Opposing effects of antibiotics and germ-free status on neuropeptide systems involved in social behaviour and pain regulation.
Recent research has revealed that the community of microorganisms inhabiting the gut affects brain development, function and behaviour. In particular, disruption of the gut microbiome during critical developmental windows can have lasting effects on host physiology. Both antibiotic exposure and germ-free conditions impact the central nervous system and can alter multiple aspects of behaviour. Social impairments are typically displayed by antibiotic-treated and germ-free animals, yet there is a lack of understanding of the underlying neurobiological changes. Since the μ-opioid, oxytocin and vasopressin systems are key modulators of mammalian social behaviour, here we investigate the effect of experimentally manipulating the gut microbiome on the expression of these pathways. We show that social neuropeptide signalling is disrupted in germ-free and antibiotic-treated mice, which may contribute to the behavioural deficits observed in these animal models. The most notable finding is the reduction in neuroreceptor gene expression in the frontal cortex of mice administered an antibiotic cocktail post-weaning. Additionally, the changes observed in germ-free mice were generally in the opposite direction to the antibiotic-treated mice. Antibiotic treatment when young can impact brain signalling pathways underpinning social behaviour and pain regulation. Since antibiotic administration is common in childhood and adolescence, our findings highlight the potential adverse effects that antibiotic exposure during these key neurodevelopmental periods may have on the human brain, including the possible increased risk of neuropsychiatric conditions later in life. In addition, since antibiotics are often considered a more amenable alternative to germ-free conditions, our contrasting results for these two treatments suggest that they should be viewed as distinct models.


Pattern and distribution of pedestrian injuries in fatal road traffic accidental cases in Dharan, Nepal.
Road traffic injuries are one of the leading causes of death in the world. The present study aims at evaluation of pattern and distribution of injuries among pedestrians thereby planning successful measures to minimize fatalities. The present study was conducted in the Department of Forensic Medicine and Toxicology, B.P. Koirala Institute of Health Sciences, Dharan, Nepal. This study included 50 cases of pedestrian victims of fatal road traffic accident, brought for medico-legal postmortem examination. Highest number (17 or 21.3%) of fatalities occurred in the 41-50 years age group followed by the age group 31-40 years (15 or 18.7%). Male victims outnumbered female resulting in male to female ratio of 1.8:1. Most of the pedestrians were illiterate (26 or 32.5%) followed by those who were educated up to primary school (14 or 17.5%). Nearly half of the cases (38 or 47.5%), four or more wheelers - heavy vehicles - were involved. Fracture was the most common type of injuries (55 or 28.9%) followed by laceration (50 or 26.3%). In 44 (55%) cases, primary impact injuries were noted, secondary impact injuries in 55 (68.7%) cases, and secondary injuries in 62 (77.5%) cases. More than one-fourth (22 or 27.5%) of the deaths were due to pelvic and extremities injuries. Pedestrians, people who travel by foot, wheelchair, stroller, or similar means, are most vulnerable users of the road. Before head out on foot for a stroll, power walk, or errand, there are important safety tips to remember. A greater awareness about traffic rules will go a long way in curbing the incidence of fatal pedestrian accidents.


The H3K9 Methyltransferase G9a Represses E-cadherin and is Associated with Myometrial Invasion in Endometrial Cancer.
Emerging evidence suggests that G9a, a histone methyltransferase, is involved in tumor progression and metastasis. However, the functional significance of G9a in endometrial carcinogenesis has not been defined. The differential expression of G9a in cancer and normal tissues was assessed using an array of 28 paired samples. Tissue specimens from 94 patients with endometrial cancer who underwent primary surgery were immunohistochemically evaluated for G9a and E-cadherin expression. To assess the biologic role of G9a in endometrial cancer, G9a was either stably knocked down or knocked down using a tetracycline-controllable system in endometrial cancer cells, followed by functional assays. Increased G9a expression was identified in endometrial cancer tissues, and its expression was specifically correlated with deep myometrial invasion. Cell invasiveness was inhibited by an RNAi-mediated knockdown of G9a in invasive endometrial cancer cells in vitro and in vivo. An important mediator of G9a-induced tumor invasion is the epigenetic silencing of E-cadherin. Knockdown of G9a restored E-cadherin expression by reducing H3K9me2 levels and decreasing CDH1 promoter DNA methyltransferase recruitment. Knockdown of RNAi-mediated E-cadherin substantially relieved the invasion suppression imposed by G9a suppression. A significant negative correlation between G9a and E-cadherin expression was observed in endometrial cancer (Spearman's rho, -0.27; P = 0.02). This study provides the first clear evidence that G9a contributes to endometrial cancer progression. Mechanistic investigations suggest that E-cadherin repression mediates the effects of G9a. Targeting G9a-mediated epigenetic pathway dysregulation may be a therapeutic strategy for endometrial cancers.


Exploring the impact of pharmacist-led feedback on prescribing behaviour: A qualitative study.
Prescribing errors occur frequently in hospital settings. Interventions to influence prescribing behaviour are needed with feedback one potential intervention to improve prescribing practice. Doctors have reported a lack of feedback on their prescribing previously whilst the literature exploring the impact of feedback on prescribing behaviour is limited. To explore the impact of pharmacist-led feedback on prescribing behaviour. Semi-structured interviews were conducted with doctors who had received prescribing error feedback. A topic guide was used to explore the type of error and what impact feedback was having on prescribing behaviour. All interviews were transcribed verbatim and analysed thematically using a framework approach. Twenty-three prescribers were interviewed and 65 errors discussed over 38 interviews. Key themes included; affective behaviour, learning outcome, prescribing behaviour and likelihood of error recurrence. Feedback was educational whilst a range of adaptive prescribing behaviours were also reported. Prescribers were more mindful and engaged with the prescribing process whilst feedback facilitated reflection, increased self-awareness and informed self-regulation. Greater information and feedback-seeking behaviours were reported whilst prescribers also reported greater situational awareness, and that they were making fewer prescribing errors following feedback. Pharmacist-led feedback was perceived to positively influence prescribing behaviour. Reported changes in prescriber behaviour resonate with the non-technical skills (NTS) of prescribing with prescribers adapting their prescribing behaviour depending on the environment and prescribing conditions. A model of prescribing is proposed with NTS activated in response to error provoking conditions. These findings have implications for prescribing education to make it a more contextualised educational process.


The genome sequence of Xanthomonas oryzae pathovar oryzae KACC10331, the bacterial blight pathogen of rice.
The nucleotide sequence was determined for the genome of Xanthomonas oryzae pathovar oryzae (Xoo) KACC10331, a bacterium that causes bacterial blight in rice (Oryza sativa L.). The genome is comprised of a single, 4 941 439 bp, circular chromosome that is G + C rich (63.7%). The genome includes 4637 open reading frames (ORFs) of which 3340 (72.0%) could be assigned putative function. Orthologs for 80% of the predicted Xoo genes were found in the previously reported X.axonopodis pv. citri (Xac) and X.campestris pv. campestris (Xcc) genomes, but 245 genes apparently specific to Xoo were identified. Xoo genes likely to be associated with pathogenesis include eight with similarity to Xanthomonas avirulence (avr) genes, a set of hypersensitive reaction and pathogenicity (hrp) genes, genes for exopolysaccharide production, and genes encoding extracellular plant cell wall-degrading enzymes. The presence of these genes provides insights into the interactions of this pathogen with its gramineous host.


Translating current basic research into future therapies for neurofibromatosis type 1.
Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients. In this review, we outline previous strategies aimed at targeting these signalling pathways or cells in the microenvironment, agents that are currently in clinical trials, and the latest advances in basic research that could culminate in the development of novel therapeutics for patients with NF1.


Biological screening of select Puerto Rican plants for cytotoxic and antitumor activities.
The objective of this study was to evaluate the cytotoxic and anticancer activities of extracts from 7-species of endemic and native plants from Puerto Rico. The plant species selected for this study were Canella winterana, Croton discolor, Goetzea elegans, Guaiacum officinale, Pimenta racemosa, Simarouba tulae, and Thouinia striata. The dried plant material was extracted with a 1:1 mixture of CH2CI2-MeOH. The resulting crude extract was suspended in water and extracted with solvents of different polarities. The extracts were evaluated for their cytotoxic effects against Artemia salina and 3 breast cancer cell lines. About 50% of the extracts evaluated against Artemia salina exhibited LC50 values of less than or equal to 200 μg/mL. The strongest activity was detected in the chloroform and ethyl acetate extracts of Guaiacum officinale, with lethality values below 10 μg/mL. The extracts were further evaluated for their bioactivity as possible inhibitors of several breast cancer cell lines, with the extracts from Simarouba tulae and Croton discolor showing the highest percentages of growth inhibition. The dose- effect data analysis for the crude extracts of the different plants also confirms the high cytotoxicities of Guaiacum officinale, Simarouba tulae, and Croton discolor. Based on our results, we concluded that the Simarouba, Croton, and Guaiacum plant extracts show cytotoxic and anticancer activities that merit closer investigation in order to identify the chemical compounds responsible for these bioactivities.


Current Status of Computer-Aided Drug Design for Type 2 Diabetes.
Diabetes is a metabolic disorder that requires multiple therapeutic approaches. The pancreas loses its functionality to properly produce the insulin hormone in patients with diabetes mellitus. In 2012, more than one million people worldwide died as a result of diabetes, which was the eighth leading cause of death. Most drugs currently available and approved by the U.S. Food and Drug Administration cannot reach an adequate level of glycemic control in diabetic patients, and have many side effects; thus, new classes of compounds are required. Efforts based on computer-aided drug design (CADD) can mine a large number of databases to produce new and potent hits and minimize the requirement of time and dollars for new discoveries. Pharmaceutical sciences have made progress with advances in drug design concepts. Virtual screening of large databases is most compatible with different computational methods such as molecular docking, pharmacophore, quantitative structure-activity relationship, and molecular dynamic simulation. Contribution of these methods in selection of antidiabetic compounds has been discussed. The computer-aided drug design (CADD) approach has contributed to successful discovery of novel anti-diabetic agents. This mini-review focuses on CADD approach on currently approved drugs and new therapeutic agents-indevelopment that may achieve suitable glucose levels and decrease the risk of hypoglycemia, which is a major obstacle to glucose control and a special concern for therapies that increase insulin levels. Drug design and development for type 2 diabetes have been actively studied. However, a large number of antidiabetic drugs are still in early stages of development. The conventional target- and structure-based approaches can be regarded as part of the efforts toward therapeutic mechanism-based drug design for treatment of type 2 diabetes. It is expected that further improvement in CADD approach will enhance the new discoveries.


