Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.
The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.


Breeding transients in capture-recapture modeling and their consequences for local population dynamics.
Standard procedures for capture-mark-recapture modelling (CMR) for the study of animal demography include running goodness-of-fit tests on a general starting model. A frequent reason for poor model fit is heterogeneity in local survival among individuals captured for the first time and those already captured or seen on previous occasions. This deviation is technically termed a transience effect. In specific cases, simple, uni-state CMR modeling showing transients may allow researchers to assess the role of these transients on population dynamics. Transient individuals nearly always have a lower local survival probability, which may appear for a number of reasons. In most cases, transients arise due to permanent dispersal, higher mortality, or a combination of both. In the case of higher mortality, transients may be symptomatic of a cost of first reproduction. A few studies working at large spatial scales actually show that transients more often correspond to survival costs of first reproduction rather than to permanent dispersal, bolstering the interpretation of transience as a measure of costs of reproduction, since initial detections are often associated with first breeding attempts. Regardless of their cause, the loss of transients from a local population should lower population growth rate. We review almost 1000 papers using CMR modeling and find that almost 40% of studies fitting the searching criteria (N = 115) detected transients. Nevertheless, few researchers have considered the ecological or evolutionary meaning of the transient phenomenon. Only three studies from the reviewed papers considered transients to be a cost of first reproduction. We also analyze a long-term individual monitoring dataset (1988-2012) on a long-lived bird to quantify transients, and we use a life table response experiment (LTRE) to measure the consequences of transients at a population level. As expected, population growth rate decreased when the environment became harsher while the proportion of transients increased. LTRE analysis showed that population growth can be substantially affected by changes in traits that are variable under environmental stochasticity and deterministic perturbations, such as recruitment, fecundity of experienced individuals, and transient probabilities. This occurred even though sensitivities and elasticities of these parameters were much lower than those for adult survival. The proportion of transients also increased with the strength of density-dependence. These results have implications for ecological and evolutionary studies and may stimulate other researchers to explore the ecological processes behind the occurrence of transients in capture-recapture studies. In population models, the inclusion of a specific state for transients may help to make more reliable predictions for endangered and harvested species.


Rates of cardiovascular disease following smoking cessation in patients with HIV infection: results from the D:A:D study(*).
The aim of the study was to estimate the rates of cardiovascular disease (CVD) events after stopping smoking in patients with HIV infection. Patients who reported smoking status and no previous CVD prior to enrolment in the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study were included in this study. Smoking status is collected at each visit as current smoker (yes/no) and ever smoker (yes/no). Time since stopping smoking was calculated for persons who had reported current smoking during follow-up and no current smoking subsequently. Endpoints were: myocardial infarction (MI); coronary heart disease (CHD: MI plus invasive coronary artery procedure or death from other CHD); CVD (CHD plus carotid artery endarterectomy or stroke); and all-cause mortality. Event rates were calculated for never, previous and current smokers, and smokers who stopped during follow-up. Incidence rate ratios (IRRs) were determined using Poisson regression adjusted for age, sex, cohort, calendar year, family history of CVD, diabetes, lipids, blood pressure and antiretroviral treatment. A total of 27 136 patients had smoking status reported, with totals of 432, 600, 746 and 1902 MI, CHD, CVD and mortality events, respectively. The adjusted IRR of CVD in patients who stopped smoking during follow-up decreased from 2.32 within the first year of stopping to 1.49 after >3 years compared with those who never smoked. Similar trends were observed for the MI and CHD endpoints. Reductions in risk were less pronounced for all-cause mortality. The risk of CVD events in HIV-positive patients decreased with increasing time since stopping smoking. Smoking cessation efforts should be a priority in the management of HIV-positive patients.


Effects of hypothyroidism on vascular 125I-albumin permeation and blood flow in rats.
Effects of hypothyroidism on vascular 125I-albumin permeation and on blood flow were assessed in multiple tissues of male Sprague-Dawley rats rendered hypothyroid by dietary supplementation with 0.5% (wt/wt) 2-thiouracil or by thyroidectomy. In both thiouracil-treated and thyroidectomized rats, body weights, kidney weight, arterial blood pressure, and pulse rate were decreased significantly v age-matched controls. After 10 to 12 weeks of thiouracil treatment, 125I-albumin permeation was increased significantly in the kidney, aorta, eye (anterior uvea, choroid, retina), skin, and new granulation tissue, remained unchanged in brain, sciatic nerve, and heart, and was decreased in forelimb skeletal muscle. A similar pattern was observed in thyroidectomized rats, except that increases in 125I-albumin permeation for all tissues were smaller than those observed in thiouracil-treated rats, and 125I-albumin permeation in retina did not differ from controls. In both thiouracil-treated and thyroidectomized rats, changes in blood flow (assessed with 15-microns, 85Sr-labeled microspheres) relative to the decrease in arterial blood pressure were indicative of a decrease in regional vascular resistance except in the choroid and in the kidney, in which vascular resistance was increased significantly. Glomerular filtration rate was decreased, but filtration fraction and urinary excretion of albumin remained unchanged by thiouracil treatment and thyroidectomy. These results indicate that vascular hemodynamics and endothelial cell barrier functional integrity are modulated in many different tissues by the thyroid. In view of the correspondence of hypothyroid- and diabetes-induced vascular permeability changes, these results raise the possibility that altered thyroid function in diabetes may play a role in the pathogenesis of diabetic vascular disease.


Association of objectively measured physical activity with body components in European adolescents.
Physical activity (PA) is suggested to contribute to fat loss not only through increasing energy expenditure "per se" but also increasing muscle mass; therefore, it would be interesting to better understand the specific associations of PA with the different body's components such as fat mass and muscle mass. The aim of the present study was to examine the association between objectively measured PA and indices of fat mass and muscle components independently of each other giving, at the same time, gender-specific information in a wide cohort of European adolescents. A cross-sectional study in a school setting was conducted in 2200 (1016 males) adolescents (14.7 ± 1.2 years). Weight, height, skinfold thickness, bioimpedance and PA (accelerometry) were measured. Indices of fat mass (body mass index, % fat mass, sum of skinfolds) and muscular component (assessed as fat-free mass) were calculated. Multiple regression analyses were performed adjusting for several confounders including fat-free mass and fat mass when possible. Vigorous PA was positively associated with height (p<0.05) in males, whilst, vigorous PA, moderate-vigorous PA and average PA were negatively associated with all the indices of fat mass (all p<0.01) in both genders, except for average PA in relation with body mass index in females. Regarding muscular components, vigorous PA showed positive associations with fat-free mass and muscle mass (all p<0.05) in both genders. Average PA was positively associated with fat-free mass (both p<0.05) in males and females. The present study suggests that PA, especially vigorous PA, is negatively associated with indices of fat mass and positively associated with markers of muscle mass, after adjusting for several confounders (including indices of fat mass and muscle mass when possible). Future studies should focus not only on the classical relationship between PA and fat mass, but also on PA and muscular components, analyzing the independent role of both with the different PA intensities.


The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation.
The three types of peroxisome proliferator activated receptor (PPAR), alpha, beta (or delta), and gamma, each with a specific tissue distribution, compose a subfamily of the nuclear hormone receptor gene family. Although peroxisome proliferators, including fibrates and fatty acids, activate the transcriptional activity of these receptors, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR gamma subtype, which also binds thiazolidinedione antidiabetic agents with high affinity. Activated PPARs heterodimerize with RXR and alter the transcription of target genes after binding to specific response elements or PPREs, consisting of a direct repeat of the nuclear receptor hexameric DNA core recognition motif spaced by one nucleotide. The different PPARs can be considered key messengers responsible for the translation of nutritional, pharmacological and metabolic stimuli into changes in the expression of genes, more specifically those genes involved in lipid metabolism. PPAR alpha is involved in stimulating beta-oxidation of fatty acids. In rodents, a PPAR alpha-mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis. In addition to their role in peroxisome proliferation in rodents, PPAR is also involved in the control of HDL cholesterol levels by fibrates and fatty acids in rodents and humans. This effect is, at least partially, based on a PPAR-mediated transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic action of fibrates and fatty acids also involves PPARs and can be summarized as follows: (1) an increased lipolysis and clearance of remnant particles, due to changes in LPL and apo C-III levels, (2) a stimulation of cellular fatty acid uptake and their conversion to acyl-CoA derivatives by the induction of FAT, FATP and ACS activity, (3) an induction of fatty acid beta-oxidation pathways, (4) a reduction in fatty acid and triglyceride synthesis, and finally (5) a decrease in VLDL production. Hence, both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles are mechanisms that contribute to the hypolipidemic effect of fibrates and FFAs. Whereas for PPAR beta no function so far has been identified, PPAR gamma triggers adipocyte differentiation by inducing the expression of several genes critical for adipogenesis.


Modelling factors for Aboriginal and Torres Strait Islander child neurodevelopment outcomes: A latent class analysis.
The Australian Early Development Census (AEDC) provides a measure of early child development upon school entry. Understanding which combination of factors influences Aboriginal child neurodevelopment is important to inform policy and practice. The primary objective was to use latent class analysis (LCA) to model AEDC profiles and identify the highest need profiles. The secondary objective was to determine the associations of these high need profiles on the likelihood of a child becoming developmentally vulnerable. We designed a prospective population-based birth cohort study (n = 2715) using linked data sets with information on Aboriginal cohort children, and their mothers and siblings in Western Australia. Specific developmental indicators in the 2009 and 2012 AEDC were used to assess developmental vulnerability. LCA methods were used to determine need profiles and their association with developmental vulnerability. 49.3% of Aboriginal children were vulnerable on at least one developmental domain, and 37.5% were vulnerable on two or more domains. LCA found six unique profiles. High needs family, High needs young mother, and Preterm infant comprised 42% of the cohort and were considered to have high need configurations. These groups were at least 1.7 times as likely to have children who had at least one or two developmental vulnerabilities compared with the Healthy family group. Many Aboriginal children in Western Australia enter school with at least one developmental vulnerability. This study highlights a range of unique profiles that can be used to empower Aboriginal families for change and develop targeted programmes for improving the early development of young Aboriginal children.


