Impact of sex on cardiovascular outcome in patients at high cardiovascular risk: analysis of the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) and the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET).
Epidemiological data suggest that sex independently contributes to cardiovascular risk. Clinical trials are often hampered by the enrollment of few female patients. The Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET) and the parallel Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND) included a large proportion of female patients (9378 female versus 22 168 male patients). Differences in male and female patients enrolled in ONTARGET/TRANSCEND were analyzed for the primary 4-fold end point (composite of cardiovascular death, myocardial infarction, stroke, or admission to hospital for heart failure), a secondary 3-fold end point (cardiovascular death, myocardial infarction, stroke), and individual components of the primary composite. Baseline characteristics included age, ethnicity, body mass index, physical activity, tobacco use, alcohol consumption, formal education, clinical diagnosis for study entry, patient history, and concomitant medication. Patients were followed up until death or the end of the study (median, 56 months). Compared with male patients, female patients had a 19% significantly lower risk for the 4-fold end point and 21% for the 3-fold end point (after adjustment for study, treatment, and the above baseline values). Similarly, the adjusted risk for cardiovascular death (17%) and myocardial infarction (22%), but not for stroke and hospitalization for heart failure, was also significantly lower in women. Diabetic female patients were characterized by a higher risk for acute myocardial infarction compared with diabetic male patients, whereas alcohol consumption resulted in significantly lower risk in women. In our analysis made up of 70.3% male and 29.7% female patients, an ≈20% lower risk for the combined cardiovascular end points in female patients was observed despite treatment with cardioprotective agents. This difference was driven primarily by a significantly lower incidence of myocardial infarction. Thus, we demonstrate in a large interventional trial that sex greatly affects the occurrence of cardiovascular events in patients with vascular disease or high-risk diabetes mellitus. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153101.


Nuclear magnetic resonance metabolomic profiling of urine provides a noninvasive alternative to the identification of biomarkers associated with endometriosis.
To investigate whether urine metabolomic profile can be used to identify biomarkers associated to endometriosis. Prospective study. For each subject, a urine sample was collected after overnight fasting and before surgery. University medical center. The clinical cohort included 45 endometriosis patients, diagnosed at early (n = 6) and advanced (n = 39) stages of the disease, and 36 healthy women. All women underwent diagnostic laparoscopy to visually confirm the presence or absence of endometriotic lesions. Metabolomic profiling of urine samples based on (1)H-nuclear magnetic resonance (NMR) spectroscopy in combination with statistical approaches. Comparative identification of metabolites present in urine from endometriosis patients and healthy women. The urine metabolomic profile of endometriosis patients exhibited higher concentrations of N(1)-methyl-4-pyridone-5-carboxamide, guanidinosuccinate, creatinine, taurine, valine, and 2-hydroxyisovalerate and decreased concentrations of lysine compared with healthy women. Most of these metabolites are involved in inflammation and oxidative stress processes. These pathophysiologic events had been previously described to be present in ectopic endometrial proliferation foci. Overall, the results demonstrate the potential of (1)H-NMR-based metabolomics, a rapid and noninvasive approach, to identify metabolic changes associated to endometriosis in urine samples. This information could be useful to get a better understanding of the pathogenesis of endometriosis, thus providing support to the noninvasive diagnosis of this pathology.


Effects of monitoring versus blunting on the public's preferences for information in a hypothetical cancer diagnosis scenario.
Monitoring and blunting are coping styles that characterize how people respond when faced with personally threatening situations. High monitors tend to pay more attention to, scan for, and amplify threatening cues; high blunters tend to avoid information and seek distractions when faced with a threatening event. This study sought to investigate possible differential effects of monitoring and blunting coping styles on information preferences in a hypothetical cancer diagnosis scenario in the adult general public of Minnesota. In a survey administered at a large public venue (2016 Minnesota State Fair), participants were asked to imagine they carried a gene mutation and were diagnosed with colon cancer. They indicated their information preference [modified Cassileth Information Styles Questionnaire (MCISQ)], completed two coping style measures [Miller Behavioral Style Scale (MBSS) and Threatening Medical Situations Inventory (TMSI)], rated their perceived severity of colon cancer (low, moderate, high), and answered demographic questions. Eight hundred fifty-five individuals provided usable data. Participants classified as monitors on the TMSI had significantly higher MCISQ scores (i.e., preferred more information) than those classified as blunters (p = .004). Those scoring high on monitoring and low on blunting on the MBSS preferred significantly more information than those scoring high on both monitoring and blunting (p = .04). Linear regression analysis revealed being a monitor (TMSI), scoring high on monitoring (MBSS), rating colon cancer as more severe, and having a higher education level were significant positive predictors of MCISQ scores. Results suggest individual differences in coping style, perceived severity, and education level affect desire for information. Genetic counselors should consider these patient characteristics (e.g., asking patients about their information preferences) and tailor their approaches accordingly.


A fluorescent pH probe for acidic organelles in living cells.
A water-soluble pH sensor, 2-(6-(4-aminostyryl)-1,3-dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)-N, N-dimethylethanamine (ADA), was synthesized based on the molecular design of photoinduced electron transfer (PET) and intramolecular charge transfer (ICT). The fluorescence emission response against a pH value is in the range 3-6, which is suitable for labelling intracellular pH-dependent microenvironments. After biological evolution, ADA is more than a pH biosensor because it is also an endocytosis pathway tracking biosensor that labels endosomes, late endosomes, and lysosome pH gradients. From this, the emissive aggregates of ADA and protonated-ADA in these organs were evaluated to explore how this probe stresses emission colour change to cause these unique cellular images.


Epilepsy and the family: a review of current literature.
Although the negative effect of epilepsy on patient's psychosocial well-being has been increasingly documented in the last decade, the influence of the condition on the family has attracted much less interest. This paper reviews the present state of family research, examining the influence of both childhood and adulthood epilepsy on the psychological and social well-being of family members. Studies indicate that epilepsy may cause high levels of psychosocial difficulties for all family members, including stigmatization, stress, psychiatric morbidity, marital problems, poor self esteem and restriction of social activities. Studies also suggest that the family environment may be an important intervening factor between the condition and the outcome for the family unit, and a number of family factors are reviewed which have been suggested to mediate this relationship, with recommendations being made for their use in intervention studies. Shortcomings of the family studies to date are discussed and these include: concentration on examination of issues around family life, studies being based on reports from single members of the family and the selection of subjects from clinical populations. Recommendations are made concerning methodological and conceptual issues that need addressing for future research.


Serum adiponectin levels in gestational diabetes mellitus.
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.[1] Pregnancy is a unique situation in which there is a physiological temporary increase in insulin resistance (IR). The mechanisms responsible for the gestational-induced IR are not completely understood. The current study was undertaken to compare adiponectin levels during 24-28 weeks period of gestation in drug-naive newly diagnosed GDM women with a cohort of normoglycemic pregnant women. A total of 47 pregnant women in the age group of 18-40 years were included in this cross-sectional study, of which 13 were GDM cases and 34 were normoglycemic controls. Serum adiponectin level was analyzed by enzyme-linked immunosorbent assay. The mean adiponectin level was 16.92 ng/ml (standard deviation [SD] = 2.78) and 19.38 ng/ml (SD = 2.71) in case and control groups, respectively, and the difference was found to be statistically significant (P = 0.008). Our study demonstrated decreased serum adiponectin levels in women with GDM when compared with age- and body mass index-matched euglycemic pregnant women.


Blocking lymphocyte trafficking with FTY720 prevents inflammation-sensitized hypoxic-ischemic brain injury in newborns.
Intrauterine infection (chorioamnionitis) aggravates neonatal hypoxic-ischemic (HI) brain injury, but the mechanisms linking systemic inflammation to the CNS damage remain uncertain. Here we report evidence for brain influx of T-helper 17 (TH17)-like lymphocytes to coordinate neuroinflammatory responses in lipopolysaccharide (LPS)-sensitized HI injury in neonates. We found that both infants with histological chorioamnionitis and rat pups challenged by LPS/HI have elevated expression of the interleukin-23 (IL-23) receptor, a marker of early TH17 lymphocytes, in the peripheral blood mononuclear cells. Post-LPS/HI administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor agonist that blocks lymphocyte trafficking, mitigated the influx of leukocytes through the choroid plexus and acute induction of nuclear factor-κB signaling in the brain. Subsequently, the FTY720 treatment led to attenuated blood-brain barrier damage, fewer cluster of differentiation 4-positive, IL-17A-positive T-cells in the brain, less proinflammatory cytokine, and better preservation of growth and white matter functions. The FTY720 treatment also provided dose-dependent reduction of brain atrophy, rescuing >90% of LPS/HI-induced brain tissue loss. Interestingly, FTY720 neither opposed pure-HI brain injury nor directly inhibited microglia in both in vivo and in vitro models, highlighting its unique mechanism against inflammation-sensitized HI injury. Together, these results suggest that the dual hit of systemic inflammation and neonatal HI injury triggers early onset of the TH17/IL-17-mediated immunity, which causes severe brain destruction but responds remarkably to the therapeutic blockade of lymphocyte trafficking.


The thiazolidinedione pioglitazone increases cholesterol biosynthetic gene expression in primary cortical neurons by a PPARgamma-independent mechanism.
In a recent clinical study, the thiazolidinedione (TZD) pioglitazone (Actos was reported to preserve cognitive function in patients with mild to moderate Alzheimer's disease and type II diabetes mellitus. TZDs are agonists of the nuclear hormone receptor peroxisome proliferator-activated receptor-gamma (PPARgamma), are peripheral insulin sensitizers, and have recently been reported to increase mitochondrial biogenesis in the central nervous system and dendritic spine density. We report a transcriptional profile of the TZD pioglitazone and the non-TZD PPARgamma agonist GW347845 in primary cortical culture. We observed that pioglitazone, but not GW347845, increased cholesterol biosynthetic and lipogenic gene expression after 6 h, and the expression of the cholesterol efflux transporters Abca1 and Abcg1 after 24 h. Co-treatment of pioglitazone with the PPARgamma antagonist GW9662 did not significantly reduce these effects, suggesting a PPARgamma-independent mechanism. These findings suggest a novel effect of TZDs in neurons that may be of relevance as a novel approach against Alzheimer's disease.