What happens next? The predictability of natural behaviour viewed through CCTV cameras.
Can potentially antisocial or criminal behaviour be predicted? Our study aimed to ascertain (a) whether observers can successfully predict the onset of such behaviour when viewing real recordings from CCTV; (b) where, in the sequence of events, it is possible to make this prediction; and (c) whether there may be a difference between naïve and professional observers. We used 100 sample scenes from UK urban locations. Of these, 18 led to criminal behaviour (fights or vandalism). A further 18 scenes were matched as closely as possible to the crime examples, but did not lead to any crime, and 64 were neutral scenes chosen from a wide variety of noncriminal situations. A signal-detection paradigm was used in conjunction with a 6-point rating scale. Data from fifty naïve and fifty professional observers suggest that (a) observers can distinguish crime sequences from neutral sequences and from matches; (b) there are key types of behaviour (particularly gestures and body position) that allow predictions to be made; (c) the performance of naïve observers is comparable to that of experts. However, because the experts were predominantly male, the absence of an effect of experience may have been due to gender differences, which were investigated in a subsidiary experiment. The results of experiment 2 leave open the possibility that females perform better than males at such tasks.


The low-affinity receptor for IgE (CD23) on B lymphocytes is spatially associated with HLA-DR antigens.
Two hybridomas that produce the mAbs 135 and 449 B4 were obtained that inhibited the binding of IgE to the Fc epsilon RL/CD23 on the EBV-transformed B cell line RPMI 8866. mAb 135 was obtained from a mouse immunized with RPMI 8866 cells, whereas mAb 449B4 was obtained from a mouse immunized with a partially purified preparation of Fc epsilon RL/CD23 obtained as the eluate of an IgE immunoabsorbent loaded with a soluble extract of RPMI 8866 cells. These two mAbs bound to Fc epsilon RL/CD23- cell lines and precipitated two polypeptides with 36,000 Mr and 28,000 Mr, which were the HLA-DR alpha and beta chains, respectively. Immunoprecipitation with mAb 135 of NP-40 lysates from dithio-bis(succinimidyl propionate) (DSP) crosslinked 125I-labeled RPMI 8866 or normal B cells incubated with rIL-4 showed three polypeptides with 42,000, 36,000, and 28,000 Mr. The 42,000 Mr polypeptide is identical to the Fc epsilon RL/CD23 since it could be precipitated by the anti-Fc epsilon RL/CD23 mAb 25 after resolubilization from the SDS-PAGE gel. Immunoprecipitations of the crosslinked cell extracts carried out with the anti-Fc epsilon RL/CD23 mAb 25 yielded the same three polypeptides. Furthermore, when RPMI 8866 or rIL-4 preincubated normal B cells were solubilized with a digitonin buffer, which prevents the dissociation of noncovalently linked polypeptide complexes, mAb 135 and mAb 25 precipitated complexes composed of three molecules with 42,000, 36,000, and 28,000 Mr. The well-characterized anti-HLA-DR mAb L243 was unable to block the binding of either IgE or mAb 135 to RPMI 8866 cells, although it could immunoprecipitate the complex (HLA-DR-Fc epsilon RL/CD23) from crosslinked cell lysates. Since mAb 135 and L243 were able to both bind the RPMI 8866 cells, it demonstrates that they bind to different epitopes of the HLA-DR complex, the mAb 135 epitope of the HLA-DR molecule being close to the IgE binding site of the Fc epsilon RL/CD23. These data demonstrated that the Fc epsilon RL/CD23 and HLA-DR antigens are spatially associated on the B cell membrane.


Urbanization in India: Population and Urban Classification Grids for 2011.
India is the world's most populous country, yet also one of the least urban. It has long been known that India's official estimates of urban percentages conflict with estimates derived from alternative conceptions of urbanization. To date, however, the detailed spatial and settlement boundary data needed to analyze and reconcile these differences have not been available. This paper presents gridded estimates of population at a resolution of 1 km along with two spatial renderings of urban areas-one based on the official tabulations of population and settlement types (i.e., statutory towns, outgrowths, and census towns) and the other on remotely-sensed measures of built-up land derived from the Global Human Settlement Layer. We also cross-classified the census data and the remotely-sensed data to construct a hybrid representation of the continuum of urban settlement. In their spatial detail, these materials go well beyond what has previously been available in the public domain, and thereby provide an empirical basis for comparison among competing conceptual models of urbanization.


The utility of intraoperative MRI during pediatric brain tumor surgery: a single-surgeon case series.
The authors sought to evaluate the utility of intraoperative MRI (ioMRI) during brain tumor excision in pediatric patients and to suggest guidelines for its future use. All patients who underwent brain tumor surgery by the senior author at Boston Children's Hospital using ioMRI between 2005 and 2009 were included in this retrospective review of hospital records and the neurosurgeon's operative database. Prior to the review, the authors defined the utility of ioMRI into useful and not useful categories based on how the technology affected operative management. They determined that ioMRI was useful if it 1) effectively guided the extent of resection; 2) provided a baseline postoperative scan during the same anesthesia session; or 3) demonstrated or helped to prevent an intraoperative complication. The authors determined that ioMRI was not useful if 1) the anatomical location of the tumor had precluded a tumor's total resection, even though the surgeon had employed ioMRI for that purpose; 2) the tumor's imaging characteristics prevented an accurate assessment of resection during intraoperative imaging; 3) the surgeon deemed the technology not required for tumor resection; or 4) the intraoperative MR images were uninterpretable for technical reasons. Follow-up data provided another gauge of the long-term benefit of ioMRI to the patient. A total of 53 brain tumor patients were operated on using ioMRI, 6 of whom had a second ioMRI procedure during the study period. Twenty-six patients were female, and 27 were male. The mean follow-up was 4.8 ± 3.85 years (range 0-12 years). By the criteria outlined above, ioMRI technology was useful in 38 (64.4%) of the 59 cases, most frequently for its help in assessing extent of resection. Intraoperative MRI technology was useful in the majority of brain tumor resections in this series, especially in those tumors that were contrast enhancing and located largely within accessible areas of the brain. The percentage of patients for whom ioMRI is useful could be increased by preoperatively evaluating the tumor's imaging characteristics to determine if ioMRI would accurately assess the extent of tumor resection, and by the surgeon's preoperative understanding that use of the ioMRI will not lead to resection of an anatomically unresectable tumor. The ioMRI can prove useful in unresectable tumors if specific operative goals are defined preoperatively.


DHEA enhances emotion regulation neurocircuits and modulates memory for emotional stimuli.
Dehydroepiandrosterone (DHEA) is a neurosteroid with anxiolytic, antidepressant, and antiglucocorticoid properties. It is endogenously released in response to stress, and may reduce negative affect when administered exogenously. Although there have been multiple reports of DHEA's antidepressant and anxiolytic effects, no research to date has examined the neural pathways involved. In particular, brain imaging has not been used to link neurosteroid effects to emotion neurocircuitry. To investigate the brain basis of DHEA's impact on emotion modulation, patients were administered 400 mg of DHEA (N=14) or placebo (N=15) and underwent 3T fMRI while performing the shifted-attention emotion appraisal task (SEAT), a test of emotional processing and regulation. Compared with placebo, DHEA reduced activity in the amygdala and hippocampus, enhanced connectivity between the amygdala and hippocampus, and enhanced activity in the rACC. These activation changes were associated with reduced negative affect. DHEA reduced memory accuracy for emotional stimuli, and also reduced activity in regions associated with conjunctive memory encoding. These results demonstrate that DHEA reduces activity in regions associated with generation of negative emotion and enhances activity in regions linked to regulatory processes. Considering that activity in these regions is altered in mood and anxiety disorders, our results provide initial neuroimaging evidence that DHEA may be useful as a pharmacological intervention for these conditions and invite further investigation into the brain basis of neurosteroid emotion regulatory effects.


Interpreting behaviors from accelerometry: a method combining simplicity and objectivity.
Quantifying the behavior of motile, free-ranging animals is difficult. The accelerometry technique offers a method for recording behaviors but interpretation of the data is not straightforward. To date, analysis of such data has either involved subjective, study-specific assignments of behavior to acceleration data or the use of complex analyses based on machine learning. Here, we present a method for automatically classifying acceleration data to represent discrete, coarse-scale behaviors. The method centers on examining the shape of histograms of basic metrics readily derived from acceleration data to objectively determine threshold values by which to separate behaviors. Through application of this method to data collected on two distinct species with greatly differing behavioral repertoires, kittiwakes, and humans, the accuracy of this approach is demonstrated to be very high, comparable to that reported for other automated approaches already published. The method presented offers an alternative to existing methods as it uses biologically grounded arguments to distinguish behaviors, it is objective in determining values by which to separate these behaviors, and it is simple to implement, thus making it potentially widely applicable. The R script coding the method is provided.


First evidence of Seoul hantavirus in the wild rat population in the Netherlands.
We report the first detection of Seoul hantavirus (SEOV)-specific antibodies in the wild brown rat population in the Netherlands. SEOV-reactive antibodies were found in three rats out of 16 in a repeated series of tests including immunofluorescence assay, immunoblot, and enzyme-linked immunosorbent assay. Focus reduction neutralization test confirmed the presence of SEOV-specific antibodies, and reverse-transcription polymerase chain reaction (RT-PCR) confirmed the presence of hantaviral RNA. This discovery follows the recent findings of SEOV infections in wild and pet brown rats and humans in England, Wales, France, Belgium, and Sweden, indicating an even higher importance of this hantavirus for public health in large areas of Europe.