Frequency of Penile-Vaginal Intercourse is Associated with Verbal Recognition Performance in Adult Women.
Previous studies have identified a number of factors that contribute to improved cognitive function, and to memory function specifically, in cognitively normal individuals. One such factor, frequency of penile-vaginal intercourse (PVI), has been reported in a number of animal studies to be advantageous to memory for previously presented objects by increasing neurogenesis in the dentate gyrus of the hippocampus. However, studies investigating the potential benefits of frequent PVI on memory function in young women are to the best of our knowledge absent from the literature. The current study thus investigated whether the self-reported frequency of sexual intercourse was related to memory function in healthy female college students. To determine whether variation in PVI would be associated with memory performance, we asked 78 heterosexual women aged 18-29 years to complete a computerized memory paradigm consisting of abstract words and neutral faces. Results showed that frequency of PVI was positively associated with memory scores for abstract words, but not faces. Because memory for words depends to a large extent on the hippocampus, whereas memory for faces may rely to a greater extent on surrounding extra-hippocampal structures, our results appear to be specific for memory believed to rely on hippocampal function. This may suggest that neurogenesis in the hippocampus is higher in those women with a higher frequency of PVI, in line with previous animal research. Taken together, these results suggest that PVI may indeed have beneficial effects on memory function in healthy young women.


Induction of cytopathogenicity in human glioblastoma cells by chikungunya virus.
Chikungunya virus (CHIKV), an arthritogenic old-world alphavirus, has been implicated in the central nervous system (CNS) infection in infants and elderly patients. Astrocytes are the major immune cells of the brain parenchyma that mediate inflammation. In the present study we found that a local isolate of CHIKV infect and activate U-87 MG cells, a glioblastoma cell line of human astrocyte origin. The infection kinetics were similar in infected U-87 MG cells and the human embryo kidney (HEK293) cells as indicated by immunofluorescence and plaque assays, 24h post-infection (p.i.). In infected U-87 MG cells, apoptosis was detectable from 48h p.i. evidenced by DNA fragmentation, PARP cleavage, loss of mitochondrial membrane potential, nuclear condensation and visible cytopathic effects in a dose and time-dependent manner. XBP1 mRNA splicing and eIF2α phosphorylation studies indicated the occurrence of endoplasmic reticulum stress in infected cells. In U-87 MG cells stably expressing a green fluorescent protein-tagged light chain-3 (GFP-LC3) protein, CHIKV infection showed increased autophagy response. The infection led to an enhanced expression of the mRNA transcripts of the pro-inflammatory cytokines IL-1β, TNF-α, IL-6 and CXCL9 within 24h p.i. Significant up-regulation of the proteins of RIG-I like receptor (RLR) pathway, such as RIG-I and TRAF-6, was observed indicating the activation of the cytoplasmic-cellular innate immune response. The overall results show that the U-87 MG cell line is a potential in vitro model for in depth study of these molecular pathways in response to CHIKV infection. The responses in these cells of CNS origin, which are inherently defective in Type I interferon response, could be analogous to that occurring in infants and very old patients who also have a compromised interferon-response. The results also point to the intriguing possibility of using this virus for studies to develop oncolytic virus therapy approaches against glioblastoma, a highly aggressive malignancy.


The effect of a novel curcumin derivative on pancreatic islet regeneration in experimental type-1 diabetes in rats (long term study).
Several studies highlight curcumin's benefit as a hypoglycemic agent, however; a limited number of reports present the importance of curcumin in improvement of pancreatic islets in diabetes. The aim of the present study is to evaluate the antidiabetic effect of a novel curcumin derivative and its effect on pancreatic islet regeneration in type I diabetes-induced by STZ. Rats were divided into diabetic rats and diabetic rats treated orally with the novel curcumin derivative (NCD) for 40 days. Fasting blood samples were withdrawn periodically from all rats to estimate plasma glucose, insulin and C-peptide for 10 months. Histopathology was performed to allow the assessment of pancreatic islet morphology. Insulin and CD105 were detected immunohistochemically. In diabetic rats, the plasma glucose, insulin and C-peptide levels remained within the diabetic range for about 4 months, after which a gradual decrease in glucose and increase in insulin and C-peptide was observed, which reached almost normal levels after 10 months. NCD treated diabetic rats showed significantly lowered plasma glucose and increased plasma insulin and C-peptide levels. This was followed by a further significant decrease in plasma glucose and increase in plasma insulin and C-peptide after two months from oral administration of the NCD. The plasma insulin and C-peptide continued to increase for ten months reaching levels significantly higher than the basal level. Histopathological examination of diabetic rat pancreas revealed absence of islets of Langerhans, minimal adipose tissue infiltration and localized lymphocytic infiltrates. However, after 6 months of induction of diabetes, rat pancreas showed the appearance of small well formed islets and positive insulin cells but no CD105 positive cells. NCD treated rats showed the appearance of primitive cell collections, large insulin positive cells and CD105 positive cells in the adipose tissue infiltrating the pancreatic tissues. This was followed by the gradual appearance of insulin positive cells in the islets while, CD 105 positive cells remained in the adipose tissue. After 5 and 10 months from the onset of diabetes, rat pancreas showed, well developed larger sized islets with disappearance of primitive cell collections and CD 105 positive cells. Also, insulin positive islets of variable size with disappearance of insulin positive cells in adipose tissue were detected. The NCD possesses antidiabetic actions and enhanced pancreatic islets regeneration.


The role of Transposable Elements in shaping the combinatorial interaction of Transcription Factors.
In the last few years several studies have shown that Transposable Elements (TEs) in the human genome are significantly associated with Transcription Factor Binding Sites (TFBSs) and that in several cases their expansion within the genome led to a substantial rewiring of the regulatory network. Another important feature of the regulatory network which has been thoroughly studied is the combinatorial organization of transcriptional regulation. In this paper we combine these two observations and suggest that TEs, besides rewiring the network, also played a central role in the evolution of particular patterns of combinatorial gene regulation. To address this issue we searched for TEs overlapping Estrogen Receptor α (ERα) binding peaks in two publicly available ChIP-seq datasets from the MCF7 cell line corresponding to different modalities of exposure to estrogen. We found a remarkable enrichment of a few specific classes of Transposons. Among these a prominent role was played by MIR (Mammalian Interspersed Repeats) transposons. These TEs underwent a dramatic expansion at the beginning of the mammalian radiation and then stabilized. We conjecture that the special affinity of ERα for the MIR class of TEs could be at the origin of the important role assumed by ERα in Mammalians. We then searched for TFBSs within the TEs overlapping ChIP-seq peaks. We found a strong enrichment of a few precise combinations of TFBS. In several cases the corresponding Transcription Factors (TFs) were known cofactors of ERα, thus supporting the idea of a co-regulatory role of TFBS within the same TE. Moreover, most of these correlations turned out to be strictly associated to specific classes of TEs thus suggesting the presence of a well-defined "transposon code" within the regulatory network. In this work we tried to shed light into the role of Transposable Elements (TEs) in shaping the regulatory network of higher eukaryotes. To test this idea we focused on a particular transcription factor: the Estrogen Receptor α (ERα) and we found that ERα preferentially targets a well defined set of TEs and that these TEs host combinations of transcriptional regulators involving several of known co-regulators of ERα. Moreover, a significant number of these TEs turned out to be conserved between human and mouse and located in the vicinity (and thus candidate to be regulators) of important estrogen-related genes.


Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review.
Nausea and vomiting affects approximately 85% of pregnant women. The most severe form, hyperemesis gravidarum, affects up to 3% of women and can have significant adverse physical and psychological sequelae. To summarize current evidence on effective treatments for nausea and vomiting in pregnancy and hyperemesis gravidarum. Databases were searched to June 8, 2016. Relevant websites and bibliographies were also searched. Titles and abstracts were assessed independently by 2 reviewers. Results were narratively synthesized; planned meta-analysis was not possible because of heterogeneity and incomplete reporting of findings. Seventy-eight studies (n = 8930 participants) were included: 67 randomized clinical trials (RCTs) and 11 nonrandomized studies. Evidence from 35 RCTs at low risk of bias indicated that ginger, vitamin B6, antihistamines, metoclopramide (for mild symptoms), pyridoxine-doxylamine, and ondansetron (for moderate symptoms) were associated with improved symptoms compared with placebo. One RCT (n = 86) reported greater improvements in moderate symptoms following psychotherapy (change in Rhodes score [range, 0 {no symptoms} to 40 {worst possible symptoms}], 18.76 [SD, 5.48] to 7.06 [SD, 5.79] for intervention vs 19.18 [SD, 5.63] to 12.81 [SD, 6.88] for comparator [P < .001]). For moderate-severe symptoms, 1 RCT (n = 60) suggested that pyridoxine-doxylamine combination taken preemptively reduced risk of recurrence of moderate-severe symptoms compared with treatment once symptoms begin (15.4% vs 39.1% [P < .04]). One RCT (n = 83) found that ondansetron was associated with lower nausea scores on day 4 than metoclopramide (mean visual analog scale [VAS] score, 4.1 [SD, 2.9] for ondansetron vs 5.7 [SD, 2.3] for metoclopramide [P = .023]) but not episodes of emesis (5.0 [SD, 3.1] vs 3.3 [SD, 3], respectively [P = .013]). Although there was no difference in trend in nausea scores over the 14-day study period, trend in vomiting scores was better in the ondansetron group (P = .042). One RCT (n = 159) found no difference between metoclopramide and promethazine after 24 hours (episodes of vomiting, 1 [IQR, 0-5] for metoclopramide vs 2 [IQR, 0-3] for promethazine [P = .81], VAS [0-10 scale] for nausea, 2 [IQR, 1-5] vs 2 [IQR, 1-4], respectively [P = .99]). Three RCTs compared corticosteroids with placebo or promethazine or metoclopramide in women with severe symptoms. Improvements were seen in all corticosteroid groups, but only a significant difference between corticosteroids vs metoclopramide was reported (emesis reduction, 40.9% vs 16.5% at day 2; 71.6% vs 51.2% at day 3; 95.8% vs 76.6% at day 7 [n = 40, P < .001]). For other interventions, evidence was limited. For mild symptoms of nausea and emesis of pregnancy, ginger, pyridoxine, antihistamines, and metoclopramide were associated with greater benefit than placebo. For moderate symptoms, pyridoxine-doxylamine, promethazine, and metoclopramide were associated with greater benefit than placebo. Ondansetron was associated with improvement for a range of symptom severity. Corticosteroids may be associated with benefit in severe cases. Overall the quality of evidence was low.