A multicenter randomized clinical trial investigating the cost-effectiveness of treatment strategies with or without antibiotics for uncomplicated acute diverticulitis (DIABOLO trial).
Conservative treatment of uncomplicated or mild diverticulitis usually includes antibiotic therapy. It is, however, uncertain whether patients with acute diverticulitis indeed benefit from antibiotics. In most guidelines issued by professional organizations antibiotics are considered mandatory in the treatment of mild diverticulitis. This advice lacks evidence and is merely based on experts' opinion. Adverse effects of the use of antibiotics are well known, including allergic reactions, development of bacterial resistance to antibiotics and other side-effects. A randomized multicenter pragmatic clinical trial comparing two treatment strategies for uncomplicated acute diverticulitis. I) A conservative strategy with antibiotics: hospital admission, supportive measures and at least 48 hours of intravenous antibiotics which subsequently are switched to oral, if tolerated (for a total duration of antibiotic treatment of 10 days). II) A liberal strategy without antibiotics: admission only if needed on clinical grounds, supportive measures only. Patients are eligible for inclusion if they have a diagnosis of acute uncomplicated diverticulitis as demonstrated by radiological imaging. Only patients with stages 1a and 1b according to Hinchey's classification or "mild" diverticulitis according to the Ambrosetti criteria are included. The primary endpoint is time-to-full recovery within a 6-month follow-up period. Full recovery is defined as being discharged from the hospital, with a return to pre-illness activities, and VAS score below 4 without the use of daily pain medication. Secondary endpoints are proportion of patients who develop complicated diverticulitis requiring surgery or non-surgical intervention, morbidity, costs, health-related quality of life, readmission rate and acute diverticulitis recurrence rate. In a non-inferiority design 264 patients are needed in each study arm to detect a difference in time-to-full recovery of 5 days or more with a power of 85% and a confidence level of 95%. With an estimated one percent of patients lost to follow up, a total of 533 patients will be included. A clinically relevant difference of more than 5 days in time-to-full recovery between the two treatment strategies is not expected. The liberal strategy without antibiotics and without the strict requirement for hospital admission is anticipated to be more a more cost-effective approach. NCT01111253.


Dynamics of Dual Specificity Phosphatases and Their Interplay with Protein Kinases in Immune Signaling.
Dual specificity phosphatases (DUSPs) have a well-known role as regulators of the immune response through the modulation of mitogen-activated protein kinases (MAPKs). Yet the precise interplay between the various members of the DUSP family with protein kinases is not well understood. Recent multi-omics studies characterizing the transcriptomes and proteomes of immune cells have provided snapshots of molecular mechanisms underlying innate immune response in unprecedented detail. In this study, we focus on deciphering the interplay between members of the DUSP family with protein kinases in immune cells using publicly available omics datasets. Our analysis resulted in the identification of potential DUSP-mediated hub proteins including MAPK7, MAPK8, AURKA, and IGF1R. Furthermore, we analyzed the association of DUSP expression with TLR4 signaling and identified VEGF, FGFR, and SCF-KIT pathway modules to be regulated by the activation of TLR4 signaling. Finally, we identified several important kinases including LRRK2, MAPK8, and cyclin-dependent kinases as potential DUSP-mediated hubs in TLR4 signaling. The findings from this study have the potential to aid in the understanding of DUSP signaling in the context of innate immunity. Further, this will promote the development of therapeutic modalities for disorders with aberrant DUSP signaling.


Adaptive dynamic programming for finite-horizon optimal control of discrete-time nonlinear systems with ε-error bound.
In this paper, we study the finite-horizon optimal control problem for discrete-time nonlinear systems using the adaptive dynamic programming (ADP) approach. The idea is to use an iterative ADP algorithm to obtain the optimal control law which makes the performance index function close to the greatest lower bound of all performance indices within an ε-error bound. The optimal number of control steps can also be obtained by the proposed ADP algorithms. A convergence analysis of the proposed ADP algorithms in terms of performance index function and control policy is made. In order to facilitate the implementation of the iterative ADP algorithms, neural networks are used for approximating the performance index function, computing the optimal control policy, and modeling the nonlinear system. Finally, two simulation examples are employed to illustrate the applicability of the proposed method.


The effects of several anorexigenics on monkey social behavior.
The effects of fenfluramine HCl, diethylpropion HCl, and methylphenidate HCl on social behavior were studied in a heterosexual group of stumptailed monkeys (M. arctoides). Subjects were treated concurrently (i.e., every monkey received the same treatment on a given day). The range of doses studied was: fenfluramine (1.0-10 mg/kg), methylphenidate (1.0-5.0 mg/kg), and diethylpropion (2.0-20 mg/kg). In general most drug/dose combinations produced decreases in social interactions. However, there was one notable exception; presenting was dramatically increased following dosing with methylphenidate and diethylpropion. Some of the solitary behaviors recorded were also observed to increase, notably, vocalization and self-grooming, which at the higher doses of diethylpropion and methylphenidate took the form of intensely idiosyncratic stereotypies. Finally, food consumption was observed to decrease in some subjects (more dominant) and increase in others (less dominant) indicating that social variables may interact with pharmacological variables.


No Difference in Hip Muscle Volumes and Fatty Infiltration in Those With Hip-Related Pain Compared to Controls.
Little is known about muscle morphology in people with hip-related pain, without signs of femoro-acetabular impingement syndrome (FAIS). Identifying changes in hip muscle volume, fatty infiltrate and establishing relationships between muscle volume and strength, may provide insight into potential early treatment strategies. To: (i) compare the volumes and fatty infiltrate of gluteus maximus, gluteus medius, gluteus minimis, tensor fascia latae and quadratus femoris between symptomatic and less-symptomatic sides of participants with hip-related pain; (ii) compare the volumes and fatty infiltrate of hip muscles between healthy controls and symptomatic participants; and (iii) explore relationships of hip muscle volumes to muscle strength and patient-reported outcome measures in people with hip-related pain. Cross-sectional study. Muscle volume and fatty infiltrate (from magnetic resonance imaging), hip muscle strength, patient-reported symptoms, function and quality of life (QOL) were determined for 16 participants with hip-related pain (no clinical signs of FAIS; 37±9 years) and 15 controls (31±9 years). Using One Way Analysis of Co-Variance tests, muscle volume and fatty infiltrate was compared between the symptomatic and less-symptomatic sides in participants with hip-related pain as well as between healthy controls and symptomatic participants. In addition, hip muscle volume was correlated with hip muscle strength, hip-reported symptoms, function and QOL. No differences in all the studied muscle volumes or fatty infiltrate were identified between the symptomatic and less-symptomatic hips of people with hip-related pain; or between people with and without hip-related pain. Greater GMED volume on the symptomatic side was associated with less symptoms and better function and QOL (ρ=0.522-0.617) for those with hip-related pain. Larger GMAX volume was associated with greater hip abduction and internal rotation strength, larger GMED volume was associated with greater hip extension strength, and larger QF volume was associated with greater hip abduction strength (rho=0.507-0.638). People with hip-related pain and no clinical signs of FAIS have hip muscle volumes that are not significantly different than those of matched pain-free controls or their less-symptomatic hip. Larger GMED muscle volume was associated with fewer symptoms and greater strength. Level 3a.


Self-Cleaning Ceramic Tiles Produced via Stable Coating of TiO₂ Nanoparticles.
The high photocatalytic power of TiO₂ nanoparticles has drawn great attention in environmental and medical applications. Coating surfaces with these particles enables us to benefit from self-cleaning properties and decomposition of pollutants. In this paper, two strategies have been introduced to coat ceramic tiles with TiO₂ nanoparticles, and the self-cleaning effect of the surfaces on degradation of an organic dye under ultraviolent (UV) exposure is investigated. In the first approach, a simple one-step heat treatment method is introduced for coating, and different parameters of the heat treatment process are examined. In the second method, TiO₂ nanoparticles are first aminosilanized using (3-Aminopropyl)triethoxysilane (APTES) treatment followed by their covalently attachment onto CO₂ plasma treated ceramic tiles via N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) and N-Hydroxysuccinimide (NHS) chemistry. We monitor TiO₂ nanoparticle sizes throughout the coating process using dynamic light scattering (DLS) and characterize developed surfaces using X-ray photoelectron spectroscopy (XPS). Moreover, hydrophilicity of the coated surfaces is quantified using a contact angle measurement. It is shown that applying a one-step heat treatment process with the optimum temperature of 200 °C for 5 h results in successful coating of nanoparticles and rapid degradation of dye in a short time. In the second strategy, the APTES treatment creates a stable covalent coating, while the photocatalytic capability of the particles is preserved. The results show that coated ceramic tiles are capable of fully degrading the added dyes under UV exposure in less than 24 h.


