence to and completion of directly observed antituberculous therapy can thus be attained by drug users in treatment, despite ongoing drug misuse. Substance abuse treatment programs provide opportunities for enhanced compliance, and should thus be viewed as critical components of strategies to address the tuberculosis epidemic in drug users.


The Relationship Between Employee's Status Perception and Organizational Citizenship Behaviors: A Psychological Path of Work Vitality.
Studies have shown that status-based rankings exist within almost every human social group and influence most aspects of organizational life. However, few studies have discussed the relationship between employees' status and organizational citizenship behaviors (OCBs). Based on social cognitive theory, this paper explores the relationship between employees' status perception and two types of OCBs: challenging and affiliative, as well as the mechanism underlying this relationship by introducing work vitality as the mediator and dominance motivation as the moderator. We collected the empirical data from different enterprises located in major cities in China following a two-stage sampling procedure. The final sample consists of 330 employees. Hierarchical multiple regression analysis was used to test the hypothesis. Employee status perception is positively related to work vitality (b = 0.103, p = 0.027), challenging OCBs (b = 0.160, p < 0.001) and affiliative OCBs (b = 0.105, p = 0.006). Work vitality mediates the relationship between employee status perception and challenging OCBs with 95% bias-corrected confidence intervals [0.004, 0.063], and it also mediates the relationship between employee status perception and affiliative OCBs with 95% bias-corrected confidence intervals [0.004, 0.049]. The interaction of status perception and dominance motivation is significantly related to work vitality (b = 0.121, p = 0.041). Specifically, when dominance motivation is at low level, the effect of status perception on work vitality is -0.008 (non-significant); when dominance motivation is high level, the effect is 0.175 (p = 0.005). The result suggests that employees' perceptions of status are positively and significantly related to their challenging and affiliative OCBs, and employee's work vitality mediates this relationship. It further indicates that dominance motivation moderates the relation between status perception and work vitality. Specifically, the positive relationship between employee status perception and work vitality is stronger when an employee has high dominance motivation than low dominance motivation.


Social connections and risk of incident mild cognitive impairment, dementia, and mortality in 13 longitudinal cohort studies of ageing.
Previous meta-analyses have linked social connections and mild cognitive impairment, dementia, and mortality. However, these used aggregate data from North America and Europe and examined a limited number of social connection markers. We used individual participant data (N = 39271, Mage = 70.67 (40-102), 58.86% female, Meducation = 8.43 years, Mfollow-up = 3.22 years) from 13 longitudinal ageing studies. A two-stage meta-analysis of Cox regression models examined the association between social connection markers with our primary outcomes. We found associations between good social connections structure and quality and lower risk of incident mild cognitive impairment (MCI); between social structure and function and lower risk of incident dementia and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality. Different aspects of social connections - structure, function, and quality - are associated with benefits for healthy aging internationally. Social connection structure (being married/in a relationship, weekly community group engagement, weekly family/friend interactions) and quality (never lonely) were associated with lower risk of incident MCI. Social connection structure (monthly/weekly friend/family interactions) and function (having a confidante) were associated with lower risk of incident dementia. Social connection structure (living with others, yearly/monthly/weekly community group engagement) and function (having a confidante) were associated with lower risk of mortality. Evidence from 13 longitudinal cohort studies of ageing indicates that social connections are important targets for reducing risk of incident MCI, incident dementia, and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality.


DNA mapping in growth and developmental disorders.
DNA mapping techniques are being increasingly applied to familial and acquired disorders affecting growth and development. To understand the potential applications of these techniques, one must first have a good understanding of the components and basic structure of DNA, the genetic code, the basic structure of genes and the roles that various components of gene structure play in regulating gene expression. Following review of this basic information, a variety of DNA mapping techniques including in situ hybridization, Southern blotting, polymerase chain reaction amplification, DNA sequencing and linkage analysis will be covered. Applications of these techniques can enable mapping of unknown genes by detection of loss of allelic heterozygosity or use of linkage analysis and genetic maps. With increasing ease, mutations such as deletions, expansions, rearrangements and point mutations can be detected in diseases such as congenital adrenal hyperplasia, cystic fibrosis, diabetes insipidus, growth hormone deficiency, fragile X syndrome, Laron dwarfism and Turner syndrome. From this discussion, a better understanding of methods of gene localization, uses of genetic maps and rapid, convenient methods to detect a variety of molecular derangements causing familial disorders affecting growth and development will be gained.