The LMC Skills, Confidence & Preparedness Index (SCPI): development and evaluation of a novel tool for assessing self-management in patients with diabetes.
Optimal diabetes care requires a specific set of self-management behaviours. The purpose of this study was to present the development and initial psychometric evaluation of a new tool to measure three key aspects of a patient's diabetes self-management: knowledge of the skill, confidence in being able to perform the skill and preparedness to implement the skill. A sequential exploratory mixed-methods design was used. A panel of educators, researchers and clinicians established a scale with items that would adequately capture skills, confidence and preparedness in seven core health behaviours central to diabetes care. The psychometric properties of the items were pilot tested on 120 participants with diabetes from a tertiary referral centre, and repeated 6 months later on 70 participants. Item selection was informed by factor analysis, item-total statistics and the need for brevity. Twenty five items from a pool of 36 were retained, with an excellent overall intraclass correlation (ICC) of 0.94 (95% CI 0.92-0.99; p < 0.001). Internal consistency for the subscales (skills-9 items, confidence - 8 items, preparedness - 8 items) was very good (intraclass correlation between 0.83 and 0.88), and retest reliability after 6 months was also good (r = 0.48; p < 0.01). The scale was positively correlated to established scales that assess skill (Michigan Diabetes Knowledge Test) (r = 0.21;p = 0.01), and assess skill and confidence (Diabetes Empowerment Scale) (r = 0.28;p < 0.01). The Skills, Confidence & Preparedness Index is a brief and easy to administer new scale that is more comprehensive than existing tools. It should be used to assess self-management in patients with diabetes, optimize the resources applied to each patient, and determine educational needs and direct clinical management. The scale should be further evaluated in a broader population of patients with diabetes.


PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing.
Mammalian gene silencing is established through methylation of histones and DNA, although the order in which these modifications occur remains contentious. Using the human beta-globin locus as a model, we demonstrate that symmetric methylation of histone H4 arginine 3 (H4R3me2s) by the protein arginine methyltransferase PRMT5 is required for subsequent DNA methylation. H4R3me2s serves as a direct binding target for the DNA methyltransferase DNMT3A, which interacts through the ADD domain containing the PHD motif. Loss of the H4R3me2s mark through short hairpin RNA-mediated knockdown of PRMT5 leads to reduced DNMT3A binding, loss of DNA methylation and gene activation. In primary erythroid progenitors from adult bone marrow, H4R3me2s marks the inactive methylated globin genes coincident with localization of PRMT5. Our findings define DNMT3A as both a reader and a writer of repressive epigenetic marks, thereby directly linking histone and DNA methylation in gene silencing.


Cell and molecular biology of simian virus 40: implications for human infections and disease.
Simian virus 40 (SV40), a polyomavirus of rhesus macaque origin, was discovered in 1960 as a contaminant of polio vaccines that were distributed to millions of people from 1955 through early 1963. SV40 is a potent DNA tumor virus that induces tumors in rodents and transforms many types of cells in culture, including those of human origin. This virus has been a favored laboratory model for mechanistic studies of molecular processes in eukaryotic cells and of cellular transformation. The viral replication protein, named large T antigen (T-ag), is also the viral oncoprotein. There is a single serotype of SV40, but multiple strains of virus exist that are distinguishable by nucleotide differences in the regulatory region of the viral genome and in the part of the T-ag gene that encodes the protein's carboxyl terminus. Natural infections in monkeys by SV40 are usually benign but may become pathogenic in immunocompromised animals, and multiple tissues can be infected. SV40 can replicate in certain types of simian and human cells. SV40-neutralizing antibodies have been detected in individuals not exposed to contaminated polio vaccines. SV40 DNA has been identified in some normal human tissues, and there are accumulating reports of detection of SV40 DNA and/or T-ag in a variety of human tumors. This review presents aspects of replication and cell transformation by SV40 and considers their implications for human infections and disease pathogenesis by the virus. Critical assessment of virologic and epidemiologic data suggests a probable causative role for SV40 in certain human cancers, but additional studies are necessary to prove etiology.


Utility of MRI in assessment of pituitary iron overload.
Beta thalassemia is highly prevalent in Pakistan with a carrier rate of 5-8%. The main complication of beta thalassemia major is iron overload, especially in reticuloendothelial system, heart, joints and endocrine glands. Pituitary siderosis leads to hypogonadotropic hypogonadism and growth hormone deficiency. Measures of plasma ferritin levels and hepatic iron level are used for assessing body iron overload but these are limited for various reasons particularly in case of pituitary siderosis. Magnetic Resonance Imaging (MRI) is a reliable, non invasive and easily available utility for assessing tissue siderosis. We assessed a 20 year old female beta thalassemic diagnosed with hypogonadotropic hypogonadism and pituitary siderosis using routine spin echo (SE) T1 and T2 weighted sequences of MRI and special Gradient Recalled Echo (GRE) sequence of MRI. We found MRI signal intensity to be decreased on all three sequences but most so on GRE suggesting its greatest sensitivity to pituitary iron deposition. MRI signal hypo-intensity due to paramagnetic effects of iron has been validated for liver siderosis but is still under investigation for pituitary siderosis. Our findings suggest that MRI especially GRE sequence can be used in conjunction with laboratory data to evaluate pituitary siderosis and to prevent further pituitary dysfunction.


Reversed neurovegetative symptoms of depression: a community study of Ontario.
Most research on depression with reversed neurovegetative features (hypersomnia, hyperphagia, and weight gain) has been based on site-specific clinic-based samples. The goal of this study was to delineate the epidemiology of reversed symptoms in a large community sample and to use other symptom patterns for comparison. Interviewers assessed 8,116 subjects across Ontario, aged 15-64 years, by using the World Health Organization Composite International Diagnostic Interview. Individuals who met the DSM-III-R criteria for major depression, current or lifetime, were classified into four groups on the basis of lifetime neurovegetative symptoms: episodes of typical symptoms only, episodes of reversed symptoms only, neither type, or both types (fluctuating-symptom group). The groups were compared on demographic characteristics, comorbidity, disability, and health care utilization. Of the 653 individuals with lifetime major depression, 11.3% had episodes of reversed symptoms only, and another 5.8% were classified as fluctuating. Most of the differences among the four groups were due to the unique characteristics of the groups with neither type of episode or a fluctuating pattern; individuals who had experienced only reversed symptoms were remarkably similar to those who had had only typical symptoms. The fluctuating-symptom group had high rates of comorbidity, substance abuse, and health care utilization. Several popular beliefs about depression with reversed features did not hold true for this community sample. Identifying individuals who fluctuate between reversed and typical episodes may be important in studies of major depression, in particular when reversed neurovegetative symptoms are a consideration.


Tunable binary retarder using self-aligned liquid crystal on anisotropic polymer film by photo-assisted imprinting.
We demonstrate an electrically tunable binary retarder (ETBR) with a self-aligned liquid crystal (LC) on an anisotropic polymer film produced by photo-assisted imprinting. The ETBR has two parts: a tunable optical layer of an LC and a static optical layer of an imprinted anisotropic polymer film possessing two different in-plane optic axes. The anisotropic polymer film was produced using reactive mesogens spontaneously aligned along the topographic microgrooves by imprinting under the exposure of ultraviolet light. An electrically tunable hybrid wave plate, whose phase retardation varies from a quarter to a half-wave, is constructed using the self-aligned LC layer on the imprinted polymer film that behaves as a quarter wave plate with two alternating optic axes. This approach can be used to design a new class of tunable optical devices with multiple in-plane optic axes.


Detection of Panulirus argus Virus 1 in Caribbean spiny lobsters.
Panulirus argus Virus 1 (PaV1) is a pathogenic virus that infects Caribbean spiny lobsters P. argus in the Florida Keys. We have developed a PCR detection assay for PaV1 for the purpose of studying the natural history of the virus and for monitoring the prevalence of infection. The detection of the virus in hemolymph and other tissues is based on the PCR amplification of a 499 bp product using specific primers designed from a cloned fragment of the PaV1 genome. The sensitivity limit for the assay was 1.2 fg of purified viral DNA. The PaV1 primers did not react with lobster DNA, oyster DNA, Ostreid Herpesvirus 1, or murine cytomegalovirus. Using this assay, we successfully followed the course of infection in lobsters inoculated with PaV1 and we detected infections in wild-caught lobsters from the Florida Keys. We have also established guidelines for interpreting infection results from the PCR assay for PaV1.