Confirmation of association between multiple sclerosis and CYP27B1.
Multiple sclerosis, MS (OMIM No. 126200), is a complex inflammatory disease that is characterized by lesions in the central nervous system. Both genes and other environmental factors influence disease susceptibility. One of the environmental factors that has been implicated in MS and autoimmune disease, such as type 1 diabetes, is vitamin D deficiency, in which patients have lower levels of 25-hydroxyvitamin D3 (25-OHD(3)) in blood than do controls. Previtamin D(3) is produced in the skin, and turned into 25-OHD(3) in the liver. In the kidney, skin and immune cells, 25-OHD(3) is turned into bioactive 1,25(OH)(2)D(3) by the enzyme coded by CYP27B1 (cytochrome P450 family 27 subfamily B peptide 1) on chromosome 12q13.1-3. 1,25(OH)(2)D(3) binds to the vitamin D receptor, expressed in T cells and antigen-presenting cells. 1,25(OH)(2)D(3) has a suppressive role in the adaptive immune system, decreasing T-cell and dendritic cell maturation, proliferation and differentiation, shifting the balance between T-helper 1 (Th1) and Th2 cells in favor of Th2 cells and increasing the suppressive function of regulatory T cells. Rs703842 in the 12q13-14 region was associated with MS in a recent study by the Australian and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene). We show associations with three SNPs in this region in our Swedish materials (2158 cases, 1759 controls) rs4646536, rs10877012 and rs10877015 (P=0.01, 0.01 and 3.5 × 10(-3), respectively). We imputed rs703842 SNP and performed a joint analysis with the ANZgene results, reaching a significant association for rs703842 (P=5.1 × 10(-11); odds ratio 0.83; 95% confidence interval 0.79-0.88). Owing to its close association with 25-OHD(3), our results lend further support to the role of vitamin D in MS pathology.


Regular fish consumption and age-related brain gray matter loss.
Brain health may be affected by modifiable lifestyle factors; consuming fish and antioxidative omega-3 fatty acids may reduce brain structural abnormality risk. To determine whether dietary fish consumption is related to brain structural integrity among cognitively normal elders. Data were analyzed from 260 cognitively normal individuals from the Cardiovascular Health Study with information on fish consumption from the National Cancer Institute Food Frequency Questionnaire and brain magnetic resonance imaging (MRI). The relationship between fish consumption data collected in 1989-1990 and brain structural MRI obtained in 1998-1999 was assessed using voxel-based morphometry in multiple regression analyses in 2012. Covariates were age, gender, race, education, white matter lesions, MRI-identified infarcts, waist-hip ratio, and physical activity as assessed by the number of city blocks walked in 1 week. Volumetric changes were further modeled with omega-3 fatty acid estimates to better understand the mechanistic link between fish consumption, brain health, and Alzheimer disease. Weekly consumption of baked or broiled fish was positively associated with gray matter volumes in the hippocampus, precuneus, posterior cingulate, and orbital frontal cortex even after adjusting for covariates. These results did not change when including omega-3 fatty acid estimates in the analysis. Dietary consumption of baked or broiled fish is related to larger gray matter volumes independent of omega-3 fatty acid content. These findings suggest that a confluence of lifestyle factors influence brain health, adding to the growing body of evidence that prevention strategies for late-life brain health need to begin decades earlier.


The arcuate nucleus and the control of gonadotropin and prolactin secretion in the female rhesus monkey (Macaca mulatta).
Attempts were made to destroy selectively the arcuate nucleus with radiofrequency current in adult female rhesus monkeys as a first step in identifying the areas of the mediobasal hypothalamus (MBH) that are responsible for the neural control of gonadotropin secretion in this species. Extensive or complete destruction of the arcuate region was produced in three animals and in two of these the lesion was confined primarily to the arcuate region and the dorsal aspect of the posterior median eminence. These lesions resulted in the cessation of LH and FSH secretion and blocked the positive feedback action of estradiol on gonadotropin release but did not appear to influence grossly basal thyroid and adrenocortical function, or to abolish GH discharge in response to insulin hypoglycemia. Adenohypophysial infarcts were not observed and exogenous LHRH and TRH induced marked discharges of the appropriate anterior pituitary hormones. In two additional animals with large hypothalamic lesions, destruction of the arcuate region was incomplete. In this group only partial inhibition of gonadotropin secretion was observed. LH and FSH secretion did not appear to be influenced in one animal bearing a large MBH lesion that entirely spared the arcuate region. Although serum prolactin remained at pre-lesion control levels after placement of the two relatively discrete lesions confined to the arcuate region, unambiguous increases in the secretion of this hormone were observed when the area of destruction encompassed tissue anterior and/or dorsal to the arcuate region. These observations suggest that the arcuate region is the primary structure mediating the hypothalamic control of gonadotropin secretion in the rhesus monkey. They also suggest that, in this species, the regions of the MBH involved with the regulation of gonadotropin release and those which control prolactin secretion are anatomically distinct.


IUGR decreases elastin mRNA expression in the developing rat lung and alters elastin content and lung compliance in the mature rat lung.
Complications of intrauterine growth restriction (IUGR) include increased pulmonary morbidities and impaired alveolar development. Normal alveolar development depends upon elastin expression and processing, as well as the formation and deposition of elastic fibers. This is true of the human and rat. In this study, we hypothesized that uteroplacental insufficiency (UPI)-induced IUGR decreases mRNA levels of elastin and genes required for elastin fiber synthesis and assembly, at birth (prealveolarization) and postnatal day 7 (midalveolarization) in the rat. We further hypothesized that this would be accompanied by reduced elastic fiber deposition and increased static compliance at postnatal day 21 (mature lung). We used a well characterized rat model of IUGR to test these hypotheses. IUGR decreases mRNA transcript levels of genes essential for elastic fiber formation, including elastin, at birth and day 7. In the day 21 lung, IUGR decreases elastic fiber deposition and increases static lung compliance. We conclude that IUGR decreases mRNA transcript levels of elastic fiber synthesis genes, before and during alveolarization leading to a reduced elastic fiber density and increased static lung compliance in the mature lung. We speculate that the mechanism by which IUGR predisposes to pulmonary disease may be via decreased lung elastic fiber deposition.


Allele-specific B pocket transplant in class I major histocompatibility complex protein changes requirement for anchor residue at P2 of peptide.
To investigate the role of an anchoring pocket in allele-specific peptide presentation by a major histocompatibility complex class I molecule, we "transplanted" a B pocket from HLA-A*0201 into HLA-B*2705 by site-directed mutagenesis. The resulting protein, designated B27.A2B, binds a different set of endogenous peptides than B*2705 as evidenced by complete loss of allorecognition as well as restored expression in the antigen processing-defective mutant cell line T2. B27.A2B also fails to present an HLA-B27-restricted influenza virus peptide [nucleoprotein (383-391)] to cytotoxic T lymphocytes (CTLs). However, substitution of leucine, the predominant P2 anchor residue in A*0201-restricted peptides, for arginine, the P2 anchor in nucleoprotein-(383-391) and other B*2705-restricted peptides, restores recognition of B27.A2B by the same B*2705-restricted peptide-specific CTLs. These results demonstrate that a dominant polymorphic pocket in a class I molecule, through interaction with the anchor residue of an antigenic peptide, can distinguish among peptides differing by only a single amino acid and thus determine the allelic specificity of peptide presentation.


The Not-so-Staggering Effect of Staggered Animated Transitions on Visual Tracking.
Interactive visual applications often rely on animation to transition from one display state to another. There are multiple animation techniques to choose from, and it is not always clear which should produce the best visual correspondences between display elements. One major factor is whether the animation relies on staggering-an incremental delay in start times across the moving elements. It has been suggested that staggering may reduce occlusion, while also reducing display complexity and producing less overwhelming animations, though no empirical evidence has demonstrated these advantages. Work in perceptual psychology does show that reducing occlusion, and reducing inter-object proximity (crowding) more generally, improves performance in multiple object tracking. We ran simulations confirming that staggering can in some cases reduce crowding in animated transitions involving dot clouds (as found in, e.g., animated 2D scatterplots). We empirically evaluated the effect of two staggering techniques on tracking tasks, focusing on cases that should most favour staggering. We found that introducing staggering has a negligible, or even negative, impact on multiple object tracking performance. The potential benefits of staggering may be outweighed by strong costs: a loss of common-motion grouping information about which objects travel in similar paths, and less predictability about when any specific object would begin to move. Staggering may be beneficial in some conditions, but they have yet to be demonstrated. The present results are a significant step toward a better understanding of animation pacing, and provide direction for further research.


A symbolic investigation of superspreaders.
Superspreaders are an important phenomenon in the spread of infectious disease, accounting for a higher than average number of new infections in the population. We use mathematical models to compare the impact of supershedders and supercontacters on population dynamics. The stochastic, individual based models are investigated by conversion to deterministic, population level Mean Field Equations, using process algebra. The mean emergent population dynamics of the models are shown to be equivalent with and without superspreaders; however, simulations confirm expectations of differences in variability, having implications for individual epidemics.


Apathy is not associated with reduced ventral striatal volume in patients with schizophrenia.
A growing body of neuroimaging research has revealed a relationship between blunted activation of the ventral striatum (VS) and apathy in schizophrenia. In contrast, the association between reduced striatal volume and apathy is less well established, while the relationship between VS function and structure in patients with schizophrenia remains an open question. Here, we aimed to replicate previous structural findings in a larger independent sample and to investigate the relationship between VS hypoactivation and VS volume. We included brain structural magnetic resonance imaging (MRI) data from 60 patients with schizophrenia (SZ) that had shown an association of VS hypoactivation with apathy during reward anticipation and 58 healthy controls (HC). To improve replicability, we applied analytical methods employed in two previously published studies: Voxel-based morphometry and the Multiple Automatically Generated Templates (MAGeT) algorithm. VS and dorsal striatum (DS) volume were correlated with apathy correcting for age, gender and total brain volume. Additionally, left VS activity was correlated with left VS volume. We failed to replicate the association between apathy and reduced VS volume and did not find a correlation with DS volume. Functional and structural left VS measures exhibited a trend-level correlation (rs = 0.248, p = 0.067, r2 = 0.06). Our present data suggests that functional and structural striatal neuroimaging correlates of apathy can occur independently. Replication of previous findings may have been limited by other factors (medication, illness duration, age) potentially related to striatal volume changes in SZ. Finally, associations between reward-related VS function and structure should be further explored.