Raman study of chromophore states in photochromic fluorescent proteins.
The photophysical mechanism underlying the photochromic behavior of green fluorescent protein (GFP) mutants is investigated by means of preresonant Raman spectroscopy and model calculations. The studied molecules are reversibly switchable fluorophores that can be repeatedly converted between fluorescent and nonfluorescent states by irradiation and are attracting a broad interest for a number of new applications. Experimental results on chemically synthesized isolated chromophores are analyzed within a density functional theory approach that allows us to link the detected vibrational modes to specific ground-state configurations before and after photoconversion. These data are compared to results obtained for the case of complete folded proteins including the same chromophores. Our results highlight the impact of chromophore cis-trans isomerization and protonation state in the photophysics of these proteins and provide useful guidelines for novel mutant design.


Profiling the Typical Training Load of a Law Enforcement Recruit Class.
Law enforcement academies, designed to prepare recruits for their prospective career, represent periods of high physical and mental stress, potentially contributing to recruits' injuries. Managing stress via monitoring training loads may mitigate injuries while ensuring adequate preparation. However, it is vital to first understand an academy's typical training load. The aim of this study was to profile the typical training load of law enforcement recruits over the course of 22 weeks. Data were prospectively collected using global positioning system (GPS) units placed on recruits during a portion of the academy training, while a desktop analysis was retrospectively applied to six other classes. A Bland-Altman plot was conducted to assess the agreement between the two methods. A linear mixed model was conducted to analyse the difference in distances covered per week, while other variables were presented graphically. Adequate agreement between the desktop analysis and GPS units was observed. Significant differences (p-value < 0.01) in distance covered (9.64 to 11.65 km) exist between weeks during early academy stages, which coincide with increases (~6 h) in physical training. Significant decreases in distances were experienced during the last five weeks of academy training. Most acute:chronic workload ratios stayed between the proposed 0.8 to 1.3 optimal range. Results from this study indicate that large increases in training occur early in the academy, potentially influencing injuries. Utilizing a desktop analysis is a pragmatic and reliable approach for instructors to measure load.


Experimental and theoretical investigation of the molecular and electronic structure of 3-ethoxy-4-isopropylaminocyclobut-3-ene-1,2-dione.
The title compound, 3-ethoxy-4-isopropylaminocyclobut-3-ene-1,2-dione (EIAC) has been synthesized and characterized by NMR, FT-IR, UV-vis spectroscopy and single-crystal X-ray diffraction. The (1)H NMR spectra were recorded at 300 K and 315 K in CDCl(3) to determine syn/anti conformers of the compound EIAC. Density functional theory (DFT) calculations, optimized geometrical parameters, vibrational frequencies and chemical shift values of syn/anti conformer in CDCl(3) have been performed at B3LYP/6-311G(d) level, and compared with the experimental data. The values provided with the calculations support the experimental data of the compound EIAC. The presence of NH⋯O type intermolecular H bond can be perceived from the difference between experimental calculations and results of FT-IR and NMR calculations. In addition, B3LYP/6-311G(d) basis set has been used to calculate the molecular electrostatic potential, frontier molecular orbitals and electronic absorption spectra. HOMO-LUMO electronic transition of 5.12 eV is derived from the contribution of the bands n→σ(*) or π→π(*). FT-IR, NMR and X-ray spectral results and additionally DFT calculations exhibit that the compound EIAC exists in keto-enamine tautomeric form. The experimental (1)H NMR spectra recorded at 300 K and 315 K and theoretical (1)H NMR data indicate that the compound EIAC is in syn conformer.