Cardiovascular and renal actions of the endothelin(B) receptor in pigs.
Previously we showed that blocking the endothelin (ET)A receptor subtype with BQ-153 inhibited the vasoconstrictor effects of intravenously administered ET-1. In the presence of the ET(A) antagonist, ET-1 produced marked reductions in myocardial contractility and renal blood flow. We postulated that either the ET(B) receptor, or some other, as yet unidentified, ET-receptor subtype mediated the observed hemodynamic changes. In anesthetized pigs, this hypothesis was tested by using a recently developed selective, high-affinity antagonist to the ET(B) receptor, BQ-788, and sarafotoxin S6c, a selective ET(B) agonist, to determine the contribution of this receptor subtype to cardiovascular function. Endothelin-1 (0.4 nmol/kg, i.v.) produced the characteristic biphasic hemodynamic responses, consisting of an initial transient reduction in mean arterial pressure (MAP; 83 +/- 3 to 72 +/- 4 mm Hg; n = 9) followed by a prolonged increase (112 +/- 4 mm Hg; p < 0.01). As well, cardiac output (-58%; p < 0.05), myocardial contractility (-19%; p < 0.01), and renal blood flow (63%; p < 0.05) decreased. Sarafotoxin S6c produced marked but transient reductions in MAP (p < 0.001), cardiac output (p < 0.01), myocardial contractility (p < 0.001), and renal blood flow (p < 0.05). BQ-788 (1.0 mg/kg, i.v.), administered 3 min before sarafotoxin S6c, inhibited its effects. BQ-788 also inhibited the initial transient reduction in MAP seen after the injection of ET-1, but the subsequent sustained pressor responses were enhanced as reflected in the greater increases in left ventricular pressure (p < 0.02), myocardial contractility (p < 0.05), MAP (p < 0.01), and a larger reduction in cardiac output (p < 0.05). The heart rate was not changed after the initial ET injection, but it increased 54% when the peptide was administered in the presence of BQ-788. The reduction in renal blood flow was still evident, and its magnitude (64%) remained the same (p < 0.01) after treatment with BQ-788. Only the combined administration of both the ET(A) (BQ-123) and ET(B) (BQ-788) receptor antagonists blocked the effects of ET-1 on renal blood flow (p < 0.05). These data confirm that BQ-788 is a selective and effective antagonist of the ET(B) receptor and show that activation of this receptor subtype is involved in the transient vasodilation provoked by ET-1. Additionally, the ET(B) receptor appears to oppose the vasoconstrictor effects of the ET(A) receptor, which clearly mediates vasoconstriction. Combined treatment with BQ-123 and BQ-788 attenuated the reductions in renal blood flow produced by ET-1. Furthermore, some actions of ET-1 were not blocked by these antagonists and cannot be attributed to either the ET(A) or ET(B) receptors. We hypothesize the existence of an additional ET receptor or a subtype of the ET(B) receptor that is insensitive to BQ-788.


XeOF2, F2OXeN identical with CCH3, and XeOF2.nHF: rare examples of Xe(IV) oxide fluorides.
The syntheses of XeOF2, F2OXeNCCH3, and XeOF2.nHF and their structural characterizations are described in this study. All three compounds are explosive at temperatures approaching 0 degrees C. Although XeOF2 had been previously reported, it had not been isolated as a pure compound. Xenon oxide difluoride has now been characterized in CH3CN solution by 19F, 17O, and 129Xe NMR spectroscopy. The solid-state Raman spectra of XeOF2, F2OXeNCCH3, and XeOF2.nHF have been assigned with the aid of 16O/18O and 1H/2H enrichment studies and electronic structure calculations. In the solid state, the structure of XeOF2 is a weakly associated, planar monomer, ruling out previous speculation that it may possess a polymeric chain structure. The geometry of XeOF2 is consistent with a trigonal bipyramidal, AX2YE2, VSEPR arrangement that gives rise to a T-shaped geometry in which the two free valence electron lone pairs and Xe-O bond domain occupy the trigonal plane and the Xe-F bond domains are trans to one another and perpendicular to the trigonal plane. Quantum mechanical calculations and the Raman spectra of XeOF2.nHF indicate that the structure likely contains a single HF molecule that is H-bonded to oxygen and also weakly F-coordinated to xenon. The low-temperature (-173 degrees C) X-ray crystal structure of F2OXeNCCH3 reveals a long Xe-N bond trans to the Xe-O bond and a geometrical arrangement about xenon in which the atoms directly bonded to xenon are coplanar and CH3CN acts as a fourth ligand in the equatorial plane. The two fluorine atoms are displaced away from the oxygen atom toward the Xe-N bond. The structure contains two sets of crystallographically distinct F2OXeNCCH3 molecules in which the bent Xe-N-C moiety lies either in or out of the XeOF2 plane. The geometry about xenon is consistent with an AX2YZE2 VSEPR arrangement of bond pairs and electron lone pairs and represents a rare example of a Xe(IV)-N bond.


High dose zinc increases hospital admissions due to genitourinary complications.
Zinc is a common dietary supplement that is widely believed to have beneficial health effects. To assess the impact of high dose supplemental zinc on genitourinary diseases we analyzed a recent randomized trial comparing zinc, antioxidants and their combination to placebo for complications related to the genitourinary tract. In a further analysis of the recent Age-related Eye Disease Study we examined the data pool for primary International Classification of Diseases, 9th revision codes given for hospital admissions related to urological problems. The Age-Related Eye Disease Study randomized 3,640 patients with age related macular degeneration to 1 of 4 study arms, including placebo, antioxidants (500 mg vitamin C, 400 IU vitamin E and 15 mg beta-carotene), 80 mg zinc and antioxidant plus zinc. Statistical analyses using Fisher's exact test were performed. We found a significant increase in hospital admissions due to genitourinary causes in patients on zinc vs nonzinc formulations (11.1% vs 7.6%, p = 0.0003). The risk was greatest in male patients (RR 1.26, 95% CI 1.07-1.50, p = 0.008). In the study group of 343 patients requiring hospital admission the most common primary International Classification of Diseases, 9th revision codes included benign prostatic hyperplasia/urinary retention (benign prostatic hyperplasia), urinary tract infection, urinary lithiasis and renal failure. When comparing zinc to placebo, significant increases in urinary tract infections were found (p = 0.004), especially in females (2.3% vs 0.4%, RR 5.77, 95% CI 1.30-25.66, p = 0.013). Admissions for urinary lithiasis approached significance in men on zinc compared to placebo (2.0% vs 0.5%, RR = 4.08, 95% CI 0.87-19.10). There was no increase in prostate or other cancers with zinc supplementation. A significant decrease in prostate cancer diagnoses was seen in patients receiving antioxidants vs placebo (RR = 0.6, 95% CI 0.49-0.86, p = 0.049). Subgroup analysis revealed that this finding was significant in men who smoked but not in nonsmokers. Zinc supplementation at high levels results in increased hospitalizations for urinary complications compared to placebo. These data support the hypothesis that high dose zinc supplementation has a negative effect on select aspects of urinary physiology.


Cerebral microvascular endothelial cell Na/H exchange: evidence for the presence of NHE1 and NHE2 isoforms and regulation by arginine vasopressin.
Blood-brain barrier (BBB) Na transporters are essential for brain water and electrolyte homeostasis. However, they also contribute to edema formation during the early hours of ischemic stroke by increased transport of Na from blood into brain across an intact BBB. We previously showed that a luminal BBB Na-K-Cl cotransporter is stimulated by hypoxia, aglycemia, and AVP and that inhibition of the cotransporter by intravenous bumetanide significantly reduces edema and infarct in the rat middle cerebral artery occlusion (MCAO) model of stroke. More recently, we found evidence that intravenous cariporide (HOE-642), a highly potent Na/H exchange inhibitor, also reduces brain edema after MCAO. The present study was conducted to investigate which Na/H exchange protein isoforms are present in BBB endothelial cells and to evaluate the effects of ischemic factors on BBB Na/H exchange activity. Western blot analysis of bovine cerebral microvascular endothelial cells (CMEC) and immunoelectron microscopy of perfusion-fixed rat brain revealed that Na/H exchanger isoforms 1 and 2 (NHE1 and NHE2) are present in BBB endothelial cells. Using microspectrofluorometry and the pH-sensitive dye BCECF, we found that hypoxia (2% O(2), 30 min), aglycemia (30 min), and AVP (1-200 nM, 5 min) significantly increased CMEC Na/H exchange activity, assessed as Na-dependent, HOE-642-sensitive H(+) flux. We found that AVP stimulation of CMEC Na/H exchange activity is dependent on intracellular Ca concentration and is blocked by V(1), but not V(2), vasopressin receptor antagonists. Our findings support the hypothesis that a BBB Na/H exchanger, possibly NHE1 and/or NHE2, is stimulated during ischemia to participate in cerebral edema formation.


Regional analgesia for improvement of long-term functional outcome after elective large joint replacement.
Regional analgesia is more effective than conventional analgesia for controlling pain and may facilitate rehabilitation after large joint replacement in the short term. It remains unclear if regional anaesthesia improves functional outcomes after joint replacement beyond three months after surgery. To assess the effects of regional anaesthesia and analgesia on long-term functional outcomes 3, 6 and 12 months after elective major joint (knee, shoulder and hip) replacement surgery. We performed an electronic search of several databases (CENTRAL, MEDLINE, EMBASE, CINAHL), and handsearched reference lists and conference abstracts. We updated our search in June 2015. We included randomized controlled trials (RCTs) comparing regional analgesia versus conventional analgesia in patients undergoing total shoulder, hip or knee replacement. We included studies that reported a functional outcome with a follow-up of at least three months after surgery. We used standard methodological procedures expected by Cochrane. We contacted study authors for additional information. We included six studies with 350 participants followed for at least three months. All of these studies enrolled participants undergoing total knee replacement. Studies were at least partially blinded. Three studies had a high risk of performance bias and one a high risk of attrition bias, but the risk of bias was otherwise unclear or low.Only one study assessed joint function using a global score. Due to heterogeneity in outcome and reporting, we could only pool three out of six RCTs, with range of motion assessed at three months after surgery used as a surrogate for joint function. All studies had a high risk of detection bias. Using the random-effects model, there was no statistically significant difference between the experimental and control groups (mean difference 3.99 degrees, 95% confidence interval (CI) - 2.23 to 10.21; P value = 0.21, 3 studies, 140 participants, very low quality evidence).We did not perform further analyses because immediate adverse effects were not part of the explicit outcomes of any of these typically small studies, and long-term adverse events after regional anaesthesia are rare.None of the included studies elicited or reported long-term adverse effects like persistent nerve damage. More high-quality studies are needed to establish the effects of regional analgesia on function after major joint replacement, as well as on the risk of adverse events (falls).


