Characterization of the mitochondrial complete genome of Korean indigenous catfish, Liobagrus hyeongsanensis (Siluriformes: Amblycipitidae).
Liobagrus hyeongsanensis, Korean indigenous catfish, was reported as a new species in 2015. The complete mitochondrial DNA sequence of L. hyeongsanensis was sequenced by next-generation sequencing (NGS) analysis. The mitochondrial genome was assembled with 16,529 bp in length and encoded 13 protein-coding genes (PCGs), 22 tRNAs, two rRNAs, and one control region (D-loop). Also, the gene structures such as gene order and content were totally identical with the congeneric species. Molecular phylogenetic analysis determined the taxonomical position of L. hyeongsanensis in species level among the genus Liobagrus.


In situ effects of low pH and elevated HCO3- on juvenile massive Porites spp. in Moorea, French Polynesia.
Juvenile colonies of massive Porites spp. were exposed to manipulated pH and bicarbonate ([HCO3-]) in situ to test the hypothesis that ocean acidification (OA) does not affect respiration and calcification. Incubations lasted 28 h and exposed corals to ambient temperature and light with ecologically relevant water motion. Three treatments were applied: (1) ambient conditions of pH 8.04 and 1751 μmol HCO3- kg(-1) (Treatment 1), (2) pCO2-induced ocean acidification of pH 7.73 and 2011 μmol HCO3- kg(-1) (Treatment 2), and (3) pCO2 and HCO3--enriched seawater of pH 7.69 and 2730 μmol HCO3- kg(-1) (Treatment 3). The third treatment providing elevated [HCO3-] was used to test for stimulatory effects of dissolved inorganic carbon on calcification under low pH and low saturation of aragonite (Ωarag), but it does not reflect conditions expected to occur under CO2-driven OA. Calcification of juvenile massive Porites spp. was affected by treatments, with an 81% elevation in Treatment 3 versus Treatment 1, but no difference between Treatments 1 and 2; respiration and the metabolic expenditure concurrent with calcification remained unaffected. These findings indicate that juvenile massive Porites spp. are resistant to short exposures to OA in situ, and separately, that they can increase calcification at low pH and low Ωarag if [HCO3-] is elevated. Juvenile Porites spp. may therefore be limited by dissolved inorganic carbon under ambient pCO2 conditions.


Modelling raw water quality: development of a drinking water management tool.
Ensuring future drinking water supply requires a tough management of groundwater resources. However, recent practices of economic resource control often does not involve aspects of the hydrogeochemical and geohydraulical groundwater system. In respect of analysing the available quantity and quality of future raw water, an effective resource management requires a full understanding of the hydrogeochemical and geohydraulical processes within the aquifer. For example, the knowledge of raw water quality development within the time helps to work out strategies of water treatment as well as planning finance resources. On the other hand, the effectiveness of planed measurements reducing the infiltration of harmful substances such as nitrate can be checked and optimized by using hydrogeochemical modelling. Thus, within the framework of the InnoNet program funded by Federal Ministry of Economics and Technology, a network of research institutes and water suppliers work in close cooperation developing a planning and management tool particularly oriented on water management problems. The tool involves an innovative material flux model that calculates the hydrogeochemical processes under consideration of the dynamics in agricultural land use. The program integrated graphical data evaluation is aligned on the needs of water suppliers.


Factors associated with contraceptive choice and inconsistent method use, United States, 2004.
Pregnancies among contraceptive users account for nearly half of all unintended pregnancies and are almost entirely due to inconsistent or incorrect contraceptive use. Understanding what factors contribute to inconsistent contraceptive behavior can help efforts to reduce unintended pregnancy. In 2004, a nationally representative sample of women aged 18-44 using reversible contraceptive methods were surveyed to examine factors associated with contraceptive choice and with inconsistent use of the pill and condoms. Bivariate and multivariate analyses were used to examine the data. Contraceptive choice was associated with a range of socioeconomic and partnership characteristics, and with pregnancy-, method- and provider-related experiences and attitudes; inconsistent pill or condom use was associated mainly with partnership, experiential and attitudinal factors. For example, not having a college education was negatively associated with pill use (odds ratio, 0.6) and positively associated with use of long-acting methods (1.8-1.9). Women for whom avoiding pregnancy was only a little or not important had reduced odds of using the pill (0.4) and elevated odds of using other methods, such as withdrawal or periodic abstinence (4.4), and of using condoms inconsistently (2.6). Use of a method chosen mostly out of dislike of other methods was positively associated with condom use (4.0) and negatively associated with use of the pill or long-acting methods (0.4 for each). Women who were not completely satisfied with their method were more likely than others to use their method inconsistently (1.6 for pill users and 1.9 for condom users). Greater efforts are needed to provide women and their partners with a range of method options, to facilitate selection of methods that best suit their needs and circumstances, and to identify and assist users who are dissatisfied or are having difficulties using contraceptives effectively.