Anonymity in EU Health Law: Not an Alternative to Information Governance.
Data sharing has long been a cornerstone of healthcare and research and is only due to become more important with the rise of Big Data analytics and advanced therapies. Cell therapies, for example, rely not only on donated cells but also essentially on donated information to make them traceable. Despite the associated importance of concepts such as 'donor anonymity', the concept of anonymisation remains contentious. The Article 29 Working Party's 2014 guidance on 'Anonymisation Techniques' has perhaps helped encourage a perception that anonymity is the result of data modification 'techniques', rather than a broader process involving management of information and context. In light of this enduring ambiguity, this article advocates a 'relative' understanding of anonymity and supports this interpretation with reference not only to the General Data Protection Regulation but also to European Union health-related legislation, which also alludes to the concept. Anonymity, I suggest, should be understood not as a 'technique' which removes the need for information governance but rather as a legal standard of reasonable risk-management, which can only be satisfied by effective data protection. As such, anonymity can be not so much an alternative to data protection as its mirror, requiring similar safeguards to maintain privacy and confidentiality.


Identifying Patients With Atrial Fibrillation in Administrative Data.
Identifying patients with atrial fibrillation (AF) using administrative data is important for epidemiologic and outcomes research. Although administrative data cover large populations, it is necessary to assess their validity in identifying AF patients. We used Ontario family physician electronic medical records from the Electronic Medical Record Administrative data Linked Database (EMRALD) as a reference standard to assess the accuracy of administrative data algorithms in identifying patients with AF. From a random sample of 7500 adult patients, patients with AF as recorded in family physician records were identified. The optimal algorithm consisted of any of: hospitalization or an emergency room code for AF or prescription for an AF-specific antiarrhythmic agent or billing code for cardioversion, or prescription for an anticoagulant that was accompanied by a physician billing code. for arrhythmia. The algorithm sensitivity was 80.7% (95% confidence interval [CI], 75.1-86.3), specificity 99.1% (95% CI, 98.9-99.3), positive predictive value 71.1% (95% CI, 65.1-77.1), and negative predictive value 99.5% (95% CI, 99.3-99.7). This algorithm, applied to the Ontario population, resulted in a calculated increase in AF prevalence from 1.68% to 2.36% over the years 2000-2014. Anticoagulation rates for AF patients increased from 53% in 2011 to 60% in 2014. Among AF patients receiving anticoagulants, novel oral anticoagulant utilization increased from < 5% in 2011 to > 50% in 2014. Identifying patients with AF can be done using administrative data, and the algorithm can be used to assess trends in disease burden over time and patterns of care in large populations.


How Proactive Interference during New Associative Learning Impacts General and Specific Memory in Young and Old.
Some prior research has found that older adults are more susceptible to proactive interference than young adults. The current study investigated whether age-related deficits in pFC-mediated cognitive control processes that act to detect and resolve interference underlie increased susceptibility to proactive interference in an associative memory task. Young and older adults were scanned while tasked with remembering which associate (face or scene) objects were paired with most recently during study, under conditions of high, low, or no proactive interference. After scanning, participants' memory was tested for varying levels of episodic detail about the pairings (i.e., target category vs. specific target category vs. specific target associate). Young and older adults were similarly susceptible to proactive interference. Memory for both the general target category and the specific target associate worsened as the level of proactive interference increased, with no robust age differences. For both young and older adults, the left ventrolateral pFC, which has been indicated in controlled retrieval of goal-relevant conceptual representations, was sensitive to increasing levels of interference during encoding but was insensitive to associative memory accuracy. Consistent with the Compensation-Related Utilization of Neural Circuits Hypothesis model of cognitive aging, the ventromedial pFC, which is involved in the monitoring of internally generated information, was recruited more by older than young adults to support the successful retrieval of target-object pairs at lower levels of proactive interference. Collectively, these results suggest that some older adults are able to engage in the cognitive control processes necessary to resolve proactive interference to the same extent as young adults.


Microangiopathy in diabetes mellitus: II. Features, complications and investigation.
This paper reviews the current literature on the morphological, physiological, pathological and rheological features of microangiopathy in diabetes mellitus. The current theories explaining the development of these features as well as complications resulting from them are discussed. In the first section the morphological changes including capillary basement membrane thickening as well as physiological changes such as increased permeability and reduced diffusion of oxygen across capillary endothelium are discussed. Rheological factors and functional changes in blood flow as well as capillary proliferation and degeneration are addressed. The second section of this paper deals with the complications suffered by diabetics such as retinopathy, nephropathy, neuropathy, cardiovascular disease and skin ulceration. The role of microangiopathy in the pathogenesis of these complications is reviewed. The last section discusses the investigative techniques available to the clinician and researcher in the study of micro-angiopathy. These include various methods of blood flow measurement such as plethysmography, LASER Doppler flowmetry, capillary microscopy and clearance of tracers from the skin microcirculation.