Visual Quality Adjustment for Volume Rendering in a Head-Tracked Virtual Environment.
To avoid simulator sickness and improve presence in immersive virtual environments (IVEs), high frame rates and low latency are required. In contrast, volume rendering applications typically strive for high visual quality that induces high computational load and, thus, leads to low frame rates. To evaluate this trade-off in IVEs, we conducted a controlled user study with 53 participants. Search and count tasks were performed in a CAVE with varying volume rendering conditions which are applied according to viewer position updates corresponding to head tracking. The results of our study indicate that participants preferred the rendering condition with continuous adjustment of the visual quality over an instantaneous adjustment which guaranteed for low latency and over no adjustment providing constant high visual quality but rather low frame rates. Within the continuous condition, the participants showed best task performance and felt less disturbed by effects of the visualization during movements. Our findings provide a good basis for further evaluations of how to accelerate volume rendering in IVEs according to user's preferences.


Community occupational therapy for people with dementia and family carers (COTiD-UK) versus treatment as usual (Valuing Active Life in Dementia [VALID] programme): study protocol for a randomised controlled trial.
A community-based occupational therapy intervention for people with mild to moderate dementia and their family carers (Community Occupational Therapy in Dementia (COTiD)) was found clinically and cost effective in the Netherlands but not in Germany. This highlights the need to adapt and implement complex interventions to specific national contexts. The current trial aims to evaluate the United Kingdom-adapted occupational therapy intervention for people with mild to moderate dementia and their family carers living in the community (COTiD-UK) compared with treatment as usual. This study is a multi-centre, parallel-group, pragmatic randomised trial with internal pilot. We aim to allocate 480 pairs, with each pair comprising a person with mild to moderate dementia and a family carer, who provides at least 4 hours of practical support per week, at random between COTiD-UK and treatment as usual. We shall assess participants at baseline, 12 and 26 weeks, and by telephone at 52 and 78 weeks (first 40% of recruits only) after randomisation. The primary outcome measure is the Bristol Activities of Daily Living Scale (BADLS) at 26 weeks. Secondary outcome measures will include quality of life, mood, and resource use. To assess intervention delivery, and client experience, we shall collect qualitative data via audio recordings of COTiD-UK sessions and conduct semi-structured interviews with pairs and occupational therapists. COTiD-UK is an evidence-based person-centred intervention that reflects the current priority to enable people with dementia to remain in their own homes by improving their capabilities whilst reducing carer burden. If COTiD-UK is clinically and cost effective, this has major implications for the future delivery of dementia services across the UK. Current Controlled Trials ISRCTN10748953 Date of registration: 18 September 2014.


Gata3 drives development of RORγt+ group 3 innate lymphoid cells.
Group 3 innate lymphoid cells (ILC3) include IL-22-producing NKp46(+) cells and IL-17A/IL-22-producing CD4(+) lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt(+) ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt(+) ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets.


Measurement of DDT fluxes from a historically treated agricultural soil in Canada.
Organocohlorine pesticide (OCP) residues in agricultural soils are of concern due to the uptake of these compounds by crops, accumulation in the foodchain, and reemission from soils to the atmosphere. Although it has been about three decades since DDT was banned for agricultural uses in Canada, residues persist in soils of some agricultural areas. Emission of DDT compounds to the atmosphere from a historically treated field in southern Ontario was determined in fall 2004 and spring 2005. The sigmaDDTs concentration in the high organic matter (71%) soil was 19 +/- 4 microg g(-1) dry weight. Concentration gradients in the air were measured at 5, 20, 72, and 200 cm above soil using glass fiber filter-polyurethane foam cartridges. Air concentrations of sigmaDDTs averaged 5.7 +/- 5.1 ng m(-3) at 5 cm and decreased to 1.3 +/- 0.8 ng m(-3) at 200 cm and were 60-300 times higher than levels measured at a background site 30 km away. Soil-air fugacity fractions, fs/(fs + fa), of p,p'-DDE, p,p'-DDD, and p,p'-DDT ranged from 0.42 to 0.91 using air concentrations measured above the soil and > or = 0.99 using background air concentrations, indicating that the soil was a net source to the background air. Fractionation of DDT compounds during volatilization was predicted using either liquid-phase vapor pressures (PL) or octanol-air partition coefficients (KOA). Relative emissions of p,p'-DDE and p,p'-DDT were better described by PL than KOA, whereas either PL or KOA successfully accounted for the fractionation of p,p'-DDT and o,p'-DDT. Soil-to-air fluxes were calculated from air concentration gradients and turbulent exchange coefficients determined from micrometeorological measurements. Average fluxes of sigmaDDTs were 90 +/- 24 ng m(-2) h(-1) in fall and 660 +/- 370 ng m(-2) h(-1) in spring. Higher soil temperatures in spring accounted for the higher fluxes. A volatilization half-life of approximately 200 y was estimated for sigmaDDT in the upper 5 cm of the soil column, assuming the average flux rate for 12 h d-(1) over 8 months of the year. Thus, in the absence of other dissipation processes, the soil will continue to be a source of atmospheric contamination for a very long time.


Characterisation of a human cell-adapted porcine endogenous retrovirus PERV-A/C.
Porcine endogenous retroviruses (PERVs) pose a potential risk for xenotransplantation using pig cells, tissues or organs. A special threat comes from viruses generated by recombination between human-tropic PERV-A and ecotropic PERV-C. Serial passages of a recombinant PERV-A/C on human 293 cells resulted in increased infectious titers and a multimerization of transcription factor binding sites in the viral long terminal repeat (LTR). In contrast to the LTR, the sequence of the env gene did not change, indicating that the LTR represents the determinant of high infectivity. The virus was further propagated on human cells and characterized by different methods (titration, sequencing, infection experiments, electron microscopy). Further propagation on human 293 cells resulted in deletions and mutations in the LTR. In contrast to low-titer viruses, the high-titer virus was infectious for cells from non-human primates including chimpanzees. Scanning electron microscopy revealed clustering of budding virions at the cell surface of infected human cells and transmission electron microscopy indicated that the virus infects them via receptor-mediated endocytosis. After propagation of PERV on human cells without selection pressure, viruses with different LTR were generated. High titer PERV was shown to infect cells from non-human primates. The experiments performed here simulate the situation in vivo and give an extended characterization of human cell-adapted PERVs.


Efficacy and safety of mefloquine, artesunate, mefloquine-artesunate, and praziquantel against Schistosoma haematobium: randomized, exploratory open-label trial.
Morbidity control of schistosomiasis relies on a single drug, praziquantel. The antimalarial drug mefloquine possesses interesting antischistosomal properties, yet no clinical studies have been performed. We conducted a randomized, exploratory open-label trial to assess the efficacy and safety of mefloquine (25 mg/kg), artesunate (3 doses of 4 mg/kg), mefloquine-artesunate (3 doses of 100 mg artesunate plus 250 mg mefloquine), and praziquantel (40 mg/kg) against Schistosoma haematobium. The effects on Schistosoma mansoni, malaria parasitemia, soil-transmitted helminths, and intestinal protozoa were also determined. A total of 83 S. haematobium-infected schoolchildren were included in the study. Cure rates of mefloquine, artesunate, mefloquine-artesunate, and praziquantel against S. haematobium at day 26 after treatment were 21%, 25%, 61%, and 88%, respectively. Both mefloquine-artesunate and praziquantel resulted in egg reduction rates >95%. Significantly lower egg reduction rates were seen in the artesunate (85%) and mefloquine groups (74%). In children coinfected with S. mansoni, praziquantel and mefloquine-artesunate, but not mefloquine and artesunate alone, resulted in high cure rates and egg reduction rates. Mefloquine, artesunate, and mefloquine-artesunate completely cured infections due to Plasmodium falciparum. No effects were found against soil-transmitted helminths and intestinal protozoa. Abdominal pain was the most frequent adverse event, with a higher incidence among children treated with mefloquine (89%), mefloquine-artesunate (83%), and artesunate (60%) than among children treated with praziquantel (46%). The high efficacy of mefloquine-artesunate against S. haematobium warrants further investigation. Individuals coinfected with Plasmodium and Schistosoma who were treated with a mefloquine-artesunate combination against malaria might have a dual benefit: clearance of malaria parasitemia and reduction of schistosomiasis-related morbidity. Current Controlled Trials identifier: ISRCTN06498763.


The information needs of patients treated with primary angioplasty for heart attack: an exploratory study.
As early recovery is a challenging period for cardiac patients who frequently have 'unmet' health information needs, the objective of this study was to explore the information needs of patients treated with primary angioplasty for heart attack. Qualitative methodology using semi-structured interviews with 29 patients recruited from a specialist English Cardiology centre, 3-12 days after discharge from hospital. Framework analysis techniques were used to synthesise findings. Participants were generally satisfied with the way in which health information was provided. The need for more specific information about the risk of recurrence, the level of heart muscle damage, discharge medications, appropriate levels of physical activity and diet was highlighted. There was no clear preference for informant and preferences for the timing of information delivery varied considerably. Health information provision was satisfactory for most but could be improved by the closer matching of patients' preferences with provision. The shortened hospital stay, rapid throughput and emotional shock experienced by patients influenced their ability to absorb information making the optimum timing for health information delivery variable. Current guidelines about the provision of health information for patients recovering from heart attack may need to be reviewed to reflect the recent technological advances in treatment. One approach may be to better 'stage' information to reflect patients' priorities. Home visits by specialist nurses may need to be scheduled earlier to improve continuity of care and address information 'gaps'.