Identification of Phase Transitions and Metastability in Dynamically Compressed Antimony Using Ultrafast X-Ray Diffraction.
Ultrafast x-ray diffraction at the LCLS x-ray free electron laser has been used to resolve the structural behavior of antimony under shock compression to 59 GPa. Antimony is seen to transform to the incommensurate, host-guest phase Sb-II at ∼11 GPa, which forms on nanosecond timescales with ordered guest-atom chains. The high-pressure bcc phase Sb-III is observed above ∼15 GPa, some 8 GPa lower than in static compression studies, and mixed Sb-III/liquid diffraction are obtained between 38 and 59 GPa. An additional phase which does not exist under static compression, Sb-I^{'}, is also observed between 8 and 12 GPa, beyond the normal stability field of Sb-I, and resembles Sb-I with a resolved Peierls distortion. The incommensurate Sb-II high-pressure phase can be recovered metastably on release to ambient pressure, where it is stable for more than 10 ns.


MRI study of minor physical anomaly in childhood autism implicates aberrant neurodevelopment in infancy.
MPAs (minor physical anomalies) frequently occur in neurodevelopmental disorders because both face and brain are derived from neuroectoderm in the first trimester. Conventionally, MPAs are measured by evaluation of external appearance. Using MRI can help overcome inherent observer bias, facilitate multi-centre data acquisition, and explore how MPAs relate to brain dysmorphology in the same individual. Optical MPAs exhibit a tightly synchronized trajectory through fetal, postnatal and adult life. As head size enlarges with age, inter-orbital distance increases, and is mostly completed before age 3 years. We hypothesized that optical MPAs might afford a retrospective 'window' to early neurodevelopment; specifically, inter-orbital distance increase may represent a biomarker for early brain dysmaturation in autism. We recruited 91 children aged 7-16; 36 with an autism spectrum disorder and 55 age- and gender-matched typically developing controls. All children had normal IQ. Inter-orbital distance was measured on T1-weighted MRI scans. This value was entered into a voxel-by-voxel linear regression analysis with grey matter segmented from a bimodal MRI data-set. Age and total brain tissue volume were entered as covariates. Intra-class coefficient for measurement of the inter-orbital distance was 0.95. Inter-orbital distance was significantly increased in the autism group (p = 0.03, 2-tailed). The autism group showed a significant relationship between inter-orbital distance grey matter volume of bilateral amygdalae extending to the unci and inferior temporal poles. Greater inter-orbital distance in the autism group compared with healthy controls is consistent with infant head size expansion in autism. Inter-orbital distance positively correlated with volume of medial temporal lobe structures, suggesting a link to "social brain" dysmorphology in the autism group. We suggest these data support the role of optical MPAs as a "fossil record" of early aberrant neurodevelopment, and potential biomarker for brain dysmaturation in autism.


Mathematical modelling of leprosy and its control.
Leprosy or Hansen's disease is an infectious disease caused by the bacterium Mycobacterium leprae. The annual number of new leprosy cases registered worldwide has remained stable over the past years at over 200,000. Early case finding and multidrug therapy have not been able interrupt transmission completely. Elimination requires innovation in control and sustained commitment. Mathematical models can be used to predict the course of leprosy incidence and the effect of intervention strategies. Two compartmental models and one individual-based model have been described in the literature. Both compartmental models investigate the course of leprosy in populations and the long-term impact of control strategies. The individual-based model focusses on transmission within households and the impact of case finding among contacts of new leprosy patients. Major improvement of these models should result from a better understanding of individual differences in exposure to infection and developing leprosy after exposure. Most relevant are contact heterogeneity, heterogeneity in susceptibility and spatial heterogeneity. Furthermore, the existing models have only been applied to a limited number of countries. Parameterization of the models for other areas, in particular those with high incidence, is essential to support current initiatives for the global elimination of leprosy. Many challenges remain in understanding and dealing with leprosy. The support of mathematical models for understanding leprosy epidemiology and supporting policy decision making remains vital.