Accuracy of echocardiographic assessment of pulmonary hypertension severity and right ventricular dysfunction in patients with chronic thromboembolic pulmonary hypertension.
Chronic thromboembolic pulmonary hypertension (CTEPH) results from chronic thrombotic occlusion of the pulmonary arterial circulation and may be potentially cured by pulmonary thromboendarterectomy. Echocardiography is the most practical modality for the assessment of right ventricular function and right heart pressures before and after surgery. However, there is scant data on how these estimates compare with the "gold standards" of invasive right heart catheterization and CT and MR scanning. The records of 100 consecutive patients with CTEPH who subsequently underwent pulmonary thromboendarterectomy at our institution were studied. Right atrial (RA) and right ventricular (RV) systolic pressure estimated at preoperative echocardiography were compared with measurements at preoperative cardiac catheterization. In addition, preoperative echocardiographic estimates of RV systolic function by visual assessment and by calculation of RV index of myocardial performance were compared with preoperative measurements of RV ejection fraction (EF) by computed tomography (CT) or magnetic resonance (MR) scanning. Although estimates of RA and PA systolic pressures by echocardiography correlated significantly with those at cardiac catheterization (p<0.0001) in patients with CTEPH, Bland-Altman analysis demonstrated significant variation in these measurements compared with cardiac catheterization. Cohen's Kappa analysis demonstrated that agreement between echo and cath derived values was slight (κ=0.1). RVEF assessed by CT or MR scanning correlated with echocardiographic visual assessment of RV systolic function (P<0.0001), and with RIMP (P=0.001), but actual measurements of right ventricular ejection fraction at a given assessment of right ventricular function by RIMP or visual assessment varied widely Caution is warranted in over-reliance on echo derived measurements of right heart hemodynamics and function in the setting of pulmonary hypertension, and where the clinical scenario calls the data into question, a low threshold should be maintained for proceeding to more advanced and invasive modalities of evaluation.


Fetal and neonatal germ cell tumors.
Germ cell tumors (GCTs) arise from the 'germline' - the primordial germ cells which are destined to become either the egg or the sperm. GCTs can be challenging to understand because their intrinsic pluripotency results in a wide spectrum of histologies and biologic behaviors. However, the histology of GCTs in the fetus and neonate is more restricted and the clinical spectrum more narrow than when these tumors occur later in life. GCTs in the fetus and neonate are predominately mature and immature teratomas, usually curable with surgery alone. And, given the efficacy of cisplatin-based regimens in GCTs, cure is likely even for those patients whose tumors contain the more malignant histologies, which in the neonate is usually yolk sac tumor. Recent advances in understanding the underlying aberrations in germline development continue to shed light on the genesis of these tumors and possible new avenues for treatment.


Altered Plasma Fatty Acid Abundance Is Associated with Cachexia in Treatment-Naïve Pancreatic Cancer.
Cachexia occurs in up to 80% of pancreatic ductal adenocarcinoma (PDAC) patients and is characterized by unintentional weight loss and tissue wasting. To understand the metabolic changes that occur in PDAC-associated cachexia, we compared the abundance of plasma fatty acids (FAs), measured by gas chromatography, of subjects with treatment-naïve metastatic PDAC with or without cachexia, defined as a loss of > 2% weight and evidence of sarcopenia (n = 43). The abundance of saturated, monounsaturated, and polyunsaturated FAs was not different between subjects with cachexia and those without. Oleic acid was significantly higher in subjects with cachexia (p = 0.0007) and diabetes (p = 0.015). Lauric (r = 0.592, p = 0.0096) and eicosapentaenoic (r = 0.564, p = 0.015) acids were positively correlated with age in cachexia patients. Subjects with diabetes (p = 0.021) or both diabetes and cachexia (p = 0.092) had low palmitic:oleic acid ratios. Linoleic acid was lower in subjects with diabetes (p = 0.018) and correlated with hemoglobin (r = 0.519, p = 0.033) and albumin (r = 0.577, p = 0.015) in subjects with cachexia. Oleic or linoleic acid may be useful treatment targets or biomarkers of cachexia in patients with metastatic PDAC, particularly those with diabetes.