The use of a new passive sampler for ozone and nitrogen oxides monitoring in ecological effects research.
A simple, cost-effective diffusive sampler is described that is suitable for measuring parts per billion (ppb) levels of ozone and nitrogen oxides. The diffusive sampler makes use of nitrite for ozone determination whereas for nitrogen oxides and nitrogen dioxide an active carbon tissue impregnated with sodium carbonate is used. Nitrate and nitrite, the formation of which is proportional to the pollutant concentration and sampling duration, are the two species analysed, respectively. Diffusion tubes have the advantage of being a low- cost, convenient way of mapping spatial distributions and investigating long-term trends of ozone and nitrogen oxides. The method is extremely useful for assessing long-term concentrations such as the annual mean for nitrogen oxides, as required by the Daughter Directive 1999/30/EC. Field tests to validate the method have been carried out at an urban background location with co-located passive samplers and continuous measurements of O3 and NOx. An application in ecological effects monitoring for ozone is also presented.


Overexpression, purification, and characterization of VanX, a D-, D-dipeptidase which is essential for vancomycin resistance in Enterococcus faecium BM4147.
Vancomycin resistance in Enterococcus faecium requires five genes: vanR, vanS, vanH, vanA, and vanX. The functions and mechanism of four gene products have been known, with VanR/S for signal transduction and transcriptional regulation and VanH/A to synthesize D-Ala-D-lactate. But the function of the fifth gene product, VanX, has been unknown until very recently, when Reynolds and colleagues discovered D-, D-dipeptidase activity in crude extracts of a VanX overproducer [Reynolds, P. E., et al. (1994) Mol. Microbiol. 13, 1065-1070]. We report here the expression of VanX in Escherichia coli and its purification to homogeneity. VanX has been characterized as a metal-activated D-, D-dipeptidase with an optimal pH range of 7-9. The kcat and Km of D-Ala-D-Ala in the absence of divalent metal are determined to be 4.7 s-1 and 1 mM, respectively. However, in the presence of metal cations, kcat can be as high as 788 s-1. VanX is unable to hydrolyze D-Ala-D-lactate, the substituted moiety in the peptidoglycan that leads to vancomycin resistance, not only because of low binding affinity (Ki estimated at 242 mM) but also due to a kcat less than 0.005 s-1. The more than 10(5)-fold differential in catalytic efficiency of VanX for hydrolysis of D-Ala-D-Ala vs D-Ala-D-lactate leaves D-Ala-D-lactate intact for subsequent incorporation into peptidoglycan.(ABSTRACT TRUNCATED AT 250 WORDS)


Developing and piloting a peer mentoring intervention to reduce teenage pregnancy in looked-after children and care leavers: an exploratory randomised controlled trial.
Looked-after children (LAC) are at greater risk of teenage pregnancy than non-LAC, which is associated with adverse health and social consequences. Existing interventions have failed to reduce rates of teenage pregnancy in LAC. Peer mentoring is proposed as a means of addressing many of the factors associated with the increased risk of teenage pregnancy in this group. To develop a peer mentoring intervention to reduce teenage pregnancy in LAC. Phase I and II randomised controlled trial of a peer mentoring intervention for LAC; scoping exercise and literature search; national surveys of social care professionals and LAC; and focus groups and interviews with social care professionals, mentors and mentees. Three local authorities (LAs) in England. LAC aged 14-18 years (mentees/care as usual) and 19-25 years (mentors). Recruitment and training of mentors; randomisation and matching of mentors to mentees; and 1-year individual peer mentoring. pregnancy in LAC aged 14-18 years. sexual attitudes, behaviour and knowledge; psychological health; help-seeking behaviour; locus of control; and attachment style. A health economic evaluation was also carried out. In total, 54% of target recruitment was reached for the exploratory trial and 13 out of 20 mentors (65%) and 19 out of 30 LAC aged 14-18 years (63%) (recruited during Phases I and II) were retained in the research. The training programme was acceptable and could be manualised and replicated. Recruitment and retention difficulties were attributed to systemic problems and LA lack of research infrastructure and lack of additional funding to support and sustain such an intervention. Mentees appeared to value the intervention but had difficulty in meeting weekly as required. Only one in four of the relationships continued for the full year. A future Phase III trial would require the intervention to be modified to include provision of group and individual peer mentoring; internal management of the project, with support from an external agency such as a charity or the voluntary sector; funds to cover LA research costs, including the appointment of a dedicated project co-ordinator; a reduction in the lower age for mentee recruitment and an increase in the mentor recruitment age to 21 years; and the introduction of a more formal recruitment and support structure for mentors. Given the problems identified and described in mounting this intervention, a new development phase followed by a small-scale exploratory trial incorporating these changes would be necessary before proceeding to a Phase III trial. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 85. See the NIHR Journals Library website for further project information.


Classification of the glyphosate target enzyme (5-enolpyruvylshikimate-3-phosphate synthase) for assessing sensitivity of organisms to the herbicide.
Glyphosate is the most common broad-spectrum herbicide. It targets the key enzyme of the shikimate pathway, 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), which synthesizes three essential aromatic amino acids (phenylalanine, tyrosine and tryptophan) in plants. Because the shikimate pathway is also found in many prokaryotes and fungi, the widespread use of glyphosate may have unsuspected impacts on the diversity and composition of microbial communities, including the human gut microbiome. Here, we introduce the first bioinformatics method to assess the potential sensitivity of organisms to glyphosate based on the type of EPSPS enzyme. We have precomputed a dataset of EPSPS sequences from thousands of species that will be an invaluable resource to advancing the research field. This novel methodology can classify sequences from nearly 90% of eukaryotes and >80% of prokaryotes. A conservative estimate from our results shows that 54% of species in the core human gut microbiome are sensitive to glyphosate.


The relationship between the functional complexity and the molecular organization of the Antennapedia locus of Drosophila melanogaster.
The Antp locus is involved in the development of the thorax of the larval and adult Drosophila. The absence of Antp+ function during embryogenesis results in the larval mesothorax exhibiting characteristics of the prothorax and an ensuing lethality; the loss of Antp+ function in the development of the adult thorax causes specific portions of the leg, wing and humeral imaginal discs to develop abnormally. Every Antp mutation, however, does not cause all of these developmental defects. Certain mutant alleles disrupt humeral and wing disc development without affecting leg development, and they are not deficient for the wild-type function required during embryogenesis. Other Antp mutations result in abnormal legs, but do not alter dorsal thoracic development. Mutations of each type can complement to produce a normal adult fly, which suggests that there are at least two discrete functional units within the locus. This hypothesis is supported by the fact that each of the developmental defects arises from the alteration of a different physical region within the Antp DNA. These observations indicate that the complete developmental role of the Antp locus is defined by the spatial and temporal regulation of the expression of several individual functional units.


Functional genomics in the study of mind-body therapies.
Mind-body therapies (MBTs) are used throughout the world in treatment, disease prevention, and health promotion. However, the mechanisms by which MBTs exert their positive effects are not well understood. Investigations into MBTs using functional genomics have revolutionized the understanding of MBT mechanisms and their effects on human physiology. We searched the literature for the effects of MBTs on functional genomics determinants using MEDLINE, supplemented by a manual search of additional journals and a reference list review. We reviewed 15 trials that measured global or targeted transcriptomic, epigenomic, or proteomic changes in peripheral blood. Sample sizes ranged from small pilot studies (n=2) to large trials (n=500). While the reliability of individual genes from trial to trial was often inconsistent, genes related to inflammatory response, particularly those involved in the nuclear factor-kappa B (NF-κB) pathway, were consistently downregulated across most studies. In general, existing trials focusing on gene expression changes brought about by MBTs have revealed intriguing connections to the immune system through the NF-κB cascade, to telomere maintenance, and to apoptotic regulation. However, these findings are limited to a small number of trials and relatively small sample sizes. More rigorous randomized controlled trials of healthy subjects and specific disease states are warranted. Future research should investigate functional genomics areas both upstream and downstream of MBT-related gene expression changes-from epigenomics to proteomics and metabolomics.


Bacterial mycophagy: definition and diagnosis of a unique bacterial-fungal interaction.
This review analyses the phenomenon of bacterial mycophagy, which we define as a set of phenotypic behaviours that enable bacteria to obtain nutrients from living fungi and thus allow the conversion of fungal into bacterial biomass. We recognize three types of bacterial strategies to derive nutrition from fungi: necrotrophy, extracellular biotrophy and endocellular biotrophy. Each is characterized by a set of uniquely sequential and differently overlapping interactions with the fungal target. We offer a detailed analysis of the nature of these interactions, as well as a comprehensive overview of methodologies for assessing and quantifying their individual contributions to the mycophagy phenotype. Furthermore, we discuss future prospects for the study and exploitation of bacterial mycophagy, including the need for appropriate tools to detect bacterial mycophagy in situ in order to be able to understand, predict and possibly manipulate the way in which mycophagous bacteria affect fungal activity, turnover, and community structure in soils and other ecosystems.


Changing the use of electronic fetal monitoring and labor support: a case study of barriers and facilitators.
Decreasing the use of continuous electronic fetal monitoring and increasing professional labor support for low-risk pregnancies are recommended by the Society of Obstetricians and Gynecologists of Canada. This study explored factors influencing the successful (and unsuccessful) introduction of an evidence-based fetal health surveillance guideline. This qualitative case study was conducted at two tertiary and one community hospital. Data were collected in 14 clinician focus groups (51 nurses), followed by 8 interviews with nurse administrators and educators. Analysis of verbatim transcripts and unit records included coding and categorizing data to form profiles that were compared across hospitals. Implementation of the guideline recommendations in the hospital settings was affected by many different factors originating in the practice environment, with the potential adopters, and related to the characteristics of the guideline. The influences of these diverse factors interacted sometimes to magnify or counteract each other's effect. The physical setting, adopter concerns, and the medicolegal issues surrounding the guideline played critical roles in uptake. In addition, changes preceding the introduction of the recommendations, the institution's agenda, and nursing and medical leadership influenced the uptake of guideline recommendations. The number and experience of nurses in each setting and availability of equipment also affected guideline acceptance and use. When implementing best practice, it is important to identify organizational barriers to the change that will need managing by the appropriate level of administration in the organization. Careful tailoring of implementation interventions to the barriers originating with the potential adopters is also necessary. Be prepared for unanticipated effects.