Unmaking old age: political and cognitive formats of active ageing.
Active ageing is a policy tool that dominates the way the ageing society has been constituted during the last decades. The authors argue that active ageing is an attempt at unmaking the concept of old age, by engaging in the plasticity of ageing in various ways. Through a document study of the different epistemes, models and forms used in the constitution of active ageing policies, the authors show how active ageing is not one coordinated set of policy instruments, but comes in different formats. In the WHO, active ageing configures individual lifestyle in order to expand the plasticity of ageing, based on epidemiological and public health conventions. In the EU, active ageing reforms the retirement behaviour of populations in order to integrate the plasticity of ageing into the institutions, based on social gerontological and demographic conventions. These conventional arrangements are cognitive and political in the way they aim at unmaking both the structures and the expectations that has made old age and format a new ideal of the 'good late life'. The paper examines the role of knowledge in policy and questions whether the formats of active ageing should be made to co-exist, or whether the diversity and comprehensiveness enable a local adaptation and translation of active ageing policies.


Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.


Localized protein interaction surfaces on the EntB carrier protein revealed by combinatorial mutagenesis and selection.
Carrier proteins are 80- to 100-residue way stations that are central to polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) enzymatic assembly lines. Because the biosynthetic intermediates for catalytic operations are presented on carrier proteins as covalently attached thioesters (via a 4'-phosphopantetheine prosthetic group), the specific protein-protein interactions between carrier proteins and other NRPS/PKS domains are critical for high-fidelity conversion to the final product. Here we show by combinatorial mutagenesis and selection that the aryl carrier protein of EntB (EntB-ArCP) contains localized protein interaction surfaces. Our strategy involved random mutagenesis of N-terminal regions of EntB-ArCP, then selection for clones that produce enterobactin by plating onto iron-deficient media. We identified several residues that were highly conserved from our selection, two of which (G242 and D244) constitute an interaction surface on EntB-ArCP for the phosphopantetheinyl transferases (PPTases) EntD and Sfp. This PPTase interface is distinct from a previously characterized interface on EntB-ArCP for the downstream elongation module, EntF. These results suggest that different protein components recognize different faces of EntB-ArCP in the enterobactin synthetase and that the majority of EntB-ArCP surface residues are not involved in these interactions. Therefore, designing noncognate carrier protein interactions in PKS and NRPS systems should be possible with very few mutations on a particular carrier protein.


Adolescent Intermittent Ethanol Exposure Alters Adult Exploratory and Affective Behaviors, and Cerebellar Grin2B Expression in C57BL/6J Mice.
Binge drinking is one of the most common patterns (more than 90%) of alcohol consumption by young people. During adolescence, the brain undergoes maturational changes that influence behavioral control and affective behaviors, such as cerebellar brain volume and function in adulthood. We investigated long-term impacts of adolescent binge ethanol exposure on affective and exploratory behaviors and cerebellar gene expression in adult male and female mice. Further, the cerebellum is increasingly recognized as a brain region integrating a multitude of behaviors that span from the traditional primary sensory-motor to affective functions, such as anxiety and stress reactivity. Therefore, we investigated the persistent effects of adolescent intermittent ethanol (AIE) on exploratory and affective behaviors and began to elucidate the role of the cerebellum in these behaviors through excitatory signaling gene expression. We exposed C57BL/6J mice to AIE or air (control) vapor inhalation from postnatal day 28-42. After prolonged abstinence (>34 days), in young adulthood (PND 77+) we assessed behavior in the open field, light/dark, tail suspension, and forced swim stress tests to determine changes in affective behaviors including anxiety-like, depressive-like, and stress reactivity behavior. Excitatory signaling gene mRNA levels of fragile X messenger ribonucleoprotein ( FMR1) , glutamate receptors ( Grin2a , Grin2B and Grm5 ) and excitatory synaptic markers (PSD-95 and Eaat1) were measured in the cerebellum of adult control and AIE-exposed mice. AIE-exposed mice showed decreased exploratory behaviors in the open field test (OFT) where both sexes show reduced ambulation, however only females exhibited a reduction in rearing. Additionally, in the OFT, AIE-exposed females also exhibited increased anxiety-like behavior (entries to center zone). In the forced swim stress test, AIE-exposed male mice, but not females, spent less time immobile compared to their same-sex controls, indicative of sex-specific changes in stress reactivity. Male and female AIE-exposed mice showed increased Grin2B (Glutamate Ionotropic Receptor NMDA Type Subunit 2B) mRNA levels in the cerebellum compared to their same-sex controls. Together, these data show that adolescent binge-like ethanol exposure altered both exploratory and affective behaviors in a sex-specific manner and modified cerebellar Grin2B expression in adult mice. This indicates the cerebellum may serve as an important brain region that is susceptible to long-term molecular changes after AIE. Adolescent intermittent ethanol (AIE) exposure decreased exploratory behavior in adult male and female mice.In females, but not males, AIE increased anxiety-like behavior.In males, but not females, AIE reduced stress reactivity in adulthood.These findings indicate sex differences in the enduring effects of AIE on exploratory and affective behaviors. Cerebellar Grin2B mRNA levels were increased in adulthood in both male and female AIE-exposed mice. These findings add to the small, but growing literature on behavioral AIE effects in mice, and establish cerebellar excitatory synaptic gene expression as an enduring effect of adolescent ethanol exposure.


[Diet and migraine].
Some foods in our diet can spark off migraine attacks in susceptible individuals. Some foods can bring an attack on through an allergic reaction. A certain number such as citrus fruits, tea, coffee, pork, chocolate, milk, nuts, vegetables and cola drinks have been cited as possible allergens associated with migraine. This mechanism has however been criticized: an improvement in symptoms by eliminating some food(s) from our diet does not necessarily mean an immunologically based allergic reaction. The high IgE incidence rate is not greater in such patients than in the population at large. Other allergic reactions unrelated to diet may also be associated with migraine attacks. On the other hand substances in food may be the cause of modifications in vascular tone and bring migraine on in those so prone. Among such substances are tyramine, phenylalanine, phenolic flavonoids, alcohol, food additives (sodium nitrate, monosodium glutamate, aspartame) and caffeine. Another recognized trigger for migraine is hypoglycemia. Such foods as chocolate, cheese, citrus fruits, bananas, nuts, 'cured' meats, dairy products, cereals, beans, hot dogs, pizza, food additives (sodium nitrate, monosodium glutamate in Chinese restaurant food, aspartame as a sweetener), coffee, tea, cola drinks, alcoholic drinks such as red wine, beer or whisky distilled in copper stills, all may bring on a migraine attack. For every patient we have to assess which foodstuffs are involved in the attack (not necessarily produced by consuming the product concerned) in order to try to avoid their consumptions as a means of prophylaxis for migraine.


Mothers' and fathers' autonomy-relevant parenting: longitudinal links with adolescents' externalizing and internalizing behavior.
The goal of this study was to advance the understanding of separate and joint effects of mothers' and fathers' autonomy-relevant parenting during early and middle adolescence. In a sample of 518 families, adolescents (49 % female; 83 % European American, 16 % African American, 1 % other ethnic groups) reported on their mothers' and fathers' psychological control and knowledge about adolescents' whereabouts, friends, and activities at ages 13 and 16. Mothers and adolescents reported on adolescents' externalizing and internalizing behaviors at ages 12, 14, 15, and 17. Adolescents perceived their mothers as using more psychological control and having more knowledge than their fathers, but there was moderate concordance between adolescents' perceptions of their mothers and fathers. More parental psychological control predicted increases in boys' and girls' internalizing problems and girls' externalizing problems. More parental knowledge predicted decreases in boys' externalizing and internalizing problems. The perceived levels of behavior of mothers and fathers did not interact with one another in predicting adolescent adjustment. The results generalize across early and late adolescence and across mothers' and adolescents' reports of behavior problems. Autonomy-relevant mothering and fathering predict changes in behavior problems during early and late adolescence, but only autonomy-relevant fathering accounts for unique variance in adolescent behavior problems.


Concept Drift and Anomaly Detection in Graph Streams.
Graph representations offer powerful and intuitive ways to describe data in a multitude of application domains. Here, we consider stochastic processes generating graphs and propose a methodology for detecting changes in stationarity of such processes. The methodology is general and considers a process generating attributed graphs with a variable number of vertices/edges, without the need to assume a one-to-one correspondence between vertices at different time steps. The methodology acts by embedding every graph of the stream into a vector domain, where a conventional multivariate change detection procedure can be easily applied. We ground the soundness of our proposal by proving several theoretical results. In addition, we provide a specific implementation of the methodology and evaluate its effectiveness on several detection problems involving attributed graphs representing biological molecules and drawings. Experimental results are contrasted with respect to suitable baseline methods, demonstrating the effectiveness of our approach.


Synthesis and in vitro/in vivo evaluation of novel mono- and trivalent technetium-99m labeled ghrelin peptide complexes as potential diagnostic radiopharmaceuticals.
Ghrelin is an endogenous hormone present in blood. It is released from the oxyntic cells (X/A-like cells) of the stomach and fundus and can exist in two forms: as an acylated and des-acylated ghrelin. Ghrelin is an endogenous ligand of the growth hormone receptor (growth hormone secretagogue receptor, GHS-R). Overexpression of GHS-R1a receptor was identified in cells of different types of tumors (e.g. pituitary adenoma, neuroendocrine tumors of the thyroid, lung, breast, gonads, prostate, stomach, colorectal, endocrine and non-endocrine pancreatic tumors). This fact suggests that gamma radionuclide labeled ghrelin peptide may be considered as a potential diagnostic radiopharmaceutical. Ghrelin peptide labeled with mono- and trivalent technetium-99m complexes, (99m)Tc-Lys-GHR, has been prepared on the n.c.a. scale. The physicochemical (stability, charge, shape, lipophilicity) and biological (receptor affinity, biodistribution) properties of the conjugates have been studied relevant to use the conjugates as receptor-based diagnostic radiopharmaceuticals. The obtained conjugates [(99m)Tc(CO)3LN,O(CN-Lys-GHR)](+), (99m)Tc(CO)3LS,O(CN-Lys-GHR) and (99m)Tc(NS3)(CN-Lys-GHR) show different shape, charge, lipophilicity and two of them, (99m)Tc(CO)3LS,O(CN-Lys-GHR) and (99m)Tc(NS3)(CN-Lys-GHR), high stability in neutral aqueous solutions, even in the presence of excess concentration of histidine/cysteine competitive standard ligands or human serum. The in vitro binding affinity of (99m)Tc-Lys-GHR conjugates with respect to growth hormone secretagogue receptor (GHS-R1a) present on DU-145 cells was in the range of IC50 from 45 to 54 nM. The conjugate (99m)Tc(CO)3LS,O(CN-Lys-GHR) exhibited excretion route by the liver and kidney in comparable degree, while the more lipophilic conjugate (99m)Tc(NS3)(CN-Lys-GHR)-mainly by the liver. Basing on the results concerning physicochemical and biochemical properties, the conjugates (99m)Tc(CO)3LS,O(CN-Lys-GHR) and (99m)Tc(NS3)(CN-Lys-GHR) might be considered to be promising models for diagnostic radiopharmaceutical.