Charged particle transport in magnetic fields in EGSnrc.
To accurately and efficiently implement charged particle transport in a magnetic field in EGSnrc and validate the code for the use in phantom and ion chamber simulations. The effect of the magnetic field on the particle motion and position is determined using one- and three-point numerical integrations of the Lorentz force on the charged particle and is added to the condensed history calculation performed by the EGSnrc PRESTA-II algorithm. The code is tested with a Fano test adapted for the presence of magnetic fields. The code is compatible with all EGSnrc based applications, including egs++. Ion chamber calculations are compared to experimental measurements and the effect of the code on the efficiency and timing is determined. Agreement with the Fano test's theoretical value is obtained at the 0.1% level for large step-sizes and in magnetic fields as strong as 5 T. The NE2571 dose calculations achieve agreement with the experiment within 0.5% up to 1 T beyond which deviations up to 1.2% are observed. Uniform air gaps of 0.5 and 1 mm and a misalignment of the incoming photon beam with the magnetic field are found to produce variations in the normalized dose on the order of 1%. These findings necessitate a clear definition of all experimental conditions to allow for accurate Monte Carlo simulations. It is found that ion chamber simulation times are increased by only 38%, and a 10 × 10 × 6 cm(3) water phantom with (3 mm)(3) voxels experiences a 48% increase in simulation time as compared to the default EGSnrc with no magnetic field. The incorporation of the effect of the magnetic fields in EGSnrc provides the capability to calculate high accuracy ion chamber and phantom doses for the use in MRI-radiation systems. Further, the effect of apparently insignificant experimental details is found to be accentuated by the presence of the magnetic field.


Implementation of continuous quality improvement in Aboriginal and Torres Strait Islander primary health care in Australia: a scoping systematic review.
Continuous Quality Improvement (CQI) programs have been taken up widely by Indigenous primary health care (PHC) services in Australia and there has been national policy commitment to support this. However, international evidence shows that implementing CQI is challenging, impacts are variable and little is known about the factors that impede or enhance effectiveness. A scoping review was undertaken to explore uptake and implementation in Indigenous PHC, including barriers and enablers to embedding CQI in routine practice. We provide guidance on how research and evaluation might be intensified to support implementation. Searches were conducted in MEDLINE, CINAHL and the Cochrane Database of Systematic Reviews. Key websites and publications were handsearched. Studies conducted in Indigenous PHC which demonstrated some combination of CQI characteristics and assessed some aspect of implementation were included. A two stage analysis was undertaken. Stage 1 identified the breadth and focus of literature. Stage 2 investigated barriers and enablers. The Framework for Performance Assessment in PHC (2008) was used to frame the analysis. Data were extracted on the study type, approach, timeframes, CQI strategies, barriers and enablers. Sixty articles were included in Stage 1 and 21 in Stage 2. Barriers to implementing CQI processes relate primarily to professional and organisational processes and operate at multiple levels (individual, team, service, health system) whereas barriers to improved care relate more directly to knowledge of best practice and team processes that facilitate appropriate care. Few studies described implementation timeframes, number of CQI cycles or improvement strategies implemented and only two applied a change theory. Investigating barriers and enablers that modify implementation and impacts of CQI poses conceptual and methodological challenges. More complete description of CQI processes, implementation strategies, and barriers and enablers could enhance capacity for comparisons across settings and contribute to better understanding of key success factors.


Assessment of inflammatory activity in rheumatoid arthritis: a comparative study of clinical evaluation with grey scale and power Doppler ultrasonography.
To compare the clinical assessment of overall inflammatory activity in patients with rheumatoid arthritis (RA) with grey scale and power Doppler (PD) ultrasonography (US). Ninety four consecutive patients with RA were included. Demographic and clinical data, C reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR) were recorded for each patient. The presence of tenderness, swelling, and a subjective swelling score from 1 to 3 were independently assessed by two rheumatologists, who reached a consensus in 60 joints examined in each patient. All patients underwent a US examination by a third blinded rheumatologist, using PD. US joint effusion, synovitis, and PD signal were graded from 1 to 3 in the 60 joints. Joint count and joint index for effusion, synovitis, and PD signal were recorded. A 28 joint count for clinical and US variables was calculated. Interobserver reliability of the US examination was evaluated by a fourth blinded rheumatologist. US showed significantly more joints with effusion (mean 15.2) and synovitis (mean 14.6) than clinical examination (mean 11.5, p<0.05). A significant correlation was found between joint count and joint index for swelling, US effusion, synovitis, and PD signal. The 28 joint count for effusion, synovitis, and PD signal correlated highly with the corresponding 60 joint counts. US findings correlated better with CRP and ESR than clinical measures. Interobserver reliability was better for US findings than for clinical assessment. US is a sensitive method for assessing joint inflammatory activity in RA, complementary to clinical evaluation.


Experience with the piggyback technique without caval occlusion in adult orthotopic liver transplantation.
To assess the feasibility and outcome of a piggyback technique without caval occlusion or veno-venous bypass (VB), we retrospectively reviewed 131 consecutive adult orthotopic liver transplantation (OLT) performed in 129 patients between May 1993 and February 1995. Six were second transplants, and six were combined liver-kidney transplants. The piggyback technique was attempted in all cases. We were able to perform the piggyback technique in 98 OLTs (75%). The remaining 33 OLTs (25%) were converted to the standard technique; of these, 20 (15%) required VB. The reasons for conversion to the standard technique were: anatomical (22 transplants), severe portal hypertension requiring VB (8 transplants), tumor (1 transplant), and other reasons (2 transplants). Six retransplantations were performed (four piggyback, two standard). There was no significant difference in age, United Network for Organ Sharing status, Child's classification, and diagnosis between the patients in whom piggyback was possible or not. The actuarial patient and graft survival at 1 year were similar between the piggyback group and the group of patients converted to standard technique (87/85% vs. 86/86%, respectively). No death was related to either technique. With piggyback, the average operative time was 8.6+/-1.9 hr, median amount of blood transfused intraoperatively was 2 U (33% did not require transfusion), and median intensive care unit and hospital stays were 3 and 11 days, respectively. With the piggyback technique, the mean preoperative and maximum postoperative serum creatinine levels were 1.4+/-1.0 and 1.8+/-1.5 mg/dl. The piggyback technique without caval occlusion is possible in the majority of patients. It is safe and has reduced the use of VB to 15% of our adult OLTs. The piggyback technique avoids retrocaval dissection, facilitates retransplantation, and is associated with a short anhepatic phase, low blood product usage, and short intensive care unit stay.


A comparison of microdebrider assisted endoscopic sinus surgery and conventional endoscopic sinus surgery for nasal polypi.
Nasal polyposis is often encountered in rhinology practice. Those who fail conservative management, a definitive surgery is essential to achieve sufficient ventilation and drainage of the affected sinuses by using either microdebrider or conventional instruments for functional endoscopic sinus surgery (FESS). A prospective study was conducted on 40 cases of nasal polypi in a tertiary care hospital. 20 cases were operated by conventional endoscopic instruments and 20 using the microdebrider. The study aimed at comparing the intra operative (blood loss, duration of surgery) and post operative results (crusting, scarring, discharge, symptoms, recurrence) between the two groups using Lund-Mackay scoring system and the data was statistically analysed. There was no statistically significant difference in surgical outcome for patients when either conventional endoscopic instruments or microdebrider was used. However, there was a significant symptomatic improvement in cases undergoing microdebrider FESS. Microdebrider assisted polypectomy is precise, relatively bloodless surgery though the precision depends on the surgeon's anatomical knowledge and operative skills. Study substantiates that these instruments are helpful but not a prerequisite for successful outcomes in FESS. The study re-emphasises the utility of the microdebrider to young learning FESS surgeons.


Xom: a Xenopus homeobox gene that mediates the early effects of BMP-4.
Bone morphogenetic protein-4 (BMP-4) is thought to play an important role in early Xenopus development by acting as a "ventralizing factor' and as an epidermal determinant: local inhibition of BMP-4 function in whole embryos causes the formation of an additional dorsal axis, and inhibition of BMP-4 function in isolated ectodermal cells causes the formation of neural tissue. In this paper we describe a homeobox-containing gene whose expression pattern is similar to that of BMP-4, whose expression requires BMP-4 signalling and which, when over-expressed, causes a phenotype similar to that caused by over-expression of BMP-4. We suggest that this gene, which we call Xom, acts downstream of BMP-4 to mediate its effects.


A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype.
The Ron tyrosine kinase receptor shares with the members of its subfamily (Met and Sea) a unique functional feature: the control of cell dissociation, motility, and invasion of extracellular matrices (scattering). The mature Ron protein is a heterodimer of disulfide-linked alpha and beta chains, originated by proteolytic cleavage of a single-chain precursor of 185 kDa. In a human gastric cancer cell line (KATO-III), we found abnormal accumulation of an uncleaved single-chain protein (delta-Ron) of 165 kDa; this molecule is encoded by a transcript differing from the full-length RON mRNA by an in-frame deletion of 49 amino acids in the beta-chain extracellular domain. The deleted transcript originates by an alternatively spliced cassette exon of 147 bp, flanked by two short introns. The delta-Ron tyrosine kinase is constitutively activated by disulfide-linked intracellular oligomerization because it contains an uneven number of cysteine residues. Oligomerization and constitutive tyrosine phosphorylation of the full-size Ron was obtained by site-directed mutagenesis of a single cysteine residue in the region encoded by the cassette exon, mimicking that occurring in the delta-Ron isoform. Inhibition of thiol-mediated intermolecular disulfide bonding prevented delta-Ron oligomerization. The intracellular activation of Ron is followed by acquisition of invasive properties in vitro. These data (i) provide a novel molecular mechanism for posttranscriptional activation of a tyrosine kinase receptor protein and (ii) suggest a role for the Ron receptor in progression toward malignancy.