The in-vitro antimicrobial activity of some medicinal plants against beta-lactam-resistant bacteria.
In effort to identify novel bacterial agents, this study was initiated to evaluate the antimicrobial properties of 17 crude extracts from 12 medicinal plants against beta-lactam-resistant bacteria. The antimicrobial activities of plant extracts were evaluated against clinically proved beta-lactam-resistant bacteria (Klebsiella pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Serratia marcescens, Acinetobacter baumannii, Staphylococcus aureus and Enterococcus sp.) and reference strains of bacteria (Escherichia coli ATCC 35218, Enterobacter aerogenes ATCC 29751, E. aerogenes ATCC 13048, Pseudomonas aeruginosa ATCC 27853 and Enterococcus hirae ATCC 9790) by using disc-diffusion and agar-dilution assays. The crude plant extracts demonstrated broad spectrum activity against all bacteria tested with inhibition zones in the range of 8-30 mm. The minimal inhibitory concentration (MIC) values of different plant extracts against the tested bacteria were found to range from <or= 0.3 to >or= 10 mg ml(-1). The most active plant extracts were from Dortenia picta and Bridelia micrantha (MIC: 1.25-10 mg ml(-1)) on beta-lactam-resistant Gram-negative bacilli and the extracts from B. micrantha, Mallotus oppositifolius, Garcinia lucida, Garcinia. kola, Campylospermum densiflorum (leaves) and C. zenkeri (root) on beta-lactam-resistant Gram-positive cocci (MIC: <or= 0.3-5 mg ml(-1)). Of the 17 plant extracts studied, seven showed good antimicrobial activity against the tested bacteria. The stem bark of B. micrantha and the leaves of D. picta were most active towards beta-lactamase producing Gram-negative bacilli. This study shows that medicinal plants could be sources of compounds which can be used to fight against beta-lactam resistant bacteria.


Prognostic relevance of light chain 3 (LC3A) autophagy patterns in colorectal adenocarcinomas.
The microtubule-associated protein 1 light chain 3 (LC3A) is an essential component of the autophagic vacuoles, forming a reliable marker of autophagic activity. In a previous study, the authors showed that LC3A immunohistochemistry renders three patterns of autophagic expression in breast carcinomas: diffuse cytoplasmic, perinuclear and 'stone-like' intracellular structures (SLS), each with a distinct prognostic relevance. Tumour tissues from 155 patients with stage IIA-III colorectal adenocarcinomas, treated with surgery alone, were assessed immunohistochemically for LC3A. Median values were used as cut-off points to separate groups into low and high autophagic activity. Associations with prognosis and with lactate dehydrogenase-5 (LDH5) were sought. High SLS counts were associated with metastases and poor prognosis, while the prominence of the perinuclear pattern was linked to localised disease and good prognosis. The cytoplasmic pattern was irrelevant. Furthermore, patients with increased SLS numbers, but suppressed perinuclear expression, were associated with LDH5 overexpression and had an extremely poor prognosis (3-year survival 16.5%). The prognosis improved considerably when high SLS counts were accompanied by intense perinuclear expression (3-year survival 67%) and were optimal when SLS numbers dropped below median values, irrespective of perinuclear status (3-year survival 94-100%). Multivariate analysis showed that SLS and perinuclear patterns were independent predictors of death events. Perinuclear LC3A accumulation in colorectal tumour cells is a marker of good prognosis, presumably reflecting a basal autophagic activity. An abnormal or excessive autophagic response, as indicated by increased numbers of SLS, is linked to metastasis and poor prognosis.