Dominant nonresponsiveness in the induction of autoimmunity to liver-specific F antigen.
The liver-specific F antigen, although not an autoimmunogen, can induce the production of autoantibodies in responder strains. The ability to respond is under the control of two genes, one linked to the H-2 locus of mice, the other not. Responders possessing both genes produce high anti-F titers, while the H-2-linked gene alone permits a significant but low antibody response. (Responder X nonresponder) F1 hybrids derived from parents possessing identical F molecules are nonresponders, in contrast with the dominance of responsiveness in Ir gene systems. The presence of the H-2 locus from nonresponders appears involved in the inability to respond. This is discussed in terms of self-tolerance and suppression.


Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio.
The blood-brain barrier (BBB) essentially restricts therapeutic drugs from entering into the brain. This study tests the hypothesis that brain endothelial cell derived exosomes can deliver anticancer drug across the BBB for the treatment of brain cancer in a zebrafish (Danio rerio) model. Four types of exosomes were isolated from brain cell culture media and characterized by particle size, morphology, total protein, and transmembrane protein markers. Transport mechanism, cell uptake, and cytotoxicity of optimized exosome delivery system were tested. Brain distribution of exosome delivered anticancer drugs was evaluated using transgenic zebrafish TG (fli1: GFP) embryos and efficacies of optimized formations were examined in a xenotransplanted zebrafish model of brain cancer model. Four exosomes in 30-100 diameters showed different morphologies and exosomes derived from brain endothelial cells expressed more CD63 tetraspanins transmembrane proteins. Optimized exosomes increased the uptake of fluorescent marker via receptor mediated endocytosis and cytotoxicity of anticancer drugs in cancer cells. Images of the zebrafish showed exosome delivered anticancer drugs crossed the BBB and entered into the brain. In the brain cancer model, exosome delivered anticancer drugs significantly decreased fluorescent intensity of xenotransplanted cancer cells and tumor growth marker. Brain endothelial cell derived exosomes could be potentially used as a carrier for brain delivery of anticancer drug for the treatment of brain cancer.


Palliative sedation at home in the Netherlands: a nationwide survey among nurses.
This paper is a report of a nationwide study conducted to assess experiences of nurses involved in palliative sedation at home after introduction of a physicians' guideline for palliative sedation. Most studies investigating the practice of palliative sedation focus on physicians' practices and attitudes. However, little is known about experiences and attitudes of nurses. A web-based structured questionnaire was offered to 387 nurses providing medical technical care in 2007, assessing their experiences concerning decision-making, treatment policy and communication, focussing on the last patient receiving palliative sedation. The questionnaire was filled out by 201 nurses (response rate 52%). The majority of respondents agreed with the indication for palliative sedation. However, 21% reported to have refused carrying out a palliative sedation in the preceding year. The general practitioner was not present at the start of palliative sedation in a third of the cases, but was available when needed. The sedation was considered insufficiently effective by 42% of the respondents. According to a third of the respondents, the level of sedation was not related to the required level of symptom relief nor were changes in dosage based on the severity of symptoms. Although the guideline for palliative sedation appears to be followed adequately in the majority of cases with respect to indication for palliative sedation and reportage. The survey findings revealed shortcomings in medication policy, communication, medical control over the start and continued monitoring of palliative sedation.


Paroxysmal nocturnal hemoglobinuria and telomere length predicts response to immunosuppressive therapy in pediatric aplastic anemia.
Acquired aplastic anemia is an immune-mediated disease characterized by severe defects in stem cell number resulting in hypocellular marrow and peripheral blood cytopenias. Minor paroxysmal nocturnal hemoglobinuria populations and a short telomere length were identified as predictive biomarkers of immunosuppressive therapy responsiveness in aplastic anemia. We enrolled 113 aplastic anemia patients (63 boys and 50 girls) in this study to evaluate their response to immunosuppressive therapy. The paroxysmal nocturnal hemoglobinuria populations and telomere length were detected by flow cytometry. Forty-seven patients (42%) carried a minor paroxysmal nocturnal hemoglobinuria population. The median telomere length of aplastic anemia patients was -0.99 standard deviation (SD) (range -4.01-+3.01 SD). Overall, 60 patients (53%) responded to immunosuppressive therapy after six months. Multivariate logistic regression analysis identified the absence of a paroxysmal nocturnal hemoglobinuria population and a shorter telomere length as independent unfavorable predictors of immunosuppressive therapy response at six months. The cohort was stratified into a group of poor prognosis (paroxysmal nocturnal hemoglobinuria negative and shorter telomere length; 37 patients) and good prognosis (paroxysmal nocturnal hemoglobinuria positive and/or longer telomere length; 76 patients), respectively. The response rates of the poor prognosis and good prognosis groups at six months were 19% and 70%, respectively (P<0.001). The combined absence of a minor paroxysmal nocturnal hemoglobinuria population and a short telomere length is an efficient predictor of poor immunosuppressive therapy response, which should be considered while deciding treatment options: immunosuppressive therapy or first-line hematopoietic stem cell transplantation. The trial was registered in www.umin.ac.jp with number UMIN000017972.


Frailty Severity and Cognitive Impairment Associated with Dietary Diversity in Older Adults in Taiwan.
This study aims to investigate whether frailty severity in conjunction with cognitive function, termed as" cognitive frailty", is associated with dietary diversity in older adults. This cross-sectional study used the data from the 2014-2016 Nutrition and Health Survey in Taiwan (N = 1115; age ≥ 65 years). Dietary intake was assessed using a 24 h dietary recall and food-frequency questionnaire, and dietary diversity score (DDS; range, 0-6) and food intake frequency were calculated. The presence of frailty phenotypes was determined using the FRAIL scale, which was proposed by the International Association of Nutrition and Aging, and cognitive function was assessed using the Mini-Mental State Examination (MMSE) score. The prevalence of cognitive frailty (FRAIL scale score ≥ 3 and MMSE score ≤ 26) was 4.2%. A higher consumption frequency of dairy products, whole grains, vegetables, fruit, fish and seafood, nuts, tea, and coffee, as well as lower pickled vegetable, was inversely associated with cognitive frailty. Those with prefrailty or frailty and lower DDS demonstrated a higher cognitive impairment risk (adjust odds ratio (OR) = 2.15, 95% confidence interval = 1.21-3.83) than those without frailty and higher DDS. Older adults with cognitive prefrailty or cognitive frailty were associated with lower DDS, and frailty with lower DDS was associated with worsening cognitive function.


Sialic acid utilization by Cronobacter sakazakii.
The Cronobacter genus is composed of seven species, and can cause infections in all age groups. Of particular concern is C. sakazakii, as this species is strongly associated with severe and often fatal cases of necrotizing enterocolitis and meningitis in neonates and infants. Whole genome sequencing has revealed that the nanAKT gene cluster required for the utilisation of exogenous sialic acid is unique to the C. sakazakii species (ESA_03609-13).Sialic acid is found in breast milk, infant formula, intestinal mucin, and gangliosides in the brain, hence its metabolism by C. sakazakii is of particular interest. Therefore its metabolism could be an important virulence factor. To date, no laboratory studies demonstrating the growth of C. sakazakii on sialic acid have been published nor have there been reports of sialidase activity. The phylogenetic analysis of the nan genes is of interest to determine whether the genes have been acquired by horizontal gene transfer. Phylogenetic analysis of 19 Cronobacter strains from 7 recognised species revealed the nanAKTR genes formed a unique cluster, separate from other Enterobacteriaceae such as E. coli K1 and Citrobacter koseri, which are also associated with neonatal meningitis. The gene organisation was similar to Edwardsiella tarda in that nanE gene (N-acetylmannosamine-6-phosphate-2epimerase) was not located within the nanATK cluster. Laboratory studies confirmed that only C. sakazakii, and not the other six Cronobacter species, was able to use sialic acid as a carbon source for growth. Although the ganglioside GM1 was also used as carbon source, no candidate sialidase genes were found in the genome, instead the substrate degradation is probably due to β-galactosidase activity. Given the relatively recent evolution of both C. sakazakii (15-23 million years ago) and sialic acid synthesis in vertebrates, sialic acid utilization may be an example of co-evolution by one species of the Cronobacter genus with the mammalian host. This has possibly resulted in additional virulence factors contributing to severe life-threatening infections in neonates due to the utilization of sialic acid from breast milk, infant formula, milk (oligosaccharides), mucins lining the intestinal wall, and even gangliosides in the brain after passing through the blood-brain barrier.


Community factors influencing child and adolescent depression: A systematic review and meta-analysis.
Depression has been identified as a priority disorder among children and adolescents. While numerous reviews have examined the individual and family factors that contribute to child and adolescent depressive symptoms, less is known about community-level risk and protective factors. The aim of this study was to complete a systematic review to identify community risk and protective factors for depression in school-aged children (4-18 years). The review adopted the procedures recommended by the Cochrane Non-Randomised Studies Methods Working Group and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive literature search was conducted to identify both observational and intervention study designs in both peer-reviewed and non-peer reviewed publications. A total of 21 studies met the inclusion criteria. Seventeen of the 18 community association studies and 2 of the 3 intervention studies reported one or more significant effects. Results indicated that community safety and community minority ethnicity and discrimination act as risk factors for depressive symptoms in school-aged children. Community disadvantage failed to achieve significance in meta-analytic results but findings suggest that the role of disadvantage may be influenced by other factors. Community connectedness was also not directly associated with depressive symptoms. There is evidence that a number of potentially modifiable community-level risk and protective factors influence child and adolescent depressive symptoms suggesting the importance of continuing research and intervention efforts at the community-level.