The Trp53 delta proline (Trp53ΔP) mouse exhibits increased genome instability and susceptibility to radiation-induced, but not spontaneous, tumor development.
The tumor suppressor TP53 can initiate a plethora of anti-proliferative effects to maintain genomic integrity under conditions of genotoxic stress. The N-terminal proline-rich domain (PRD) of TP53 is important in the regulation of TP53 activity and stability. A common polymorphism at codon 72 in this region has been associated with altered cancer risk in humans. The Trp53ΔP mouse, which carries a germline homozygous deletion of a region of the PRD, does not develop spontaneous tumors in a mixed 129/Sv and C57BL/6 genetic background, but is highly susceptible to a broad range of tumor types following total body exposure to 4 Gy gamma (γ) radiation. This contrasts with the tumor spectrum in Trp53 null (-/-) mice, which mainly develop thymic lymphomas and osteosarcomas. Analysis of genomic instability in tissues and cells from Trp53ΔP mice demonstrated elevated basal levels of aneuploidy, but this is not sufficient to drive spontaneous tumorigenesis, which requires an additional DNA damage stimulus. Levels of genomic instability did not increase significantly in Trp53ΔP mice following irradiation exposure, suggesting that other radiation effects including tissue inflammation, altered metabolism or autophagy, may play an important role. The Trp53ΔP mouse is a novel model to dissect the mechanisms of tumor development induced by radiation exposure. © 2015 Wiley Periodicals, Inc.


Increased midgestational IFN-γ, IL-4 and IL-5 in women bearing a child with autism: A case-control study.
Immune anomalies have been documented in individuals with autism spectrum disorders (ASDs) and their family members. It is unknown whether the maternal immune profile during pregnancy is associated with the risk of bearing a child with ASD or other neurodevelopmental disorders. Using Luminex technology, levels of 17 cytokines and chemokines were measured in banked serum collected from women at 15 to 19 weeks of gestation who gave birth to a child ultimately diagnosed with (1) ASD (n = 84), (2) a developmental delay (DD) but not autism (n = 49) or (3) no known developmental disability (general population (GP); n = 159). ASD and DD risk associated with maternal cytokine and chemokine levels was estimated by using multivariable logistic regression analysis. Elevated concentrations of IFN-γ, IL-4 and IL-5 in midgestation maternal serum were significantly associated with a 50% increased risk of ASD, regardless of ASD onset type and the presence of intellectual disability. By contrast, elevated concentrations of IL-2, IL-4 and IL-6 were significantly associated with an increased risk of DD without autism. The profile of elevated serum IFN-γ, IL-4 and IL-5 was more common in women who gave birth to a child subsequently diagnosed with ASD. An alternative profile of increased IL-2, IL-4 and IL-6 was more common for women who gave birth to a child subsequently diagnosed with DD without autism. Further investigation is needed to characterize the relationship between these divergent maternal immunological phenotypes and to evaluate their effect on neurodevelopment.


Histotype-specific copy-number alterations in ovarian cancer.
Epithelial ovarian cancer is characterized by multiple genomic alterations; most are passenger alterations which do not confer tumor growth. Like many cancers, it is a heterogeneous disease and can be broadly categorized into 4 main histotypes of clear cell, endometrioid, mucinous, and serous. To date, histotype-specific copy number alterations have been difficult to elucidate. The difficulty lies in having sufficient sample size in each histotype for statistical analyses. To dissect the heterogeneity of ovarian cancer and identify histotype-specific alterations, we used an in silico hypothesis-driven approach on multiple datasets of epithelial ovarian cancer. In concordance with previous studies on global copy number alterations landscape, the study showed similar alterations. However, when the landscape was de-convoluted into histotypes, distinct alterations were observed. We report here significant histotype-specific copy number alterations in ovarian cancer and showed that there is genomic diversity amongst the histotypes. 76 cancer genes were found to be significantly altered with several as potential copy number drivers, including ERBB2 in mucinous, and TPM3 in endometrioid histotypes. ERBB2 was found to have preferential alterations, where it was amplified in mucinous (28.6%) but deleted in serous tumors (15.1%). Validation of ERBB2 expression showed significant correlation with microarray data (p=0.007). There also appeared to be reciprocal relationship between KRAS mutation and copy number alterations. In mucinous tumors where KRAS mutation is common, the gene was not significantly altered. However, KRAS was significantly amplified in serous tumors where mutations are rare in high grade tumors. The study demonstrates that the copy number landscape is specific to the histotypes and identification of these alterations can pave the way for targeted drug therapy specific to the histotypes.


Motor intention determines sensory attenuation of brain responses to self-initiated sounds.
One of the functions of the brain is to predict sensory consequences of our own actions. In auditory processing, self-initiated sounds evoke a smaller brain response than passive sound exposure of the same sound sequence. Previous work suggests that this response attenuation reflects a predictive mechanism to differentiate the sensory consequences of one's own actions from other sensory input, which seems to form the basis for the sense of agency (recognizing oneself as the agent of the movement). This study addresses the question whether attenuation of brain responses to self-initiated sounds can be explained by brain activity involved in movement planning rather than movement execution. We recorded ERPs in response to sounds initiated by button presses. In one condition, participants moved a finger to press the button voluntarily, whereas in another condition, we initiated a similar, but involuntary, finger movement by stimulating the corresponding region of the primary motor cortex with TMS. For involuntary movements, no movement intention (and no feeling of agency) could be formed; thus, no motor plans were available to the forward model. A portion of the brain response evoked by the sounds, the N1-P2 complex, was reduced in amplitude following voluntary, self-initiated movements, but not following movements initiated by motor cortex stimulation. Our findings demonstrate that movement intention and the corresponding feeling of agency determine sensory attenuation of brain responses to self-initiated sounds. The present results support the assumptions of a predictive internal forward model account operating before primary motor cortex activation.


Employment trends during preschool years among mothers of term singletons born with low birth weight.
Children born at term with low birth weight (LBW) are regarded growth restricted and are at particular risk of adverse health outcomes requiring a high degree of parental participation in the day-to-day care. This study examined whether their increased risk of special health care needs compared to other children may influence mothers' opportunities for participation in the labor market at different times after delivery. Data from 32,938 participants in the population-based Norwegian Mother and Child Cohort Study with singleton children born at term in 2004-2006 were linked to national registers in order to investigate the mothers' employment status when their children were 1-3 years in 2007 and 4-6 years in 2010. Children weighing less than two standard deviations below the gender-specific mean were defined as LBW children. Although not significantly different from mothers of children in the normal weight range, mothers of LBW children had the overall highest level of non-employment when the children were 1-3 years. At child age 4-6 years on the other hand, LBW was associated with an increased risk of non-employment (RR 1.39: 95 % CI 1.11-1.75) also after adjustment for factors associated with employment in general. In accordance with employment trends in the general population, our findings show that while mothers of normal birth weight children re-enter the labor market as their children grow older, mothers of LBW children born at term participate to a lesser extent in paid employment and remain at levels similar to those of mothers with younger children.


Design, characterization, and aerosol dispersion performance modeling of advanced spray-dried microparticulate/nanoparticulate mannitol powders for targeted pulmonary delivery as dry powder inhalers.
The purpose was to design and characterize inhalable microparticulate/nanoparticulate dry powders of mannitol with essential particle properties for targeted dry powder delivery for cystic fibrosis mucolytic treatment by dilute organic solution spray drying, and, in addition, to tailor and correlate aerosol dispersion performance delivered as dry powder inhalers based on spray-drying conditions and solid-state physicochemical properties. Organic solution advanced spray drying from dilute solution followed by comprehensive solid-state physicochemical characterization and in vitro dry powder aerosolization were used. The particle size distribution of the spray-dried (SD) powders was narrow, unimodal, and in the range of ∼500 nm to 2.0 μm. The particles possessed spherical particle morphology, relatively smooth surface morphology, low water content and vapor sorption (crystallization occurred at exposure above 65% relative humidity), and retention of crystallinity by polymorphic interconversion. The emitted dose, fine particle fraction (FPF), and respirable fraction (RF) were all relatively high. The mass median aerodynamic diameters were below 4 μm for all SD mannitol aerosols. The in vitro aerosol deposition stage patterns could be tailored based on spray-drying pump rate. Positive linear correlation was observed between both FPF and RF values with spray-drying pump rates. The interplay between various spray-drying conditions, particle physicochemical properties, and aerosol dispersion performance was observed and examined, which enabled tailoring and modeling of high aerosol deposition patterns.


Trs130 participates in autophagy through GTPases Ypt31/32 in Saccharomyces cerevisiae.
Trs130 is a specific component of the transport protein particle II complex, which functions as a guanine nucleotide exchange factor (GEF) for Rab GTPases Ypt31/32. Ypt31/32 is known to be involved in autophagy, although the precise mechanism has not been thoroughly studied. In this study, we investigated the potential involvement of Trs130 in autophagy and found that both the cytoplasm-to-vacuole targeting (Cvt) pathway and starvation-induced autophagy were defective in a trs130ts (trs130 temperature-sensitive) mutant. Mutant cells could not transport Atg8 and Atg9 to the pre-autophagosomal structure/phagophore assembly site (PAS) properly, resulting in multiple Atg8 dots and Atg9 dots dispersed in the cytoplasm. Some dots were trapped in the trans-Golgi. Genetic studies showed that the effect of the Trs130 mutation was downstream of Atg5 and upstream of Atg1, Atg13, Atg9 and Atg14 on the autophagic pathway. Furthermore, overexpression of Ypt31 or Ypt32, but not of Ypt1, rescued autophagy defects in trs130ts and trs65ts (Trs130-HA Trs120-myc trs65Δ) mutants. Our data provide mechanistic insight into how Trs130 participates in autophagy and suggest that vesicular trafficking regulated by GTPases/GEFs is important in the transport of autophagy proteins from the trans-Golgi to the PAS.