Grading of severity of the condition in burn patients by serum protein and albumin/globulin studies.
Capillary permeability increases after inflammation with consequent leak of fluid, electrolytes, and proteins. The albumin molecule size being smaller (69 kDa) than the globulin molecule (90-156 kDa) will leak relatively at an early stage of the disease (with moderate increase in capillary pore size) than globulin leading to albumin/globulin reversal. In cases with severe permeability changes with rapid progression to larger pore size with simultaneous leak of both albumin and globulin, albumin/globulin reversal will not occur. In this study estimation the serum protein and albumin/globulin (A/G) ratio at frequent intervals was done to grade the severity of the condition of burn patients by assessing the severity of capillary leak.A total of 61 admitted patients (from March 2002 to December 2004) based on the protein values were divided into 3 groups (group 1: 6-8 g/dL, group 2: 5.1-5.9 g/dL, group 3: < or =5.0 g/dL), and all the patients who showed change in their protein levels during the study were shifted to appropriate group and were classified as group shifters. The mean survival time and mortality of various groups were compared, and A/G ratio of all the expired cases was analyzed.Group 3 patients showed higher mortality (95%) as compared to that in other groups (group 1 and 2: 0% each and group shifters: 30.2%). Median survival time of group 3 was significantly low as compared to that of group 1 (P < 0.0026), group 2 (P < 0.0006), and group shifters (P < 0.0000). In group shifters the mean time (days) required for shifting from one group to other just before death or discharge in survivors was significantly higher than that in expired cases. Of 26 cases expired during the study, initial A/G ratio at the time of first assigning the group was not reversed in 22 cases (84.6%).The study concluded that the severity (indicated by lower serum protein values) and speed (judged by A/G ratio changes and median survival time analysis) of capillary permeability changes were associated with high mortality, and therefore, it is possible to grade the severity of the condition in burn patients.


Reinforcement Learning, Fast and Slow.
Deep reinforcement learning (RL) methods have driven impressive advances in artificial intelligence in recent years, exceeding human performance in domains ranging from Atari to Go to no-limit poker. This progress has drawn the attention of cognitive scientists interested in understanding human learning. However, the concern has been raised that deep RL may be too sample-inefficient - that is, it may simply be too slow - to provide a plausible model of how humans learn. In the present review, we counter this critique by describing recently developed techniques that allow deep RL to operate more nimbly, solving problems much more quickly than previous methods. Although these techniques were developed in an AI context, we propose that they may have rich implications for psychology and neuroscience. A key insight, arising from these AI methods, concerns the fundamental connection between fast RL and slower, more incremental forms of learning.


Hepatitis C risk perceptions and attitudes towards reinfection among HIV-diagnosed gay and bisexual men in Melbourne, Australia.
Gay and bisexual men (GBM) are at increased risk of hepatitis C/HIV co-infection. In Australia, the availability of subsidized direct-acting antiviral treatment for hepatitis C has rendered eliminating co-infection possible. High reinfection rates in subgroups with continued exposure may compromise elimination efforts. To inform the development of hepatitis C risk reduction support in GBM, we explored reinfection risk perceptions and attitudes among GBM living with HIV recently cured from hepatitis C. Between April and August 2017, 15 GBM living with diagnosed HIV were recruited from high caseload HIV primary care services in Melbourne following successful hepatitis C treatment. In-depth interviews were conducted exploring understandings of hepatitis C risks, experiences of co-infection and attitudes towards reinfection. Constructivist grounded theory guided data aggregation. Participants' understandings of their hepatitis C infection and reinfection trajectories were captured in three categories. Hepatitis C and HIV disease dichotomies: Hepatitis C diagnosis was a shock to most participants and contrasted with feelings of inevitability associated with HIV seroconversion. While HIV was normalized, hepatitis C was experienced as highly stigmatizing. Despite injecting drug use, interviewees did not identify with populations typically at risk of hepatitis C. Risk environments and avoiding reinfection: Interviewees identified their social and sexual networks as risk-perpetuating environments where drug use was ubiquitous and higher risk sex was common. Avoiding these risk environments to avoid reinfection resulted in community disengagement, leaving many feeling socially isolated. Hepatitis C care as a catalyst for change: Engagement in hepatitis C care contributed to a better understanding of hepatitis C risks. Interviewees were committed to applying their improved competencies around transmission risk reduction to avoid reinfection. Interviewees also considered hepatitis C care as a catalyst to reduce their drug use. Hepatitis C/HIV co-infection among GBM cannot be understood in isolation from co-occurring drug use and sex, nor as separate from their HIV infection. Hepatitis C prevention must address subcultural heterogeneity and the intersectionality between multiple stigmatized social identities. Hepatitis C care presents an opportunity to provide support beyond cure. Peer support networks could mitigate social capital loss following a commitment to behaviour change and reduce hepatitis C reinfection risks.