Community-based organisations for vulnerable children in South Africa: Reach, psychosocial correlates, and potential mechanisms.
Community-based organisations (CBOs) have the potential to provide high quality services for orphaned and vulnerable children in resource-limited settings. However, evidence is lacking as to whether CBOs are reaching those who are most vulnerable, whether attending these organisations is associated with greater psychosocial wellbeing, and how they might work. This study addressed these three questions using cross-sectional data from 1848 South African children aged 9-13. Data were obtained from the Young Carers and Child Community Care studies, which both investigated child wellbeing in South Africa using standardised self-report measures. Children from the Child Community Care study were all CBO attenders, whereas children from Young Carers were not receiving any CBO services, thereby serving as a comparison group. Multivariable regression analyses were used to test whether children attending CBOs were more deprived on socio-demographic variables (e.g., housing), and whether CBO attendance was in turn associated with better psychosocial outcomes (e.g., child depression). Mediation analysis was conducted to test whether more positive home environments mediated the association between CBO attendance and significantly higher psychological wellbeing. Overall, children attending CBOs did show greater vulnerability on most socio-demographic variables. For example, compared to children not attending any CBO, CBO-attending children tended to live in more crowded households (OR 1.22) and have been exposed to more community violence (OR 2.06). Despite their heightened vulnerability, however, children attending CBOs tended to perform better on psychosocial measures: for instance, showing fewer depressive symptoms (B=-0.33) and lower odds of experiencing physical (OR 0.07) or emotional abuse (OR 0.22). Indirect effects of CBO attendance on significantly higher child psychological wellbeing (lower depressive symptoms) was observed via lower rates of child abuse (B=-0.07) and domestic conflict/violence (B=-0.03) and higher rates of parental praise (B=-0.03). Null associations were observed between CBO attendance and severe psychopathology (e.g., suicidality). These cross-sectional results provide promising evidence regarding the potential success of CBO reach and impact but also highlight areas for improvement.


Perinatal mortality in rural Burkina Faso: a prospective community-based cohort study.
There is a scarcity of reliable data on perinatal mortality (PNM) in Sub-Saharan Africa. The PROMISE-EBF trial, during which we promoted exclusive breastfeeding, gave us the opportunity to describe the epidemiology of PNM in Banfora Health District, South-West in Burkina Faso. To measure the perinatal mortality rate (PNMR) in the PROMISE-EBF cohort in Banfora Health District and to identify potential risk factors for perinatal death. We used data collected prospectively during the PROMISE-EBF-trial to estimate the stillbirth rate (SBR) and early neonatal mortality rate (ENMR). We used binomial regression with generalized estimating equations to identify potential risk factors for perinatal death. 895 pregnant women were enrolled for data collection in the EBF trial and followed-up to 7 days after birth. The PNMR, the SBR and the ENMR, were 79 per 1000 (95% CI: 59-99), 54 per 1000 (95% CI: 38-69) and 27 per 1000 (95% CI: 9-44), respectively. In a multivariable analysis, nulliparous women (RR = 2.90, 95% CI: 1.6-5.0), primiparae mothers (RR = 2.20, 95% CI: 1.2-3.9), twins (RR = 4.0, 95% CI: 2.3-6.9) and giving birth during the dry season (RR = 2.1 95% CI: 1.3-3.3) were factors associated with increased risk of perinatal death. There was no evidence that risk of perinatal death differed between deliveries at home and at a health centre Our study observed the highest PNMR ever reported in Burkina. There is an urgent need for sustainable interventions to improve maternal and newborn health in the country.


Developing an Indonesian fertility preservation questionnaire for health care providers treating patients with cancer: A preliminary pilot study.
Background: Early detection and advanced treatment increases the five-year survival rate of patients with cancer. However, long-term cancer therapy, such as chemotherapy and radiotherapy, can have negative effects, such as infertility. This study aimed to develop a standardized Indonesian questionnaire, which would be used to assess the quality of health care providers' knowledge, attitude, and practice regarding fertility preservation in patients with cancer. Methods: A pilot study was performed in January and February 2018 at Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia. An existing questionnaire was translated from English to Indonesian using forward translation, back translation, expert panel, pretesting, and cognitive interviewing. Ten subspecialists in the following departments made up an expert panel, who were involved in pretesting and cognitive interviewing: pediatric hematology-oncology, hematology-oncology/internal medicine, gynecologic oncology, gynecologic immune-endocrinology, radiology-oncology, and surgical oncology. Results: The questionnaire was successfully translated. The ten respondents stated that the maximum age for women's fertility preservation is 40 years of age (60%), 45 years of age (30%), or had no maximum age (10%). Additionally, the respondents stated that the maximum age for men's fertility preservation is 40 years of age (30%), 50 years of age (20%), or had no maximum age (50%). The respondents' knowledge stated that > 50% of them were aware but do not know enough about fertility preservation. The respondents stated that more than 50% of them give feedback agreeing to fertility preservation, and they always give advice about fertility preservation to their patients. Conclusion: The translation of the questionnaire followed translation steps from the World Health Organization and was adjusted based on the expert panel's comments concerning fertility preservation. This validated questionnaire tool in Indonesian can be used for research purposes and clinical evaluation of fertility preservation among health care providers in Indonesia.


Cold stress induces metabolic activation of thyrotrophin-releasing hormone-synthesising neurones in the magnocellular division of the hypothalamic paraventricular nucleus and concomitantly changes ovarian sympathetic activity parameters.
Recent studies suggest thyrotrophin-releasing hormone (TRH) serves as a neurotransmitter and thereby provides a functional vegetative connection between the brain and the ovary. In the present study, magnocellular neurones of the paraventricular nucleus (PVN) in animals subjected to cold exposure were studied to determine the hypothalamic origin of the TRH involved in this pathway. In situ hybridisation analysis of hypothalamic tissue showed that cold exposure causes a two-fold increase in the total number of neurones expressing TRH mRNA in the PVN. Immunohistochemical studies showed that TRH peptide is localised to the magnocellular PVN and that the number of TRH immunoreactive cells increases two-fold following 64 h of cold exposure. Double-immunostaining for MAP-2 and TRH revealed that TRH peptide is localised in the perikarya of the magnocellular neurones. TRH release was measured in vivo from the magnocellular portion of the PVN using push-pull perfusion. Although controls exhibited a very low level of TRH release, animals subjected to cold showed a pulsatile-like TRH release profile with two different patterns of release: (i) low basal level with small bursts of TRH release and (ii) a profile with an up to seven-fold increase in TRH release compared to controls. The colocalisation of TRH with the specific somato-dendritic marker MAP-2 in processes of the magnocellular neurones suggested a local release of TRH. Additional studies demonstrated a reduction in ovarian noradrenaline content after 48 h of cold exposure, a feature indicative of nerve activation at the terminal organ. After 64 h of cold exposure, the ovarian noradrenaline returned to control values but the noradrenaline content of the coeliac ganglia was increased, suggesting a compensatory effect originating in the cell bodies of the sympathetic neurones that innervate the ovary. The correlation between the local release of TRH from dendrites within the magnocellular PVN in conditions of cold and the activation of the sympathetic nerves supplying the ovary raises the possibility that TRH contributes to the processing regulating sympathetic outflow and may thereby impact on the functional activity of the ovary.


Profile of a Malignant Brain Tumour in Jamaica: An Eight-year Review, 2005 to 2012.
Glioblastoma multiforme (GBM) is the most malignant and most common primary brain tumour worldwide. This study was undertaken to investigate the demographics of this tumour in Jamaica as there is to date no such published data. Data from the recently started Intracranial Tumour Registry (ITR) at the University Hospital of the West Indies was used. All cases of GBM entered into the ITR between 2005 and 2012 were gathered. Of these, only patients with pathologically proven diagnoses were entered into the study. Demographic data, including age and gender, were recorded. The distribution of the tumours by anatomic location was also documented. Of the 602 patients entered into the ITR up to that time, 42 were found to have histologically proven GBM with a male to female ratio of 2.2:1. There was an age range of 8-92 years with a mean age of diagnosis of 48 years. The majority of the tumours (66.7%) occurred in the left cerebral hemisphere with the most common lobe being the temporal lobe. Two patients (4.8%) had lesions spanning both hemispheres. This preliminary study reveals that there is a similar gender distribution of GBM within our population compared with the rest of the world. It, however, revealed that the mean age of diagnosis in our population (48 years) is lower than that quoted in the worldwide literature (53 to 64 years). One possible explanation for this is the possibility that many of our GBMs are actually secondary tumours which are thought to arise from less malignant, undiagnosed precursors. The percentage of GBMs occurring in the paediatric population was similar to the rest of the world.


Improving Attitudes Towards Personality Disorder: Is Training for Health and Social Care Professionals Effective?
Health and social care professionals are more likely to hold negative attitudes towards people with a diagnosis of personality disorder than toward people with other mental health diagnoses. Negative attitudes have also been found to adversely impact care and service provision. This review sought to systemically evaluate training aimed at improving professional attitudes towards people with a diagnosis of personality disorder. Electronic databases PsychINFO, PubMed, Embase, Web of Science, and ProQuest were searched, and 19 articles were identified. Results show that training is effective and that improvements tend to be maintained. The results suggest that (1) co-production with people with personal experience of a personality disorder diagnosis, (2) communicating a psychological model to participants, and (3) teaching participants clinical skills for use in their work improve effectiveness. Further research in the form of randomized controlled trials that use validated measures and follow-up participants for at least 6 months is needed.