It made my life a little easier: primary care providers' beliefs and attitudes about using opioid treatment agreements.
To understand primary care providers (PCPs)' experiences, beliefs, and attitudes about using opioid treatment agreements (OTAs) for patients with chronic pain. Qualitative research study. Twenty-eight internists and family medicine physicians at two health centers. Semistructured telephone interviews, informed by the Integrative Model of Behavioral Prediction. Themes were analyzed using a Grounded Theory approach, and similarities and differences in themes were examined among OTA adopters, nonadopters, and selective adopters. Participants were 64 percent female and 68 percent white, and practiced for a mean of 9.5 years. Adoption of OTAs varied: seven were adopters, five were nonadopters, and 16 were selective adopters. OTA adoption reflected PCPs' beliefs and attitudes in the following three thematic categories: 1) perceived effect of OTA use on the therapeutic alliance, 2) beliefs about the utility of OTAs for patients or providers, and 3) perception of patients' risk for opioid misuse. PCPs commonly believed that OTAs were useful for physician self-protection, but few believed that they prevent opioid misuse. Selective adopters expressed ambivalent beliefs and made decisions about OTA use for individual patients based on both observed data and a subjective sense of each patient's risk for misuse. Substantial variability in PCP use of OTAs reflects differences in PCP beliefs and attitudes. Research to understand the impact of OTA use on providers, patients, and the therapeutic alliance is urgently needed to guide best practices.


A case report of a renal anastomosing hemangioma and a literature review: an unusual variant histologically mimicking angiosarcoma.
Anastomosing hemangioma, a benign vascular neoplasm histologically simulating angiosarcoma, is newly recognized and has been described primarily in the genitourinary tract. Here, we present a case of renal anastomosing hemangioma originating in the left kidney of a 32-year-old Chinese man with detailed computerized tomography (CT) and enhanced CT image information. The patient had no obvious signs and symptoms. The tumor was incidentally found by color Doppler imaging during a routine heath check-up. Subsequently, a detailed CT and an enhanced CT scan were performed. The tumor was well demarcated, and mahogany brown lesions, which measured 2.6 cm in maximum diameter, were observed. Microscopically, the tumor shows a lobular architecture with alternating cellular areas composed of anastomosing sinusoidal capillary-sized vessels lined by hobnail endothelial cells and edematous, hyaline paucicellular areas. Cytologically, the tumor cells were generally bland and exhibited positivity for CD31 and CD34 immunohistochemically. The patient had good status without evidence of tumor recurrence 21 months after the surgery. We suggest that more attention should be focused on this rare renal hemangioma variant and that it should not be over-diagnosed as a malignance, particularly an angiosarcoma. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_159.


Benefits of napping and an extended duration of recovery sleep on alertness and immune cells after acute sleep restriction.
Understanding the interactions between sleep and the immune system may offer insight into why short sleep duration has been linked to negative health outcomes. We, therefore, investigated the effects of napping and extended recovery sleep after sleep restriction on the immune and inflammatory systems and sleepiness. After a baseline night, healthy young men slept for a 2-h night followed by either a standard 8-h recovery night (n=12), a 30-min nap (at 1 p.m.) in addition to an 8-h recovery night (n=10), or a 10-h extended recovery night (n=9). A control group slept 3 consecutive 8-h nights (n=9). Subjects underwent continuous electroencephalogram polysomnography and blood was sampled every day at 7 a.m. Leukocytes, inflammatory and atherogenesis biomarkers (high-sensitivity C-reactive protein, interleukin-8, myeloperoxidase, fibrinogen and apolipoproteins ApoB/ApoA), sleep patterns and sleepiness were investigated. All parameters remained unchanged in the control group. After sleep restriction, leukocyte and - among leukocyte subsets - neutrophil counts were increased, an effect that persisted after the 8-h recovery sleep, but, in subjects who had a nap or a 10-h recovery sleep, these values returned nearly to baseline. Inflammatory and atherogenesis biomarkers were unchanged except for higher myeloperoxidase levels after sleep restriction. The increased sleepiness after sleep restriction was reversed better in the nap and extended sleep recovery conditions. Saliva cortisol decreased immediately after the nap. Our results indicate that additional recovery sleep after sleep restriction provided by a midday nap prior to recovery sleep or a sleep extended night can improve alertness and return leukocyte counts to baseline values.


Construction of cis-regulatory input functions of yeast promoters.
Promoters contain a large number of binding sites for transcriptional factors transmitting signals from a variety of cellular pathways. The promoter processes these input signals and sets the level of gene expression, the output of the gene. Here, we describe how to design genetic constructs and measure gene expression to deliver data suitable for quantitative analysis. Synthetic genetic constructs are well suited to precisely control and measure gene expression to construct cis-regulatory input functions. These functions can be used to predict gene expression based on signal intensities transmitted to activators and repressors in the gene regulatory region. Simple models of gene expression are presented for competitive and noncompetitive repressions. Complex phenomena, exemplified by synergistic silencing, are modeled by reaction-diffusion equations.


Neurological Complications After Transcatheter Versus Surgical Aortic Valve Replacement in Intermediate-Risk Patients.
Neurological events after aortic valve interventions are associated with increased mortality and morbidity. Transcatheter aortic valve replacement (TAVR) is increasingly offered for lower-risk patients with severe aortic stenosis, previously considered candidates for surgical aortic valve replacement (SAVR). Differences in post-procedural neurological events have important implications in treatment allocation. The authors sought to analyze the neurological events in the randomized SURTAVI (Surgical Replacement and Transcatheter Aortic Valve Implantation) trial. Patients with severe, symptomatic aortic stenosis at intermediate surgical risk were randomized 1:1 to TAVR or SAVR. The rates of neurological events and quality of life were analyzed at 30 days, and 6 and 12 months post-procedure in a modified intention-to-treat population (mean age 79.8 ± 6.2 years; N = 1,660). The rates of early (30-day) stroke and post-procedural encephalopathy were higher after SAVR versus TAVR (5.4% vs. 3.3%; p = 0.031; and 7.8% vs. 1.6%; p < 0.001, respectively). At 12 months, the rate of stroke was not different between SAVR and TAVR (6.9% vs. 5.2%; p = 0.136). Early stroke and early encephalopathy resulted in an elevated mortality at 12 months in both treatment groups. Quality of life after an early stroke was significantly lower in SAVR versus TAVR patients at 30 days and was similar at 6 and 12 months. The early stroke rate was lower after TAVR than SAVR. In patients with early strokes, QOL improved earlier after TAVR. At 12-month follow-up, stroke rates and QOL were not different between TAVR and SAVR patients. (Surgical Replacement and Transcatheter Aortic Valve Implantation [SURTAVI]; NCT01586910).


Efficacy of ultrasound-guided bilateral erector spinae plane block in pediatric laparoscopic cholecystectomy: Case series.
Postoperative opioid administration can cause various side effects, such as drowsiness, respiratory distress, postoperative nausea, and vomiting. The use of non-opioid medications as part of a multimodal analgesia method has been increasingly suggested in the management of acute postsurgical pain. Erector spinae plane block (ESPB), which is a regional anesthesia technique, blocks both visceral and somatic nerve fibers. Though it is infrequently used in young patients, presently described is a series of cases in which ESPB was successfully used in the performance of pediatric laparoscopic cholecystectomy. Ultrasound-guided bilateral ESPB was performed on 4 patients who underwent a laparoscopic cholecystectomy. An injection of 0.25% bupivacaine was administered into the interfascial area on each side in the pre-incisional period after the anesthesia induction (total anesthetic: 2.5 mg/kg). Postoperative pain control was planned at 10 mg/kg intravenous paracetamol every 8 hours. Numeric rating scale pain scores were less than 3 points in the post-anesthetic care unit, and at 1, 2, 4, 8, 12, and 24 hours. No rescue analgesic (1 mg/kg tramadol) was needed. None of the typical complications, such as drowsiness or nausea, were observed and no block-related complications were recorded. Bilateral ESPB that is a part of multimodal analgesia regimen can provide effective analgesia for pediatric laparoscopic cholecystectomy patients in the first 24 hours postoperatively.


Incidental findings in the maxillofacial region detected by cone beam CT.
The purpose of this study was to determine the location, nature, and occurrence of incidental maxillofacial findings on cone beam computed tomography (CBCT) scans performed for maxillofacial diagnostic purposes. CBCT images of 207 consecutive patients (129 females and 78 males) were examined. The sample consisted of 85 temporomandibular joint (TMJ) disorder patients, 45 paranasal sinusitis patients, 30 obstructive sleep apnea syndrome patients, 15 implant patients, and 32 others. The overall rate of incidental findings was 92.8%. The highest rate of incidental findings was in the airway area (51.8%), followed by impacted teeth (21.7%), TMJ findings (11.1%), endodontic lesions (4.3%), condensing osteitis (1%), and others (2.9%). The airway incidental findings included mucosal thickening (21.3%), deviation of the nasal septum (12.6%), conchal hypertrophy (11.1%), bullous concha (3.9%), and retention cysts (2.9%). The impacted teeth consisted of third molars (18.8%) and canines (2.9%). The incidental findings for the TMJ patients were erosion of the condyle (4.8%), osteophytes (3.4%), and bifid condyle (2.9%). Oral radiologists should be aware of possible incidental findings and should be vigilant about comprehensively evaluating possible underlying diseases.