Post-traumatic stress influences the brain even in the absence of symptoms: A systematic, quantitative meta-analysis of neuroimaging studies.
Stress affects brain function, and may lead to post-traumatic stress disorder (PTSD). Considerable empirical data for the neurobiology of PTSD has been derived from neuroimaging studies, although findings have proven inconsistent. We used an activation likelihood estimation analysis to explore differences in brain activity between adults with and without PTSD in response to affective stimuli. We separated studies by type of control group: trauma-exposed and trauma-naïve. This revealed distinct patterns of differences in functional activity. Compared to trauma-exposed controls, regions of the basal ganglia were differentially active in PTSD; whereas the comparison with trauma-naïve controls revealed differential involvement in the right anterior insula, precuneus, cingulate and orbitofrontal cortices known to be involved in emotional regulation. Changes in activity in the amygdala and parahippocampal cortex distinguished PTSD from both control groups. Results suggest that trauma has a measurable, enduring effect upon the functional dynamics of the brain, even in individuals who experience trauma but do not develop PTSD. These findings contribute to the understanding of whole-brain network activity following trauma, and its transition to clinical PTSD.


Ablation of TRalpha2 and a concomitant overexpression of alpha1 yields a mixed hypo- and hyperthyroid phenotype in mice.
Thyroid hormone governs a diverse repertoire of physiological functions through receptors encoded in the receptor genes alpha and beta, which each generate variant proteins. In mammals, the alpha gene generates, in addition to the normal receptor TRalpha1, a non-hormone-binding variant TRalpha2 whose exact function is unclear. Here, we present the phenotype associated with the targeted ablation of TRalpha2 expression. Selective ablation of TRalpha2 resulted in an inevitable, concomitant overexpression of TRalpha1. Both TRalpha2 +/- and -/- mice show a complex phenotype with low levels of free T3 and free T4, and have inappropriately normal levels of TSH. The thyroid glands exhibit mild morphological signs of dysfunction and respond poorly to TSH, suggesting that the genetic changes affect the ability of the gland to release thyroid hormones. However, the phenotype of the mutant mice also has features of hyperthyroidism, including decreased body weight, elevated heart rate, and a raised body temperature. Furthermore, TRalpha2-/- and TRalpha2+/- mice are obese and exhibit skeletal alterations, associated with a late-onset growth retardation. The results thus suggest that the overexpression of TRalpha1 and the concomitant decrease in TRalpha2 expression lead to a mixed hyper- and hypothyroid phenotype, dependent on the tissue studied. The phenotypes suggest that the balance of TRalpha1:TRalpha2 expressed from the TRalpha gene provides an additional level of tuning the control of growth and homeostasis in mammalian species.


Sarconesin II, a New Antimicrobial Peptide Isolated from Sarconesiopsis magellanica Excretions and Secretions.
Antibiotic resistance is at dangerous levels and increasing worldwide. The search for new antimicrobial drugs to counteract this problem is a priority for health institutions and organizations, both globally and in individual countries. Sarconesiopsis magellanica blowfly larval excretions and secretions (ES) are an important source for isolating antimicrobial peptides (AMPs). This study aims to identify and characterize a new S. magellanica AMP. RP-HPLC was used to fractionate ES, using C18 columns, and their antimicrobial activity was evaluated. The peptide sequence of the fraction collected at 43.7 min was determined by mass spectrometry (MS). Fluorescence and electronic microscopy were used to evaluate the mechanism of action. Toxicity was tested on HeLa cells and human erythrocytes; physicochemical properties were evaluated. The molecule in the ES was characterized as sarconesin II and it showed activity against Gram-negative (Escherichia coli MG1655, Pseudomonas aeruginosa ATCC 27853, P. aeruginosa PA14) and Gram-positive (Staphylococcus aureus ATCC 29213, Micrococcus luteus A270) bacteria. The lowest minimum inhibitory concentration obtained was 1.9 μM for M. luteus A270; the AMP had no toxicity in any cells tested here and its action in bacterial membrane and DNA was confirmed. Sarconesin II was documented as a conserved domain of the ATP synthase protein belonging to the Fli-1 superfamily. The data reported here indicated that peptides could be alternative therapeutic candidates for use in infections against Gram-negative and Gram-positive bacteria and eventually as a new resource of compounds for combating multidrug-resistant bacteria.