Significant increase of colonic mutated crypts in ulcerative colitis correlatively with duration of illness.
Mild periodic acid-Schiff (mPAS) staining can discriminate non-O-acetylated(mPAS positive) from O-acetylated (mPAS negative) epithelial sialoglycoproteins in human colonic mucosa, giving three haplotypes of expression of a single polymorphic autosomal gene (oat). Increase in mPAS-positive crypts in heterozygotes is an indication of mutations, and wholly mPAS-positive (stem cell mutated) crypts and clusters of two or more mPAS-positive crypts in heterozygotes of ulcerative colitis (P < 0.0001) were found to be increased significantly, compared with controls. The observed correlation with ulcerative colitis duration (r = 0.892 and 0.853, respectively) supports a chronic inflammation-carcinoma sequence.


A review of one thousand cases of intracapsular cataract extraction: II. Visual results and astigmatic analysis.
A review of 1,000 cases of intracapsular cataract extraction revealed that in eyes in which no factor predisposed to complication, the early visual results were equal to or better than 20/40 in 97% of the cases. Complications of surgery in this group accounted for decreased visual acuity in only 1.7% of the eyes. In the group of patients with high myopia, previous surgery, known corneal disease, or some other factor thought to predispose to a complication, the visual acuity was equal to or better than 20/40 in only 74% of the cases, most of the decrease being due to preexisting factors within the eye rather than complications themselves. In the first group, the total amount of astigmatism produced by all the suturing techniques reviewed was similar. With interrupted suturing techniques, the axis of the correcting cylinder was more often against the rule while continuous closures with monofilament nylon more frequently produced with the rule astigmatism.


On the phylogenetic position of a rare Iberian endemic mammal, the Pyrenean desman (Galemys pyrenaicus).
The nucleotide sequences of the complete mitochondrial genome and nine partial nuclear genes of the Pyrenean desman (Galemys pyrenaicus) were determined in order to establish the relative phylogenetic position of this species at different taxonomic levels within the placental tree. Phylogenetic relationships of desman within the family Talpidae were inferred based on complete mitochondrial cytochrome b gene nucleotide sequence data. The Pyrenean desman was unambiguously recovered as sister group of the Russian desman (Desmana moschata) confirming the monophyly of the subfamily Desmaninae. However, phylogenetic relationships among major lineages within the Talpidae could not be confidently resolved. Phylogenetic analyses based on mitochondrial (at the amino acid level) and nuclear (at the nucleotide level) sequence data sets confidently placed desman within the Eulipotyphla (that also included moles, shrews, and hedgehogs), and partially recovered placental interordinal relationships. The monophyly of Laurasiatheria (including Eulipotyphla, Chiroptera, Carnivora, Pholidota, Perissodactyla, and Cetartiodactyla) was strongly supported. Mitochondrial amino acid sequences of Pholidota (pangolins) were found to bias phylogenetic inferences due to long-branch attraction effects. A Bayesian inference based on a combined mitochondrial and nuclear data set without Pholidota arrived at an almost fully resolved tree that supported the basal position of Eulipotyphla within Laurasiatheria.


Progestogens and pregnancy loss.
Progestational agents are often prescribed to prevent pregnancy loss. Progestogens affect implantation, cytokine balance, natural killer cell activity, arachidonic acid release and myometrial contractility. Progestogens have therefore been used at all stages of pregnancy including luteal-phase support prior to pregnancy, threatened miscarriage, recurrent miscarriage, and to prevent preterm labor. In luteal support, a Cochrane review reported that progestogens were associated with a higher rate of live births or ongoing pregnancy in the progesterone group (odds ratio 1.77, 95% confidence interval (CI) 1.09-2.86). Evidence suggests that progestogens are also effective for treating threatened miscarriage. Again, in a Cochrane Database review, progestogens were associated with a reduced odds ratio of 0.53 (95% CI 0.35-0.79) when progestogens were used. In recurrent miscarriage, progestogens also seem to have a beneficial effect. A meta-analysis of progestational agents showed a 28% increase in the live birth rate (relative risk 0.72, 95% CI 0.53-0.97). For the last 30 years, progestogens have been used to prevent preterm labor. Recent meta-analyses also report beneficial effects. This review summarizes the literature and the author's experience using progestogens to prevent pregnancy loss.