A versatile palindromic amphipathic repeat coding sequence horizontally distributed among diverse bacterial and eucaryotic microbes.
Intragenic tandem repeats occur throughout all domains of life and impart functional and structural variability to diverse translation products. Repeat proteins confer distinctive surface phenotypes to many unicellular organisms, including those with minimal genomes such as the wall-less bacterial monoderms, Mollicutes. One such repeat pattern in this clade is distributed in a manner suggesting its exchange by horizontal gene transfer (HGT). Expanding genome sequence databases reveal the pattern in a widening range of bacteria, and recently among eucaryotic microbes. We examined the genomic flux and consequences of the motif by determining its distribution, predicted structural features and association with membrane-targeted proteins. Using a refined hidden Markov model, we document a 25-residue protein sequence motif tandemly arrayed in variable-number repeats in ORFs lacking assigned functions. It appears sporadically in unicellular microbes from disparate bacterial and eucaryotic clades, representing diverse lifestyles and ecological niches that include host parasitic, marine and extreme environments. Tracts of the repeats predict a malleable configuration of recurring domains, with conserved hydrophobic residues forming an amphipathic secondary structure in which hydrophilic residues endow extensive sequence variation. Many ORFs with these domains also have membrane-targeting sequences that predict assorted topologies; others may comprise reservoirs of sequence variants. We demonstrate expressed variants among surface lipoproteins that distinguish closely related animal pathogens belonging to a subgroup of the Mollicutes. DNA sequences encoding the tandem domains display dyad symmetry. Moreover, in some taxa the domains occur in ORFs selectively associated with mobile elements. These features, a punctate phylogenetic distribution, and different patterns of dispersal in genomes of related taxa, suggest that the repeat may be disseminated by HGT and intra-genomic shuffling. We describe novel features of PARCELs (Palindromic Amphipathic Repeat Coding ELements), a set of widely distributed repeat protein domains and coding sequences that were likely acquired through HGT by diverse unicellular microbes, further mobilized and diversified within genomes, and co-opted for expression in the membrane proteome of some taxa. Disseminated by multiple gene-centric vehicles, ORFs harboring these elements enhance accessory gene pools as part of the "mobilome" connecting genomes of various clades, in taxa sharing common niches.


Localization and fate of Fgf10-expressing cells in the adult mouse brain implicate Fgf10 in control of neurogenesis.
We used Fgf10-lacZ reporter mice to investigate the distribution and fate of Fgf10-expressing cells in the developing and adult mouse brain. We find that the domain of Fgf10 expression expands post-natally and new niches emerge in the adult brain. Fgf10 is expressed in the adult cerebellum, thalamic, mid- and hindbrain nuclei and hippocampal CA fields, as previously reported in the rat brain. In addition though, we have discovered expression in: the hippocampal dentate gyrus; a discrete trail linking the ventral telencephalon with the olfactory bulbs; ventral ependyma of the third ventricle from where cells appear to disperse into the hypothalamus; and in the pituitary gland. Most Fgf10-expressing cells or their immediate descendants appear immature but a subset differentiates into neurons and glial cells. The manner in which Fgf10 is expressed in these active and quiescent neurogenic niches implicates it in control of neurogenesis and/or conservation of neurogenic potential.


Antimicrobial-related severe adverse events during treatment of bone and joint infection due to methicillin-susceptible Staphylococcus aureus.
Prolonged antimicrobial therapy is recommended for methicillin-susceptible Staphylococcus aureus (MSSA) bone and joint infections (BJI), but its safety profile and risk factors for severe adverse events (SAE) in clinical practice are unknown. We addressed these issues in a retrospective cohort study (2001 to 2011) analyzing antimicrobial-related SAE (defined according to the Common Terminology Criteria for Adverse Events) in 200 patients (male, 62%; median age, 60.8 years [interquartile range {IQR}, 45.5 to 74.2 years]) with MSSA BJI admitted to a reference regional center with acute (66%) or chronic arthritis (7.5%), osteomyelitis (9.5%), spondylodiscitis (16%), or orthopedic device-related infections (67%). These patients received antistaphylococcal therapy for a median of 26.6 weeks (IQR, 16.8 to 37.8 weeks). Thirty-eight SAE occurred in 30 patients (15%), with a median time delay of 34 days (IQR, 14.75 to 60.5 days), including 10 patients with hematologic reactions, 9 with cutaneomucosal reactions, 6 with acute renal injuries, 4 with hypokalemia, and 4 with cholestatic hepatitis. The most frequently implicated antimicrobials were antistaphylococcal penicillins (ASP) (13 SAE/145 patients), fluoroquinolones (12 SAE/187 patients), glycopeptides (9 SAE/101 patients), and rifampin (7 SAE/107 patients). Kaplan-Meier curves and stepwise binary logistic regression analyses were used to determine the risk factors for the occurrence of antimicrobial-related SAE. Age (odds ratio [OR], 1.479 for 10-year increase; 95% confidence interval [CI], 1.116 to 1.960; P = 0.006) appeared to be the only independent risk factor for SAE. In patients receiving ASP or rifampin, daily dose (OR, 1.028; 95% CI, 1.006 to 1.051; P = 0.014) and obesity (OR, 8.991; 95% CI, 1.453 to 55.627; P = 0.018) were associated with the occurrence of SAE. The high rate of SAE and their determinants highlighted the importance of the management and follow-up of BJI, with particular attention to be paid to older persons, especially for ASP dosage, and to rifampin dose adjustment in obese patients.


Selective inhibition of human type-5 17β-hydroxysteroid dehydrogenase (AKR1C3) by baccharin, a component of Brazilian propolis.
The human aldo-keto reductase (AKR) 1C3, also known as type-5 17β-hydroxysteroid dehydrogenase and prostaglandin F synthase, has been suggested as a therapeutic target in the treatment of prostate and breast cancers. In this study, AKR1C3 inhibition was examined by Brazilian propolis-derived cinnamic acid derivatives that show potential antitumor activity, and it was found that baccharin (1) is a potent competitive inhibitor (K(i) 56 nM) with high selectivity, showing no significant inhibition toward other AKR1C isoforms (AKR1C1, AKR1C2, and AKR1C4). Molecular docking and site-directed mutagenesis studies suggested that the nonconserved residues Ser118, Met120, and Phe311 in AKR1C3 are important for determining the inhibitory potency and selectivity of 1. The AKR1C3-mediated metabolism of 17-ketosteroid and farnesal in cancer cells was inhibited by 1, which was effective from 0.2 μM with an IC(50) value of about 30 μM. Additionally, 1 suppressed the proliferation of PC3 prostatic cancer cells stimulated by AKR1C3 overexpression. This study is the first demonstration that 1 is a highly selective inhibitor of AKR1C3.


Quantifying the added value of BNP in suspected heart failure in general practice: an individual patient data meta-analysis.
Diagnosing early stages of heart failure with mild symptoms is difficult. B-type natriuretic peptide (BNP) has promising biochemical test characteristics, but its diagnostic yield on top of readily available diagnostic knowledge has not been sufficiently quantified in early stages of heart failure. To quantify the added diagnostic value of BNP for the diagnosis of heart failure in a population relevant to GPs and validate the findings in an independent primary care patient population. Individual patient data meta-analysis followed by external validation. The additional diagnostic yield of BNP above standard clinical information was compared with ECG and chest x-ray results. Derivation was performed on two existing datasets from Hillingdon (n=127) and Rotterdam (n=149) while the UK Natriuretic Peptide Study (n=306) served as validation dataset. Included were patients with suspected heart failure referred to a rapid-access diagnostic outpatient clinic. Case definition was according to the ESC guideline. Logistic regression was used to assess discrimination (with the c-statistic) and calibration. Of the 276 patients in the derivation set, 30.8% had heart failure. The clinical model (encompassing age, gender, known coronary artery disease, diabetes, orthopnoea, elevated jugular venous pressure, crackles, pitting oedema and S3 gallop) had a c-statistic of 0.79. Adding, respectively, chest x-ray results, ECG results or BNP to the clinical model increased the c-statistic to 0.84, 0.85 and 0.92. Neither ECG nor chest x-ray added significantly to the 'clinical plus BNP' model. All models had adequate calibration. The 'clinical plus BNP' diagnostic model performed well in an independent cohort with comparable inclusion criteria (c-statistic=0.91 and adequate calibration). Using separate cut-off values for 'ruling in' (typically implying referral for echocardiography) and for 'ruling out' heart failure--creating a grey zone--resulted in insufficient proportions of patients with a correct diagnosis. BNP has considerable diagnostic value in addition to signs and symptoms in patients suspected of heart failure in primary care. However, using BNP alone with the currently recommended cut-off levels is not sufficient to make a reliable diagnosis of heart failure.


Aggressive dogs are characterized by low omega-3 polyunsaturated fatty acid status.
Canine aggressive behaviour is one of the most common problems being reported by dog owners. However, the biochemical basis of this phenomenon remains unclear. In humans, alterations in omega-3 plasma polyunsatured fatty acids and elevated omega6/omega-3 ratio have been linked to behavioural alterations, including aggression. Thus far, however, the relationship between plasma polyunsatured fatty acid status and aggression has not been investigated in the dog. In the present study we sought to investigate whether polyunsatured fatty acid status could be altered in plasma of pathologically aggressive Canis familiaris. Eighteen adult male German Shepherd dogs, aged 4.9 +/- 0.9 years, showing no clinical signs but aggression, were investigated. Eighteen healthy male dogs, aged 4.8 +/- 0.7 years, with a negative history of behavioural and neurological disorders served as controls. Baseline fasting plasma polyunsatured fatty acid composition was determined by gas chromatography. Compared to normal dogs, aggressive dogs showed lower docosahexaenoic acid (22:6 n-3) concentrations and a higher omega6/omega-3 ratio. In addition, they showed reduced cholesterol and bilirubin concentrations compared to their normally behaving counterparts. Altogether, our results suggest that low omega-3 fatty acids may adversely impact behaviour in dogs, resulting in greater propensity to aggression. However, given the cross-sectional design of our study, we cannot claim any causal relationship between the presence of alterations in fatty acid status and canine aggressiveness. Whether omega-3 fatty acids supplementation may be useful to reduce aggressive behaviour in the dog deserves further investigation.