Cadherin superfamily of adhesion molecules in primary lung cancer.
Cadherins are Ca(2+-)dependent cell-cell adhesion molecules which interact with intracellular proteins called catenins. Cadherins are the most interesting adhesion molecules and among them most important is epithelial E-cadherin. Loss of the function or/and the expression of any of the elements of E-cadherin/catenins complex make the cell incapable to adhere resulting to a loss of the normal architecture of tissues. Reduced, absent or disorganised expression of E-cadherin has been found in several carcinomas, including lung cancer. Soluble E-cadherin found in serum from patients with lung cancer could be a tumor marker, while alterations observed in non-small cell lung cancer probably play a role in manifestation of a malignant phenotype. Reduced expression of E-cadherin is a key event in tumorgenicity and metastasis and possible therapeutic strategies are based on that conclusion. In addition, E-cadherin has a role as a marker of differential diagnosis between bronchioloalveolar carcinoma and conventional pulmonary carcinoma as well as between mesothelioma and metastatic pulmonary adenocarcinoma. Small cell lung cancer cells express several types of cadherins too. In conclusion, many studies are in process and it is very possible that soon some cadherins will be used as useful biomarkers and theraupeutic targets in cases of primary lung cancer.


Construction costs, chemical composition and payback time of high- and low-irradiance leaves.
The effect of irradiance on leaf construction costs, chemical composition, and on the payback time of leaves was investigated. To enable more generalized conclusions, three different systems were studied: top and the most-shaded leaves of 10 adult tree species in a European mixed forest, top leaves of sub-dominant trees of two evergreen species growing in small gaps or below the canopy in an Amazonian rainforest, and plants of six herbaceous and four woody species grown hydroponically at low or high irradiance in growth cabinets. Daily photon irradiance varied 3-6-fold between low- and high-light leaves. Specific leaf area (SLA) was 30-130% higher at low light. Construction costs, on the other hand, were 1-5% lower for low-irradiance leaves, mainly because low-irradiance leaves had lower concentrations of soluble phenolics. Photosynthetic capacity and respiration, expressed per unit leaf mass, were hardly different for the low- and high-light leaves. Estimates of payback times of the high-irradiance leaves ranged from 2-4 d in the growth cabinets, to 15-20 d for the adult tree species in the European forest. Low-irradiance leaves had payback times that were 2-3 times larger, ranging from 4 d in the growth cabinets to 20-80 d at the most shaded part of the canopy of the mixed forest. In all cases, estimated payback times were less than half the life span of the leaves, suggesting that even at time-integrated irradiances lower than 5% of the total seasonal value, investment in leaves is still fruitful from a carbon-economy point of view. A sensitivity analysis showed that increased SLA of low-irradiance leaves was the main factor constraining payback times. Acclimation in the other five factors determining payback time, namely construction costs, photosynthetic capacity per unit leaf mass, respiration per unit leaf mass, apparent quantum yield, and curvature of the photosynthetic light-response-curve, were unimportant when the observed variation in each factor was examined.


Chemical cross-linking provides a model of the gamma-secretase complex subunit architecture and evidence for close proximity of the C-terminal fragment of presenilin with APH-1.
Gamma-secretase is an intramembrane cleaving aspartyl protease complex intimately implicated in Alzheimer disease pathogenesis. The protease is composed of the catalytic subunit presenilin (PS1 or PS2), the substrate receptor nicastrin (NCT), and two additional subunits, APH-1 (APH-1a, as long and short splice forms (APH-1aL, APH-1aS), or APH-1b) and PEN-2. Apart from the Alzheimer disease-associated beta-amyloid precursor protein, gamma-secretase has been shown to cleave a large number of other type I membrane proteins. Despite the progress in elucidating gamma-secretase function, basic questions concerning the precise organization of its subunits, their molecular interactions, and their exact stoichiometry in the complex are largely unresolved. Here we isolated endogenous human gamma-secretase from human embryonic kidney 293 cells and investigated the subunit architecture of the gamma-secretase complex formed by PS1, NCT, APH-1aL, and PEN-2 by chemical cross-linking. Using this approach, we provide evidence for the close neighborhood of the PS1 N- and C-terminal fragments (NTF and CTF, respectively), the PS1 NTF and PEN-2, the PS1 CTF and APH-1aL, and NCT and APH-1aL. We thus identify a previously unrecognized PS1 CTF/APH-1aL interaction, verify subunit interactions deduced previously from indirect approaches, and provide a model of the gamma-secretase complex subunit architecture. Finally, we further show that, like the PS1 CTF, the PS2 CTF also interacts with APH-1aL, and we provide evidence that these interactions also occur with the other APH-1 variants, suggesting similar subunit architectures of all gamma-secretase complexes.


Resting state networks change in clinically isolated syndrome.
Task-functional magnetic resonance imaging studies have shown that early cortical recruitment exists in multiple sclerosis, which can partly explain the discrepancy between conventional magnetic resonance imaging and clinical disability. The study of the brain 'at rest' may provide additional information, because task-induced metabolic changes are relatively small compared to the energy use of the resting brain. We therefore questioned whether functional changes exist at rest in the early phase of multiple sclerosis, and addressed this question by a network analysis of no-task functional magnetic resonance imaging data. Fourteen patients with symptoms suggestive of multiple sclerosis (clinically isolated syndrome), 31 patients with relapsing remitting multiple sclerosis and 41 healthy controls were included. Resting state functional magnetic resonance imaging data were brought to standard space using non-linear registration, and further analysed using multi-subject independent component analysis and individual time-course regression. Eight meaningful resting state networks were identified in our subjects and compared between the three groups with non-parametric permutation testing, using threshold-free cluster enhancement to correct for multiple comparisons. Additionally, quantitative measures of structural damage were obtained. Grey and white matter volumes, normalized for head size, were measured for each subject. White matter integrity was investigated with diffusion tensor measures that were compared between groups voxel-wise using tract-based spatial statistics. Patients with clinically isolated syndrome showed increased synchronization in six of the eight resting state networks, including the default mode network and sensorimotor network, compared to controls or relapsing remitting patients. No significant decreases were found in patients with clinically isolated syndrome. No significant resting state synchronization differences were found between relapsing remitting patients and controls. Normalized grey matter volume was decreased and white matter diffusivity measures were abnormal in relapsing remitting patients compared to controls, whereas no atrophy or diffusivity changes were found for the clinically isolated syndrome group. Thus, early synchronization changes are found in patients with clinically isolated syndrome that are suggestive of cortical reorganization of resting state networks. These changes are lost in patients with relapsing remitting multiple sclerosis with increasing brain damage, indicating that cortical reorganization of resting state networks is an early and finite phenomenon in multiple sclerosis.


Increased production of chemotactic cytokines and elevated proliferation and expression of intercellular adhesion molecule-1 in rat mesangial cells treated with erythrogenic toxin type B and its precursor isolated from nephritogenic streptococci.
Previous reports have demonstrated the presence of streptococcal erythrogenic toxin type B (ETB) as well as proliferation and expression of adhesion molecules along with leukocyte infiltrations in biopsies from patients with acute post-streptococcal glomerulonephritis (APSGN). The purpose of the present study was to correlate infiltrative and proliferative events with interactions between ETB or its precursor (ETBP) and intrinsic mesangial cells. Rat mesangial cells were cultured with ETB or ETBP (50 micro g/ml) while measuring production of monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) and while examining proliferation and expression of intercellular adhesion molecule-1 (ICAM-1). After 24, 48 and 96 h of incubation, MCP-1 and MIP-2 in culture supernatants were assessed by enzyme-linked immunosorbent assay (ELISA). Cells were assessed for proliferation by incorporation of radioactive thymidine and expression of ICAM-1 was measured by indirect immunofluorescence and by cellular ELISA. Compared with controls, treatment with either ETBP or ETB significantly increased MCP-1 and MIP-2 levels in mesangial cell cultures. Mesangial cells also showed elevated proliferation at 96 h of culture when treated with streptococcal proteins. Although production of MCP-1 and MIP-2 was not correlated with proliferation, treatment with ETBP resulted in a significant correlation between MCP-1 production and proliferation. Immunofluorescence studies revealed an increased expression of ICAM-1 in ETBP/ETB-treated mesangial cells. In addition, cellular ELISA studies showed increased absorbance in cultures treated with ETBP/ETB. Finally, low serum concentrations in the culture medium potentiated the stimulatory effect of ETB on MCP-1 production. Our findings, by demonstrating a role for cationic streptococcal ETB or ETBP in the induction of chemotactic molecules as well as the proliferation and expression of adhesion molecules, delineate an additional possible pathway for the pathogenesis of APSGN.


SNP diversity of Enterococcus faecalis and Enterococcus faecium in a South East Queensland waterway, Australia, and associated antibiotic resistance gene profiles.
Enterococcus faecalis and Enterococcus faecium are associated with faecal pollution of water, linked to swimmer-associated gastroenteritis and demonstrate a wide range of antibiotic resistance. The Coomera River is a main water source for the Pimpama-Coomera watershed and is located in South East Queensland, Australia, which is used intensively for agriculture and recreational purposes. This study investigated the diversity of E. faecalis and E. faecium using Single Nucleotide Polymorphisms (SNPs) and associated antibiotic resistance profiles. Total enterococcal counts (cfu/ml) for three/six sampling sites were above the United States Environmental Protection Agency (USEPA) recommended level during rainfall periods and fall into categories B and C of the Australian National Health and Medical Research Council (NHMRC) guidelines (with a 1-10% gastrointestinal illness risk). E. faecalis and E. faecium isolates were grouped into 29 and 23 SNP profiles (validated by MLST analysis) respectively. This study showed the high diversity of E. faecalis and E. faecium over a period of two years and both human-related and human-specific SNP profiles were identified. 81.8% of E. faecalis and 70.21% of E. faecium SNP profiles were associated with genotypic and phenotypic antibiotic resistance. Gentamicin resistance was higher in E. faecalis (47% resistant) and harboured the aac(6')-aph(2') gene. Ciprofloxacin resistance was more common in E. faecium (12.7% resistant) and gyrA gene mutations were detected in these isolates. Tetracycline resistance was less common in both species while tet(L) and tet(M) genes were more prevalent. Ampicillin resistance was only found in E. faecium isolates with mutations in the pbp5 gene. Vancomycin resistance was not detected in any of the isolates. We found that antibiotic resistance profiles further sub-divided the SNP profiles of both E. faecalis and E. faecium. The distribution of E. faecalis and E. faecium genotypes is highly diverse in the Coomera River. The SNP genotyping method is rapid and robust and can be applied to study the diversity of E. faecalis and E. faecium in waterways. It can also be used to test for human-related and human-specific enterococci in water. The resolving power can be increased by including antibiotic-resistant profiles which can be used as a possible source tracking tool. This warrants further investigation.