Are Extracted Materials Truly Representative of Original Samples? Impact of C18 Extraction on CDOM Optical and Chemical Properties.
Some properties of dissolved organic matter (DOM) and chromophoric dissolved organic matter (CDOM) can be easily measured directly on whole waters, while others require sample concentration and removal of natural salts. To increase CDOM content and eliminate salts, solid phase extraction (SPE) is often employed. Biases following extraction and elution are inevitable, thus raising the question of how truly representative the extracted material is of the original. In this context, we investigated the wavelength dependence of extraction efficiency for C18 cartridges with respect to CDOM optical properties using samples obtained from the Middle Atlantic Bight (MAB) and the Equatorial Atlantic Ocean (EAO). Further, we compared the optical changes of C18 extracts and the corresponding whole water following chemical reduction with sodium borohydride (NaBH4). C18 cartridges preferentially extracted long-wavelength absorbing/emitting material for samples impacted by riverine input. Extraction efficiency overall decreased with offshore distance away from riverine input. Spectral slopes of C18-OM samples were also almost always lower than those of their corresponding CDOM samples supporting the preferential extraction of higher molecular weight absorbing material. The wavelength dependence of the optical properties (absorption, fluorescence emission, and quantum yield) of the original water samples and their corresponding extracted material were very similar. C18 extracts and corresponding water samples further exhibited comparable optical changes following NaBH4 reduction, thus suggesting a similarity in nature (structure) of the optically active extracted material, independent of geographical locale. Altogether, these data suggested a strong similarity between C18 extracts and corresponding whole waters, thus indicating that extracts are representative of the CDOM content of original waters.


Analysis of chemotaxis when the fraction of responsive cells is small--application to mammalian sperm guidance.
The detection of chemotaxis-related changes in the swimming behavior of mammalian spermatozoa in a spatial chemoattractant gradient has hitherto been an intractable problem. The difficulty is that the fraction of responsive cells in the sperm population is very small and that the large majority of the cells, though non-responsive, are motile too. Assessment of the chemotactic effects in a spatial gradient is also very sensitive to the quality of sperm tracking. To overcome these difficulties we propose a new approach, based on the analysis of the distribution of instantaneous directionality angles made by spermatozoa in a spatial gradient versus a no-gradient control. Although the use of this parameter does not allow identification of individual responding cells, it is a reliable measure of directionality, independent of errors in cell tracking caused by cell collisions, track crossings, and track splitting. The analysis identifies bias in the swimming direction of a population relative to the gradient direction. It involves statistical chi2 tests of the very large sample of measured angles, where the critical chi2 values are adjusted to the sample size by the bootstrapping procedure. The combination of the newly measured parameter and the special analysis provides a highly sensitive method for the detection of a chemotactic response, even a very small one.


Transcriptional profiling of human cavernosal endothelial cells reveals distinctive cell adhesion phenotype and role for claudin 11 in vascular barrier function.
To determine specific molecular features of endothelial cells (ECs) relevant to the physiological process of penile erection we compared gene expression of human EC derived from corpus cavernosum of men with and without erectile dysfunction (HCCEC) to coronary artery (HCAEC) and umbilical vein (HUVEC) using Affymetrix GeneChip microarrays and GeneSifter software. Genes differentially expressed across samples were partitioned around medoids to identify genes with highest expression in HCCEC. A total of 190 genes/transcripts were highly expressed only in HCCEC. Gene Ontology classification indicated cavernosal enrichment in genes related to cell adhesion, extracellular matrix, pattern specification and organogenesis. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed high expression of genes relating to ECM-receptor interaction, focal adhesions, and cytokine-cytokine receptor interaction. Real-time PCR confirmed expression differences in cadherins 2 and 11, claudin 11 (CLDN11), desmoplakin, and versican. CLDN11, a component of tight junctions not previously described in ECs, was highly expressed only in HCCEC and its knockdown by siRNA significantly reduced transendothelial electrical resistance in HCCEC. Overall, cavernosal ECs exhibited a transcriptional profile encoding matrix and adhesion proteins that regulate structural and functional characteristics of blood vessels. Contribution of the tight junction protein CLDN11 to barrier function in endothelial cells is novel and may reflect hemodynamic requirements of the corpus cavernosum.


In vivo human 3D cardiac fibre architecture: reconstruction using curvilinear interpolation of diffusion tensor images.
In vivo imaging of the cardiac 3D fibre architecture is still a challenge, but it would have many clinical applications, for instance to better understand pathologies and to follow up remodelling after therapy. Recently, cardiac MRI enabled the acquisition of Diffusion Tensor images (DTI) of 2D slices. We propose a method for the complete 3D reconstruction of cardiac fibre architecture in the left ventricular myocardium from sparse in vivo DTI slices. This is achieved in two steps. First we map non-linearly the left ventricular geometry to a truncated ellipsoid. Second, we express coordinates and tensor components in Prolate Spheroidal System, where an anisotropic Gaussian kernel regression interpolation is performed. The framework is initially applied to a statistical cardiac DTI atlas in order to estimate the optimal anisotropic bandwidths. Then, it is applied to in vivo beating heart DTI data sparsely acquired on a healthy subject. Resulting in vivo tensor field shows good correlation with literature, especially the elevation (helix) angle transmural variation. To our knowledge, this is the first reconstruction of in vivo human 3D cardiac fibre structure. Such approach opens up possibilities in terms of analysis of the fibre architecture in patients.


Do low-mercury terrestrial resources subsidize low-mercury growth of stream fish? Differences between species along a productivity gradient.
Low productivity in aquatic ecosystems is associated with reduced individual growth of fish and increased concentrations of methylmercury (MeHg) in fish and their prey. However, many stream-dwelling fish species can use terrestrially-derived food resources, potentially subsidizing growth at low-productivity sites, and, because terrestrial resources have lower MeHg concentrations than aquatic resources, preventing an increase in diet-borne MeHg accumulation. We used a large-scale field study to evaluate relationships among terrestrial subsidy use, growth, and MeHg concentrations in two stream-dwelling fish species across an in-stream productivity gradient. We sampled young-of-the-year brook trout (Salvelinus fontinalis) and Atlantic salmon (Salmo salar), potential competitors with similar foraging habits, from 20 study sites in streams in New Hampshire and Massachusetts that encompassed a wide range of aquatic prey biomass. Stable isotope analysis showed that brook trout used more terrestrial resources than Atlantic salmon. Over their first growing season, Atlantic salmon tended to grow larger than brook trout at sites with high aquatic prey biomass, but brook grew two-fold larger than Atlantic salmon at sites with low aquatic prey biomass. The MeHg concentrations of brook trout and Atlantic salmon were similar at sites with high aquatic prey biomass and the MeHg concentrations of both species increased at sites with low prey biomass and high MeHg in aquatic prey. However, brook trout had three-fold lower MeHg concentrations than Atlantic salmon at low-productivity, high-MeHg sites. These results suggest that differential use of terrestrial resource subsidies reversed the growth asymmetry between potential competitors across a productivity gradient and, for one species, moderated the effect of low in-stream productivity on MeHg accumulation.


Pupil dilation dynamics track attention to high-level information.
It has long been thought that the eyes index the inner workings of the mind. Consistent with this intuition, empirical research has demonstrated that pupils dilate as a consequence of attentional effort. Recently, Smallwood et al. (2011) demonstrated that pupil dilations not only provide an index of overall attentional effort, but are time-locked to stimulus changes during attention (but not during mind-wandering). This finding suggests that pupil dilations afford a dynamic readout of conscious information processing. However, because stimulus onsets in their study involved shifts in luminance as well as information, they could not determine whether this coupling of stimulus and pupillary dynamics reflected attention to low-level (luminance) or high-level (information) changes. Here, we replicated the methodology and findings of Smallwood et al. (2011) while controlling for luminance changes. When presented with isoluminant digit sequences, participants' pupillary dilations were synchronized with stimulus onsets when attending, but not when mind-wandering. This replicates Smallwood et al. (2011) and clarifies their finding by demonstrating that stimulus-pupil coupling reflects online cognitive processing beyond sensory gain.


Are there specific disabilities of number processing in adolescent patients with Anorexia nervosa? Evidence from clinical and neuropsychological data when compared to morphometric measures from magnetic resonance imaging.
The cerebral effect of the loss of body weight in Anorexia nervosa (A.n.)--the so-called 'pseudoatrophy'-- is well known and confirmed by several neuroimaging studies. Another subject of intensive research has been whether A.n. leads to specific cognitive impairments, especially of intelligence. However, there are no previous studies on the relations between the cerebral changes, intelligence performance, and disorders of number processing in adolescent patients with A.n. We examined n = 18 inpatients with A.n. (means at admission: age 14.5 years, SD 1.59; BMI 14.9, SD 1.36), diagnosed according to ICD-10 criteria at three different timepoints: at admission to treatment (T1), with 50 % restoration of their normal weight (T2), and with normal weight (T3). At each timepoint, a cerebral MRI scan was obtained. Based on the MRI we determined the volume of the external and internal cerebrospinal fluid cavities, fissures of Sylvius, the surface of mesencephalon and pons, and surface and length of the Corpus callosum. At T1 and T3, a neuropsychological examination was conducted including tests of the general fluid ability and general cristallized ability of intelligence (CFT-20), as well as tests of vocabulary and number processing. The same instruments were given to a group of matched controls (means: age 15.8 years, SD 1.57; BMI 20.5, SD 2.3) at one timepoint. We could show a significant volume difference of the lateral ventricles and the fissure of Sylvius between patients at T, and controls, which abaded with the patient's weight restoration. But a significant surface deficit of the mesencephalon, and less pronounced in the pons, persisted to T3 in patients when compared to controls, suggesting a selectivity of the cerebral changes in A.n. The neuropsychological examinations revealed significant changes in test performance for both the general intelligence test and number processing. At T1 the number processing performance was significantly lower in patients when compared to controls. However, when the patients had restored their normal body weight, we found 2.02 % with a 'severe disorder of arithmetic skills' and 4.45 % with a 'functional disorder of arithmetic skills'. This combined prevalence of 6.47 % of patients with a subnormal arithmetic performance is analogous to that in the normal population.