Possible protective effect of curcumin on the thyroid gland changes induced by sodium fluoride in albino rats: light and electron microscopic study.
Thyroid gland regulates the body's metabolic rate and plays an exquisitely important role in the human health. Fluoride exposure can affect thyroid function. Curcumin is a potent antioxidant that works through several mechanisms. The aim of the present study was to demonstrate the hormonal, histological, and ultrastructural changes occurred in the thyroid gland induced by exposure to sodium fluoride (NaF) and study the possible protective effect of curcumin on the NaF-induced effects. Thirty male albino rats were randomly divided into 3 equal groups (10 rats each): the control group, NaF group, and NaF+Curcumin (NaF+Cur) group. Thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) levels were assayed and thyroid tissues processed for light and transmission electron microscopic study. In NaF group, serum T3 and T4 levels were significantly decreased whereas TSH level was significantly increased compared to the control group. Thyroid tissues showed flattening of the epithelial lining with several follicular cell degenerations, hyperplasia, decreased colloid, disrupted basement membrane, cytoplasmic vacuolations, degenerated mitochondria, widening of rough endoplasmic reticulum cisternae, and vascular congestion compared to the control group. In the NaF+Cur group, serum TSH levels were significantly decreased in comparison with NaF group and no significant difference in comparison with the control group. Thyroid sections appeared apparently normal compared to the control group and NaF group. Sodium fluoride affected both the function and structure of the thyroid gland while curcumin was protective against these toxic effects.


Further studies of the role of hyperthermia in methamphetamine neurotoxicity.
The depletion of striatal dopamine (DA) that can occur after methamphetamine (METH) administration has been linked to METH-induced hyperthermia. The relationship between METH-induced hyperthermia, neurotoxicity (striatal DA depletions) and compounds that protect against METH neurotoxicity was further investigated in this study. Typically, rats exposed to METH die when their body temperatures exceed 41.3 degrees C but such hyperthermic rats can be saved by hypothermic intervention. Subsequently, rats saved by hypothermic intervention have greater depletion of striatal DA at an earlier time of onset (18 hr or less post-METH) than do METH-exposed rats that do not attain such high temperatures. Striatal damage was present 3 days post-METH in these hyperthermic rats, as assessed by silver degeneration of terminals and increases in the astrocytes that express glial fibrillary acidic protein immunoreactivity. By contrast, alterations in the number of [3H]dizoclipine (MK-801) binding sites in cortical or striatal membranes at 1, 3 or 14 days post-METH were not detected. The experiments showed that mean and maximal body temperature correlated well with striatal DA concentrations 3 days post-METH (r = -0.77, n = 58), which suggests a role for hyperthermia in METH neurotoxicity. However, hyperthermia (alone or with haloperidol present) induced by high ambient temperatures did not deplete striatal DA in the absence of METH. Haloperidol, diazepam and MK-801 all reduced METH-induced striatal DA depletion to a degree predicted by their inhibition of hyperthermia and increased ambient temperature abolished their neuroprotection. Although an interleukin-1 receptor antagonist reduced maximal body temperature enough to lower the lethality rate, it did not reduce the temperature sufficiently to block METH neurotoxicity. It was concluded that short- and long-term decreases in striatal DA levels depend on the degree of hyperthermia produced during METH exposure but cannot be produced by hyperthermia alone. In addition, several agents that block DA depletions do so by inhibiting METH-induced hyperthermia. Finally, the results suggested a role for interleukin-1 in the extreme hyperthermia and lethality produced by METH.


Understanding Emergent Dynamics: Using a Collective Activity Coordinate of a Neural Network to Recognize Time-Varying Patterns.
In higher animals, complex and robust behaviors are produced by the microscopic details of large structured ensembles of neurons. I describe how the emergent computational dynamics of a biologically based neural network generates a robust natural solution to the problem of categorizing time-varying stimulus patterns such as spoken words or animal stereotypical behaviors. The recognition of these patterns is made difficult by their substantial variation in cadence and duration. The neural circuit behaviors used are similar to those associated with brain neural integrators. In the larger context described here, this kind of circuit becomes a building block of an entirely different computational algorithm for solving complex problems. While the network behavior is simulated in detail, a collective view is essential to understanding the results. A closed equation of motion for the collective variable describes an algorithm that quantitatively accounts for many aspects of the emergent network computation. The feedback connections and ongoing activity in the network shape the collective dynamics onto a reduced dimensionality manifold of activity space, which defines the algorithm and computation actually performed. The external inputs are weak and are not the dominant drivers of network activity.


Vaccination mitigates the impact of PRRSv infection on the pharmacokinetics of ceftiofur crystalline-free acid in pigs.
The pharmacokinetics of intramuscularly administered ceftiofur crystalline-free acid (CCFA) were determined in pigs that were clinically healthy (n = 8), vaccinated with a Porcine reproductive and respiratory syndrome modified live virus (PRRS MLV) (n = 10), challenged with wild-type porcine reproductive and respiratory syndrome virus (PRRSv) VR-2385 (n = 10), or vaccinated with PRRS MLV and later challenged with wild-type PRRSv VR-2385 (n = 10). Animals were given a single dose of CCFA intramuscularly at 5 mg/kg body weight. Blood was collected at 0 (pretreatment), 0.25, 0.5, 1, 6, 12, 24, 48, 96, 144, 192, and 240 h postinjection. Plasma was analyzed using liquid chromatography-mass spectrometry. Plasma concentration-time curves for each group were evaluated with noncompartmental modeling. When compared to control animals, those receiving the PRRSv wild-type challenge only had a lower AUC0-last , higher Cl/F, and higher Vz/F. The PRRSv wild-type challenge only group had the longest T1/2λ . The Cmax did not differ among all four treatments. Control animals had no statistically significant differences from animals vaccinated with PRRS MLV alone or animals vaccinated with PRRS MLV and later challenged with wild-type PRRSv. Our results suggest that PRRSv wild-type infection has the potential to alter CCFA pharmacokinetics and PRRS MLV vaccination may attenuate those changes.


[Comparative evaluation of the osteoprotective effects of resveratrol and resveratrol/enalapril combination in the treatment of experimental osteoporosis].
The osteoprotective effect of resveratrol and a combination of resveratrol with enalapril has been investigated in white Wistar female rats with experimental osteoporosis. It is established that, in rats after ovariectomy, the endothelial dysfunction of microcirculation vessels of the osteal tissue is developed, resulting in the occurrence of osteoporosis. Resveratrol and the combination of resveratrol with enalapril prevented depression of the microcirculation level in the osteal tissue, thus preventing the thinning of osteal trabecules and preventing their microfractures.


Pre-apoptotic response to therapeutic DNA damage involves protein modulation of Mcl-1, Hdm2 and Flt3 in acute myeloid leukemia cells.
Acute myeloid leukemia (AML) cells are characterized by non-mutated TP53, high levels of Hdm2, and frequent mutation of the Flt3 receptor tyrosine kinase. The juxtamembrane mutation of FLT3 is the strongest independent marker for disease relapse and is associated with elevated Bcl-2 protein and p53 hyper-phosphorylation in AML. DNA damage forms the basic mechanism of cancer cell eradication in current therapy of AML. Hdm2 and pro-apoptotic Bcl-2 members are among the most intensely induced genes immediately after chemotherapy and Hdm2 is proposed a role in receptor tyrosine kinase regulation. Thus we examined the DNA damage related modulation of these proteins in relation to FLT3 mutational status and induction of apoptosis. Within one hour after exposure to ionizing radiation (IR), the AML cells (NB4, MV4-11, HL-60, primary AML cells) showed an increase in Flt3 protein independent of mRNA levels, while the Hdm2 protein decreased. The FLT3 mutant MV4-11 cells were resistant to IR accompanied by presence of both Mcl-1 and Hdm2 protein three hours after IR. In contrast, the FLT3 wild type NB4 cells responded to IR with apoptosis and pre-apoptotic Mcl-1 down regulation. Daunorubicin (DNR) induced continuing down regulation of Hdm2 and Mcl-1 in both cell lines followed by apoptosis. Both IR and DNR treatment resulted in concerted protein modulations of Mcl-1, Hdm2 and Flt3. Cell death induction was associated with persistent attenuation of Mcl-1 and Hdm2. These observations suggest that defining the pathway(s) modulating Flt3, Hdm2 and Mcl-1 may propose new strategies to optimize therapy for the relapse prone FLT3 mutated AML patients.


Iatrogenic lipid emulsion overdose in a case of amlodipine poisoning.
Intralipid therapy has been used successfully as "rescue therapy" in several cases of overdose. We present a case of iatrogenic lipid emulsion overdose because of a dosing error. A 71-year-old female overdosed on 27 tablets of 5 mg amlodipine. Although initially stable in the Emergency Department, she became hypotensive, oliguric, and respiratory failure developed despite medical therapy. The primary treating team felt that meaningful recovery was unlikely to occur without rapid improvement in clinical status, and 12.5 h after presentation, intralipid rescue therapy was initiated. A protocol for intralipid specifying a maximum infusion of 400 mL of 20% lipid emulsion was faxed, but the infusion was continued until 2 L of lipid emulsion was infused. There were no detectable adverse hemodynamic effects of the intralipid infusion. After this time, laboratory values were difficult to obtain. Three hours after the infusion, a metabolic panel was obtained from ultracentrifuged blood showing hyponatremia. A white blood cell (WBC) was obtained from a complete blood count (CBC) performed 22 h after the infusion, hemoglobin and hematocrit could not be obtained from this blood. A platelet count was obtained by smear estimate. Hematocrits were obtained from centrifuged blood and appeared elevated. No oxygenation could be obtained on blood gas. The patient's family chose to withdraw care on hospital day 2 and no further laboratory draws were obtained. Amlodipine was 1,500 ng/mL (ref. 3-11 ng/mL). Lipid emulsion overdose caused no detectable acute adverse hemodynamic effects. The following laboratory values were unobtainable immediately after infusion: white blood cell count, hemoglobin, hematocrit, platelet count, and a metabolic panel of serum electrolytes. Ultracentrifugation of blood allowed for detection of a metabolic panel 3 h after the infusion. Centrifuged hematocrits appeared to be higher than expected.