Serum creatinine and albumin decline predict the contraction of nosocomial aspiration pneumonia in patients undergoing hemodialysis.
Aspiration pneumonia (AP) is prevalent in older adults and the hemodialysis (HD) population has been getting older. Therefore, it is speculated that increasing number of HD patients would suffer from AP. However, the clinical aspects of AP in HD patients have not been elucidated. Consecutive HD patients with nosocomial AP hospitalized in our university hospital from April 2007 to December 2008 were recruited. Their clinical characteristics, risk factors for contraction, and the fatality of AP and treatment options were described. Nineteen out of 356 hospitalized HD patients had AP and 8 out of 19 AP patients died, indicating the incidence rate and fatality rate were 5.34% and 42.1%, respectively. Multiple regression analysis revealed that the risk factors for contracting AP included age, body mass index, serum creatinine levels (Cre) and the monthly decline rate of Cre. It also revealed that serum albumin (Alb) and basal total cholesterol levels, the decline rate of Alb and Cre levels, and the duration of AP were independent risk factors for fatality. Survivors were most often treated with tube feeding. Both contraction rate and fatality of nosocomial AP were high among HD patients. Both the malnutrition as well as the decline rate for nutrition and muscle volume indicated by falls in Alb and Cre, respectively, had clinical relevance in AP. Maintaining nutritional state by tube feeding and muscle volume seems to be the mainstay for the prevention and the treatment of AP in HD patients.


Lower Volumes, Higher Speeds: Changes to Crash Type, Timing, and Severity on Urban Roads from COVID-19 Stay-at-Home Policies.
Stay-at-home policies in response to COVID-19 transformed high-volume arterials and highways into lower-volume roads, and reduced congestion during peak travel times. To learn from the effects of this transformation on traffic safety, an analysis of crash data in Ohio's Franklin County, U.S., from February to May 2020 is presented, augmented by speed and network data. Crash characteristics such as type and time of day are analyzed during a period of stay-at-home guidelines, and two models are estimated: (i) a multinomial logistic regression that relates daily volume to crash severity; and (ii) a Bayesian hierarchical logistic regression model that relates increases in average road speeds to increased severity and the likelihood of a crash being fatal. The findings confirm that lower volumes are associated with higher severity. The opportunity of the pandemic response is taken to explore the mechanisms of this effect. It is shown that higher speeds were associated with more severe crashes, a lower proportion of crashes were observed during morning peaks, and there was a reduction in types of crashes that occur in congestion. It is also noted that there was an increase in the proportion of crashes related to intoxication and speeding. The importance of the findings lay in the risk to essential workers who were required to use the road system while others could telework from home. Possibilities of similar shocks to travel demand in the future, and that traffic volumes may not recover to previous levels, are discussed, and policies are recommended that could reduce the risk of incapacitating and fatal crashes for continuing road users.


Phase I study of oral topotecan in hematological malignancies.
In this Phase I, dose-seeking study, we investigated the dose-limiting toxicities (DLTs) and maximal tolerated dose (MTD) of oral topotecan in patients with hematological malignancies. Patients with myelodysplastic syndromes, myeloproliferative disorders, or relapsed acute myelogenous leukemia were treated with 0.6-1.9 mg/m(2)/day oral topotecan for 5 consecutive days on and 2 days off, for 3 weeks (15 doses/course) followed by 2-4 weeks of rest. The DLTs occurring during the first course of treatment were considered for defining the MTD. Preliminary results of antitumor activity were assessed by examining bone marrow status and peripheral blood cell counts. All 26 patients enrolled in the study were evaluable for toxicity, and 24 patients were evaluable for response. A total of 54 courses were administered. The most frequently reported nonhematological toxicities (percentage of courses) were diarrhea (57%), nausea/vomiting (50%), fatigue (24%), and mucositis (9%). DLTs included grade 3 or 4 nausea/vomiting and diarrhea at 1.9 mg/m(2)/day. The MTD for oral topotecan in patients with hematological malignancies was defined at 1.4 mg/m(2)/day. Hematological toxicity was noted in all 26 patients and with all courses but was not considered dose-limiting. Four (17%) patients achieved a complete response, and six (25%) patients experienced hematological improvement. Protracted administration of oral topotecan is safe and well tolerated in patients with hematological malignancies. At the dose-schedule used, single-agent oral topotecan has a definite activity in patients with myelodysplastic syndrome and acute myelogenous leukemia and warrants further investigation alone or in combination with other agents.


Reengineering red blood cells for cellular therapeutics and diagnostics.
Recently optimized technologies that permit the reversible opening of nanopores across the red blood cell membrane, give the extraordinary opportunity for reengineering human erythrocytes to be used in different biomedical applications, both for therapeutic and diagnostic purposes. Engineered erythrocytes have been exploited as a system for the controlled release of drugs in circulation upon encapsulation of prodrugs or small molecules; as bioreactors when they are endowed of recombinant enzymes able to catalyze the conversion of toxic metabolite into inert products; as drug targeting system for the delivery of compounds to the reticuloendothelial system inducing proper senescent signals on the drug-loaded erythrocyte membrane; as carrier of contrasting agents for diagnostic procedures. Preclinical development of these different applications has taken advantage from the use of proper animal models whose erythrocytes can be reengineered as the human ones or the encapsulation procedures can be adapted on the basis of their specific erythrocyte biological features. Successful results, obtained both in vitro and in preclinical studies, have prompted several clinicians to start pilot clinical investigations in different conditions and some new companies to start the industrialization of selected loading technologies and to initiate clinical development programs. This short review summarizes the key features that, to the best of our knowledge, have been crucial to advance the products toward regulatory clinical approval making reengineering of erythrocytes a modality to treat patients with limited or absent therapeutic options. WIREs Nanomed Nanobiotechnol 2017, 9:e1454. doi: 10.1002/wnan.1454 For further resources related to this article, please visit the WIREs website.


Nodal morphogens.
Nodal signals belong to the TGF-beta superfamily and are essential for the induction of mesoderm and endoderm and the determination of the left-right axis. Nodal signals can act as morphogens-they have concentration-dependent effects and can act at a distance from their source of production. Nodal and its feedback inhibitor Lefty form an activator/inhibitor pair that behaves similarly to postulated reaction-diffusion models of tissue patterning. Nodal morphogen activity is also regulated by microRNAs, convertases, TGF-beta signals, coreceptors, and trafficking factors. This article describes how Nodal morphogens pattern embryonic fields and discusses how Nodal morphogen signaling is modulated.


CTFFIND4: Fast and accurate defocus estimation from electron micrographs.
CTFFIND is a widely-used program for the estimation of objective lens defocus parameters from transmission electron micrographs. Defocus parameters are estimated by fitting a model of the microscope's contrast transfer function (CTF) to an image's amplitude spectrum. Here we describe modifications to the algorithm which make it significantly faster and more suitable for use with images collected using modern technologies such as dose fractionation and phase plates. We show that this new version preserves the accuracy of the original algorithm while allowing for higher throughput. We also describe a measure of the quality of the fit as a function of spatial frequency and suggest this can be used to define the highest resolution at which CTF oscillations were successfully modeled.


Multicenter trial of neo-adjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma.
The aim of this multicenter trial was to prospectively evaluate neo-adjuvant chemotherapy followed by extrapleural pneumonectomy (EPP) and radiotherapy, including quality of life as outcome. Eligible patients had malignant pleural mesothelioma of all histological types, World Health Organization performance status of zero to two and clinical stage T1-T3, N0-2, M0 disease considered completely resectable. Neo-adjuvant chemotherapy consisted of three cycles of cisplatin and gemcitabine followed by EPP. Postoperative radiotherapy was considered for all patients. In all, 58 of 61 patients completed three cycles of neo-adjuvant chemotherapy. Forty-five patients (74%) underwent EPP and in 37 patients (61%) the resection was complete. Postoperative radiotherapy was initiated in 36 patients. The median survival of all patients was 19.8 months [95% confidence interval (CI) 14.6-24.5]. For the 45 patients undergoing EPP, the median survival was 23 months (95% CI 16.6-32.9). Psychological distress showed minor variations over time with distress above the cut-off score indicating no morbidity with 82% (N = 36) at baseline and 76% (N = 26) at 3 months after surgery (P = 0.5). The observed rate of operability is promising. A median survival of 23 months for patients undergoing EPP compares favourably with the survival reported from single center studies of upfront surgery. This approach was not associated with an increase in psychological distress.


The good and the bad: using C reactive protein to distinguish bacterial from non-bacterial infection among febrile patients in low-resource settings.
C reactive protein (CRP), a marker for the presence of an inflammatory process, is the most extensively studied marker for distinguishing bacterial from non-bacterial infections in febrile patients. A point-of-care test for bacterial infections would be of particular use in low-resource settings where other laboratory diagnostics are not always available, antimicrobial resistance rates are high and bacterial infections such as pneumonia are a leading cause of death. This document summarises evidence on CRP testing for bacterial infections in low-income and middle-income countries (LMICs). With a push for universal health coverage and prevention of antimicrobial resistance, it is important to understand if CRP might be able to do the job. The use of CRP polarised the global health community and the aim of this document is to summarise the 'good and the bad' of CRP in multiple settings in LMICs. In brief, the literature that was reviewed suggests that CRP testing may be beneficial in low-resource settings to improve rational antibiotic use for febrile patients, but the positive predictive value is insufficient to allow it to be used alone as a single tool. CRP testing may be best used as part of a panel of diagnostic tests and algorithms. Further studies in low-resource settings, particularly with regard to impact on antibiotic prescribing and cost-effectiveness of CRP testing, are warranted.