Type 1 diabetes mellitus and components in drinking water and diet: a population-based, case-control study in Prince Edward Island, Canada.
To determine the relationship between the risk of type 1 diabetes (T1D) and daily intake of drinking water and dietary components, including nitrate, nitrite, and nitrosamines, during the year prior to diagnosis. Controls (n = 105) were matched by age at diagnosis and sex to T1D cases (n = 57) newly diagnosed during 2001-2004. Food consumption was assessed using a food frequency questionnaire. Locally available samples of foods were tested for nitrate, nitrite, and nitrosamine concentrations. Water consumption was determined through an additional questionnaire, and water samples were taken from homes and tested for routine chemical components, including nitrate. After controlling for age, age, sex, and daily energy intake, nitrate intake from food sources showed a non-significant positive trend (odds ratios and 95% confidence intervals for quartiles = 1.00, 1.63 (0.58, 4.63), 1.71 (0.54, 5.40), 3.02 (0.78, 11.74); p for trend = 0.13). Nitrite and nitrosamine intake were not related to T1D risk (p for trend = 0.77 and 0.81, respectively). When food and water components were combined, zinc and calcium intakes were marginally and inversely related to T1D risk (p for trend = 0.07 and 0.06, respectively). After further model adjustment of possible confounders and significant risk factors, an increased intake of caffeine marginally increased the risk of T1D (p = 0.07). Dietary components from both food and water sources may influence the risk of developing T1D in young persons.


Pinworm infestation mimicking crohns' disease.
We here report a case of a young man who presented to his general practitioner with diarrhea. Inflammatory bowel disease was suspected and a colonoscopy showed aphthous lesions suggestive of Crohns' disease but biopsies revealed eggs of Enterobius vermicularis. When treated for this parasite, his symptoms were alleviated and a followup colonoscopy revealed a normal colon and distal ileum. Enterobius vermicularis is the most common parasite worldwide and has been attributed with many different presentations and pathologies. It is therefore necessary to maintain vigilance, even in high-income countries, in order to diagnose patients with one of the many atypical presentations of pinworms.


No association between vitamin D deficiency and markers of bone health in athletes.
Adequate vitamin D (25(OH)D) is required to maintain good bone health, yet many athletes are 25(OH)D deficient. This study sought to examine the relation between serum 25(OH)D and measures of bone health (bone mineral density (BMD) and T-score) in an ethnically diverse athletic population. Nine hundred and fifty male athletes presented for precompetition medical assessment in our facility. An additional 436 individuals registered with a Qatari sporting federation (such as sailing, archery, shooting, bowling) but exercising <2 h·wk were used as control population. There were 30 Asian, 242 Black African, 235 Caucasian, 491 from Gulf Cooperation Countries, 336 Middle Eastern, and 52 Persian participants. All individuals undertook bone densitometry and body composition analysis by dual-energy x-ray absorptiometry and serum 25(OH)D evaluation. From 950 athletes, 17.5% demonstrated severe deficiency, 39.2% demonstrated deficiency, 24.5% demonstrated insufficiency, and 18.8% demonstrated sufficiency, compared with 436 controls, 25.9% of whom demonstrated severe deficiency, 46.3% demonstrated deficiency, 19.0% demonstrated insufficiency, and 8.7% demonstrated sufficiency. No athlete presented with a T-score suggestive of osteoporosis (-2.5 SD) or osteopenia (-1.0 SD) at hip total. After adjustment for age, anthropometry, ethnicity, and athletic participation, there was no association between 25(OH)D and any BMD and T-score at any site within athletes. African and Caucasian athletes present with greater (P < 0.05) BMD and T-scores at the spine, neck, and hip total than those of Asian, Gulf Cooperation Countries, Middle Eastern, and Persian ethnicities. Athletes participating in high-impact sports present with higher measures (P < 0.05) of bone health than control participants regardless of 25(OH)D status. There is no association between 25(OH)D and BMD and T-score for any site within male athletes after adjusting for age, ethnicity, and sporting participation.


Host-related factors explaining interindividual variability of carotenoid bioavailability and tissue concentrations in humans.
Carotenoid dietary intake and their endogenous levels have been associated with a decreased risk of several chronic diseases. There are indications that carotenoid bioavailability depends, in addition to the food matrix, on host factors. These include diseases (e.g. colitis), life-style habits (e.g. smoking), gender and age, as well as genetic variations including single nucleotide polymorphisms that govern carotenoid metabolism. These are expected to explain interindividual differences that contribute to carotenoid uptake, distribution, metabolism and excretion, and therefore possibly also their association with disease risk. For instance, digestion enzymes fostering micellization (PNLIP, CES), expression of uptake/efflux transporters (SR-BI, CD36, NPC1L1), cleavage enzymes (BCO1/2), intracellular transporters (FABP2), secretion into chylomicrons (APOB, MTTP), carotenoid metabolism in the blood and liver (LPL, APO C/E, LDLR), and distribution to target tissues such as adipose tissue or macula (GSTP1, StARD3) depend on the activity of these proteins. In addition, human microbiota, e.g. via altering bile-acid concentrations, may play a role in carotenoid bioavailability. In order to comprehend individual, variable responses to these compounds, an improved knowledge on intra-/interindividual factors determining carotenoid bioavailability, including tissue distribution, is required. Here, we highlight the current knowledge on factors that may explain such intra-/interindividual differences.


Longitudinal relationship between expressed emotion and cannabis misuse in young people with first-episode psychosis.
Carers' expressed emotion (EE) and patients' cannabis misuse are two of the most robust predictors of psychotic relapse. We aimed to examine the temporal relationship between EE and cannabis misuse. Sixty-three key carers of young people with first-episode psychosis (FEP) were assessed at baseline and 7-month follow-up. EE was measured in carers using the Family Questionnaire (FQ) and cannabis misuse in patients using the Alcohol, Smoking and Substance Involvement Screening Test (ASSIST). Correlational and hierarchical logistic regression analyses were conducted to examine the temporal relationship between EE components (i.e. criticism and emotional over involvement) and cannabis misuse. Carers' criticism at baseline significantly predicted cannabis misuse according to the ASSIST at 7-month follow-up. The association remained significant after controlling for baseline symptom severity and social functioning (B=0.15, P=.02). Conversely, baseline cannabis misuse was not associated with carers' criticism at 7-month follow-up. Patients in families with high criticism showed a tendency to increase cannabis misuse over time whereas the opposite trend was observed in those with carers with low criticism. A family environment characterized by high criticism may become a key risk factor for worsening cannabis misuse over time in young people with FEP. Further studies should investigate the potential mechanisms (e.g., patient's anxiety or perceived stress) through which criticism increases cannabis misuse in FEP.


Definitive hematopoietic stem/progenitor cells manifest distinct differentiation output in the zebrafish VDA and PBI.
One unique feature of vertebrate definitive hematopoiesis is the ontogenic switching of hematopoietic stem cells from one anatomical compartment or niche to another. In mice, hematopoietic stem cells are believed to originate in the aorta-gonad-mesonephros (AGM), subsequently migrate to the fetal liver (FL) and finally colonize the bone marrow (BM). Yet, the differentiation potential of hematopoietic stem cells within early niches such as the AGM and FL remains incompletely defined. Here, we present in vivo analysis to delineate the differentiation potential of definitive hematopoietic stem/progenitor cells (HSPCs) in the zebrafish AGM and FL analogies, namely the ventral wall of dorsal aorta (VDA) and the posterior blood island (PBI), respectively. Cell fate mapping and analysis of zebrafish runx1(w84x) and vlad tepes (vlt(m651)) mutants revealed that HSPCs in the PBI gave rise to both erythroid and myeloid lineages. However, we surprisingly found that HSPCs in the VDA were not quiescent but were uniquely adapted to generate myeloid but not erythroid lineage cells. We further showed that such distinct differentiation output of HSPCs was, at least in part, ascribed to the different micro-environments present in these two niches. Our results highlight the importance of niche in shaping the differentiation output of developing HSPCs.


Specific early-G1 blocks accompanied with stringent response in Saccharomyces cerevisiae lead to growth arrest in resting state similar to the G0 of higher eucaryotes.
Growth arrests of Saccharomyces cerevisiae cells in early G1 phase brought by various means were classified into two types according to the mode of growth recovery after release of the restraints against growth. The first type, including arrests caused by cdc25, cdc33, cdc35, and ils1 mutations at the nonpermissive temperature and also by sulfur starvation, showed a subsequent delay in the onset of budding when shifted back to permissive conditions. The length of the delay was positively correlated with the time that cells had been arrested. The second type, including those caused by cdc28 and cdc24 mutations and by alpha factor, did not affect the mode of growth recovery after the shift to permissive conditions irrespective of the time that cell proliferation had been restricted. Growth arrests of the first type seem to allow yeast cells to enter a resting state equivalent to the G0 state of higher eucaryotes because features of the G0 shown with lymphocytes and other cultured cells including unusually long delay before the growth recovery (L.H. Augenlicht and R. Baserga, 1974, Exp. Cell Res., 89:255-262; and Kumagai, J., H. Akiyama, S. Iwashita, H. lida, and I. Yahara, 1981, J. Immunol., 126:1249-1254) appeared to be associated with this type. We have noted that arrests of the first type were always accompanied with a stringent response of macromolecular synthesis and its partial release by cycloheximide. Mapping of arrest points along the path of the cell cycle by the reciprocal shift experiment suggested that arrest points in G1 that led to the G0-like arrest precede or are near the step sensitive to alpha-factor.