Sex-related differences in the presentation and outcome of out-of-hospital cardiopulmonary arrest: a multiyear, prospective, population-based study.
To examine whether previously observed sex-related differences in coronary artery disease syndromes also apply to patients with out-of-hospital sudden cardiac arrest, a probable subset of patients with coronary artery disease who are easy to recognize and are treated in a standardized fashion. Prospective, population-based study conducted over a 6-yr period. A large urban municipality (population, 1.1 million) served by a single emergency medical services system with centralized medical direction and standardized protocols. All patients with out-of-hospital, nontraumatic, primary cardiac arrest. Standardized advanced cardiac life support protocols. During the 6 yrs of the study, 4147 consecutive patients were studied, 42% of whom were women (p <.001). Although women were significantly older than men (mean age, 68.7 +/- 18 vs. 61.7 +/- 17 yrs; p =.001), there were no significant differences for the percentages of witnessed and unwitnessed arrests, response intervals, and the length and type of treatment provided. Although men were more likely to have ventricular fibrillation/ventricular tachycardia on presentation (41% vs. 30%), women had more asystole (8.8% vs. 7%) and (organized) pulseless electrical activity than men (24% vs. 18%; p <.001). Nevertheless, more women were resuscitated (13.5% vs. 10.7%; p =.005), particularly women with non-ventricular fibrillation/ventricular tachycardia presentation (12.6% vs. 9.6%; p <.02). These differences were more pronounced when controlling for age (95% confidence interval, 1.44 [1.25-1.74]). In cases of out-of-hospital sudden cardiac arrest, women have significantly better resuscitation rates than men, especially when controlling for age, particularly among women with non-ventricular fibrillation/ventricular tachycardia presentations. Additional studies are required to validate these observations, not only for long-term survival and external validity, but also for other potential genetic factors and potential discrepancies with other studies.


Adaptation of the wisconsin scales of psychosis proneness to Spanish.
Nowadays the study of vulnerability to psychosis and early intervention is an area of great clinical impact and research. The aim of this study was to adapt the Wisconsin Scales of Vulnerability to Psychosis from English to Spanish. A set of five scales (Magical Ideation, Perceptual Aberration, Physical Anhedonia, Revised Social Anhedonia and Ambivalence) assess schizotypal traits in the general population and the possible risk of developing disorders embedded in the psychotic spectrum. Additionally, this tool contains a scale of Hypomaniac Personality to detect risk of affective spectrum psychosis. The Wisconsin Scales of Vulnerability to Psychosis have been adapted following the back-translation method. The scales were translated to an original Spanish version, which was then translated again into English in order to assess the conceptual and semantic overlap with the original items. All the items were back-translated and evaluated in respect to the original ones by an expert in the scales, and all of them were rated with a perfect equivalence (Type A) or satisfactory (Type B). The Spanish version of the Wisconsin Scales of Vulnerability to Psychosis shows good equivalence with the English one, thus allowing to measure affective and schizotypal traits in samples of Spanish-speaking individuals properly. Future studies should test the reliability and validity of these scales in our environment.


Protein Kinase C: One Pathway towards the Eradication of Latent HIV-1 Reservoirs.
An effective means to eradicate latent reservoirs in HIV-1-infected individuals remains elusive. Attempts to purge these reservoirs were undertaken over a decade ago without success. The subsequent lapse in further clinical attempts since may have been justified as our knowledge of the mechanisms which underpin the latent state still evolves. Although additional novel molecular antagonists of HIV-1 latency have subsequently been reported, these candidate agents have not been tested in human trials for reservoir ablation. This review provides an overview of the protein kinase C (PKC) pathway which can be modulated by small molecular agents to induce the expression of latent HIV-1 from within infected reservoir cells. Some of these agents have been tested against select cancers with seemingly tolerable side effects. As such, modulation of the PKC pathway may yet be a viable mechanism toward HIV-1 reservoir eradication.


Effect of Calotropis procera latex on isoproterenol induced myocardial infarction in albino rats.
The alcoholic extract of the latex obtained from Calotropis procera (Asclepidaceae) was evaluated for protection against isoproterenol (20 mg/100 g body wt., s.c.)-induced myocardial infarction in albino rats. The heart damage induced by isoproterenol was indicated by elevated levels of the marker enzymes such as Creatine Kinase-isoenzyme (CK-MB), Lactate dehydrogenase (LDH), Serum Glutamate Oxaloacetic Transaminase (SGOT) and Serum Glutamate Pyruvate Transaminase (SGPT) in serum with increased lipid peroxide and reduced glutathione content in heart homogenates. Microscopical examination (histopathology) was also performed on the myocardial tissue. Pretreatment with an ethanolic latex extract of Calotropis procera at a dose of 300 mg/kg body wt., administered orally thrice a day for 30 days, reduced significantly (p < 0.01) the elevated marker enzyme levels in serum and heart homogenates in isoproterenol-induced myocardial infarction. Histopathological observation revealed a marked protection by the extract in myocardial necrotic damage.


Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury.
Identification of signaling pathways that are functional in a specific biological context is a major challenge in systems biology, and could be instrumental to the study of complex diseases and various aspects of drug discovery. Recent approaches have attempted to combine gene expression data with prior knowledge of protein connectivity in the form of a PPI network, and employ computational methods to identify subsets of the protein-protein-interaction (PPI) network that are functional, based on the data at hand. However, the use of undirected networks limits the mechanistic insight that can be drawn, since it does not allow for following mechanistically signal transduction from one node to the next. To address this important issue, we used a directed, signaling network as a scaffold to represent protein connectivity, and implemented an Integer Linear Programming (ILP) formulation to model the rules of signal transduction from one node to the next in the network. We then optimized the structure of the network to best fit the gene expression data at hand. We illustrated the utility of ILP modeling with a case study of drug induced lung injury. We identified the modes of action of 200 lung toxic drugs based on their gene expression profiles and, subsequently, merged the drug specific pathways to construct a signaling network that captured the mechanisms underlying Drug Induced Lung Disease (DILD). We further demonstrated the predictive power and biological relevance of the DILD network by applying it to identify drugs with relevant pharmacological mechanisms for treating lung injury.


Numerical study of reverse period doubling route from chaos to stability in a two-mode intracavity doubled Nd-YAG laser.
We have numerically studied the behavior of a two-mode Nd-YAG laser with an intracavity KTP crystal. It is found that when the parameter, which is a measure of the relative orientations of the KTP crystal with respect to the Nd-YAG crystal, is varied continuously, the output intensity fluctuations change from chaotic to stable behavior through a sequence of reverse period doubling bifurcations. The graph of the intensity in the X-polarized mode against that in the Y-polarized mode shows a complex pattern in the chaotic regime. The Lyapunov exponent is calculated for the chaotic and periodic regions. (c) 1999 American Institute of Physics.


A review of dual health care system use by veterans with cardiometabolic disease.
Many Veterans Affairs (VA) patients with the complications of cardiometabolic syndrome (CMS) use both VA and community providers and facilities outside of VA. Although dual health care systems increase care options, dual use also increases coordination needs. The fragmentation and duplication of health care due to the use of multiple facilities and providers may hinder effective care coordination, result in less efficient and more costly care, and lead to poorer outcomes. This article, which is based upon bibliographic searches in PubMed, reviews the evidence on dual use of VA and community health care by Veterans for acute myocardial infarction (AMI), congestive heart failure (CHF), and diabetes mellitus, the most common CMS complications requiring acute care and post-acute care services. A total of 179 articles were identified. After screening the full texts or abstracts of the 179 articles, 11 studies met the criteria, including two qualitative studies and 9 quantitative using administrative and Medicare records for veterans with AMI, CHF, or diabetes. Among the analytic studies, 3 had a cross-sectional design and 6 were cohort studies. The results of studies completed to date suggest that dual healthcare system use by older male veterans with cardiometabolic conditions is not associated with improved outcomes and may lead to unnecessary tests or procedures and increased healthcare costs. Additional research is warranted to examine the prevalence of dual health care system use by male and female veterans during recent time periods and to compare outcomes among patients who receive only VA care, only community care, or both VA and community care.


Hearing help-seeking and rehabilitation: perspectives of adults with hearing impairment.
This study investigated the perspectives of adults with hearing impairment on hearing help-seeking and rehabilitation. Individual semi-structured interviews were completed. In total, 34 adults with hearing impairment in four countries (Australia, Denmark, UK, and USA) participated. Participants had a range of experience with hearing help-seeking and rehabilitation, from never having sought help to being satisfied hearing-aid users. Qualitative content analysis identified four main categories ('perceiving my hearing impairment', 'seeking hearing help', 'using my hearing aids', and 'perspectives and knowledge') and, at the next level, 25 categories. This article reports on the densest categories: they are described, exemplified with interview quotes, and discussed. People largely described hearing help-seeking and rehabilitation in the context of their daily lives. Adults with hearing impairment rarely described clinical encounters towards hearing help-seeking and rehabilitation as a connected process. They portrayed interactions with clinicians as isolated events rather than chronologically-ordered steps relating to a common goal. Clinical implications of the findings are discussed.


A novel treatment for subclinical hyperthyroidism: a pilot study on the beneficial effects of l-carnitine and selenium.
The definition itself of subclinical hyperthyroidism (SHyper) and, therefore, the therapeutic approach to patients with SHyper still remains undefined and controversial. Therefore, the interest of finding a novel and alternative therapy for SHyper has caught the attention. An observational pilot study was performed to assess the effects of l-carnitine and selenium in the management of SHyper symptoms and endocrine profile in patients affected by this disease. Patients with TSH levels between 0.1-0.4 mIU/L and positive antibodies were recruited in this study. Subjects received orally one tablet containing 500 mg of l-carnitine and 83 mcg of selenium (L-Carn + Se), daily for 1 month. The primary outcome was the improvement of the quality of life (QoL) with the disappearance of main symptoms (subjective symptomatology) associated to SHyper, evaluated through a 9-items short form survey. Secondary outcomes included TSH, fT3, and fT4, TPOAb, TgAb measurement. Primary and secondary outcomes were evaluated at baseline, after the completion of treatment and after a successive month without treatment. After 1-month treatment, the subjective symptomatology significantly dropped from 25.61 ± 1.19 to 12.11 ± 1.15 (p < 0.05). On the other hand, during the following 1-month period without treatment, it increased back to 23.33 ± 1.35 (p < 0.05). Thyroid hormones and auto-antibodies remained in their normal range. The present pilot study has shown that L-Carn + Se significantly reduced symptoms associated with SHyper, improving QoL of patients, without significant modifications of their endocrine profile. In addition, it is noteworthy that the extension of treatment seems necessary to prevent symptoms reappearance. Prospective randomized controlled trials are needed to address clinicians to define the appropriate treatment-settings for this disorder.