17-AAG induces cytoplasmic alpha-synuclein aggregate clearance by induction of autophagy.
The accumulation and aggregation of alpha-synuclein in nerve cells and glia are characteristic features of a number of neurodegenerative diseases termed synucleinopathies. alpha-Synuclein is a highly soluble protein which in a nucleation dependent process is capable of self-aggregation. The causes underlying aggregate formation are not yet understood, impairment of the proteolytic degradation systems might be involved. In the present study the possible aggregate clearing effects of the geldanamycin analogue 17-AAG (17-(Allylamino)-17-demethoxygeldanamycin) was investigated. Towards this, an oligodendroglial cell line (OLN-93 cells), stably expressing human alpha-synuclein (A53T mutation) was used. In these cells small punctate aggregates, not staining with thioflavine S, representing prefibrillary aggregates, occur characteristically. Our data demonstrate that 17-AAG attenuated the formation of alpha-synuclein aggregates by stimulating macroautophagy. By blocking the lysosomal compartment with NH(4)Cl the aggregate clearing effects of 17-AAG were abolished and alpha-synuclein deposits were enlarged. Analysis of LC3-II immunoreactivity, which is an indicator of autophagosome formation, further revealed that 17-AAG led to the recruitment of LC3-II and to the formation of LC3 positive puncta. This effect was also observed in cultured oligodendrocytes derived from the brains of newborn rats. Inhibition of macroautophagy by 3-methyladenine prevented 17-AAG induced occurrence of LC3 positive puncta as well as the removal of alpha-synuclein aggregates in OLN-A53T cells. Our data demonstrate for the first time that 17-AAG not only causes the upregulation of heat shock proteins, but also is an effective inducer of the autophagic pathway by which alpha-synuclein can be removed. Hence geldanamycin derivatives may provide a means to modulate autophagy in neural cells, thereby ameliorating pathogenic aggregate formation and protecting the cells during disease and aging.


[A new approach to the search for antineoplastic compounds].
The necessity of using microbial test systems with regular reproduction of associated impairments in cell differentiation and division in screening of antitumor compounds is substantiated. Conditions for induction of such impairments during secondary growth in prokaryotic and eukaryotic mycelial microorganisms were developed. The fungal culture, Fusarium bulbigenum var. blasticola, the growth of whose secondary colonies was selectively inhibited by representatives of various classes of antitumor agents such as alkylating agents, antimetabolites, antibiotics, plant preparations, etc. was isolated.


Intracellular trafficking of Bordetella pertussis in human macrophages.
Although Bordetella pertussis has been observed to survive inside macrophages, its ability to resist or evade degradation in phagolysosomes has not been defined. We here investigated the trafficking of B. pertussis upon entry into human macrophages. During the first hours following phagocytosis, a high percentage of bacteria were destroyed within acidic compartments positive for the lysosome-associated membrane proteins (LAMP). However, roughly one-fourth of the bacteria taken up evade this initial killing event, remaining in nonacidic compartments. Forty-eight hours after infection, the number of intracellular bacteria per cell increased, suggesting that B. pertussis is capable of replicating in this type of compartment. Viable bacteria accumulated within phagosomal compartments positive for the early endosomal marker Rab5 but not the late endosomal marker LAMP. Moreover, B. pertussis-containing phagosomes acquired exogenously added transferrin, indicating that intracellular bacteria have access to extracellular components and essential nutrients via the host cell recycling pathway. Overall, these results suggest that B. pertussis survives and eventually replicates in compartments with characteristics of early endosomes, potentially contributing to its extraordinary ability to persist within hosts and populations.