Abdominopelvic CT findings in patients with novel coronavirus disease 2019 (COVID-19).
Some patients with novel coronavirus disease 2019 (COVID-2019) present with abdominal symptoms. Abdominal manifestations of COVID on imaging are not yet established. The goal of this study was to quantify the frequency of positive findings on abdominopelvic CT in COVID-positive patients, and to identify clinical factors associated with positive findings to assist with imaging triage. This retrospective study included adult COVID-positive patients with abdominopelvic CT performed within 14 days of their COVID PCR nasal swab assay from 3/1/2020 to 5/1/2020. Clinical CT reports were reviewed for the provided indication and any positive abdominopelvic findings. Demographic and laboratory data closest to the CT date were recorded. Multivariate logistic regression model with binary outcome of having no reported positive abdominopelvic findings was constructed. Of 141 COVID-positive patients having abdominopelvic CT (average age 64 years [± 16], 91 [64%] women), 80 (57%) had positive abdominopelvic findings. Abdominal pain was the most common indication, provided in 54% (43/80) and 74% (45/61) of patients with and without reported positive abdominopelvic findings, respectively (p = 0.015). 70% (98/141) of patients overall had reported findings in the lung bases. Findings either typical or intermediate for COVID were reported in 50% (40/80) and 64% (39/61) of patients with and without positive abdominopelvic findings, respectively (p = 0.099). Of 80 patients with positive abdominopelvic findings, 25 (31%) had an abnormality of gastrointestinal tract, and 14 (18%) had solid organ infarctions or vascular thromboses. In multivariate analysis, age (OR 0.85, p = 0.023), hemoglobin (OR 0.83, p = 0.029) and male gender (OR 2.58, p = 0.032) were independent predictors of positive abdominopelvic findings, adjusted for race and Charlson comorbidity index. Abdominopelvic CT performed on COVID-positive patients yielded a positive finding in 57% of patients. Younger age, male gender, and lower hemoglobin were associated with higher odds of having reportable positive abdominopelvic CT findings.


Adrenocortical Challenge Response and Genomic Analyses in Scottish Terriers With Increased Alkaline Phosphate Activity.
Scottish terriers (ST) frequently have increased serum alkaline phosphatase (ALP) of the steroid isoform. Many of these also have high serum concentrations of adrenal sex steroids. The study's objective was to determine the cause of increased sex steroids in ST with increased ALP. Adrenal gland suppression and stimulation were compared by low dose dexamethasone (LDDS), human chorionic gonadotropin (HCG) and adrenocorticotropic hormone (ACTH) response tests. Resting plasma pituitary hormones were measured. Steroidogenesis-related mRNA expression was evaluated in six ST with increased ALP, eight dogs of other breeds with pituitary-dependent hyperadrenocorticism (HAC), and seven normal dogs. The genome-wide association of single nucleotide polymorphisms (SNP) with ALP activity was evaluated in 168 ST. ALP (reference interval 8-70 U/L) was high in all ST (1,054 U/L) and HAC (985 U/L) dogs. All HAC dogs and 2/8 ST had increased cortisol post-ACTH administration. All ST and 2/7 Normal dogs had increased sex steroids post-ACTH. ST and Normal dogs had similar post-challenge adrenal steroid profiles following LDDS and HCG. Surprisingly, mRNA of hydroxysteroid 17-beta dehydrogenase 2 (HSD17B2) was lower in ST and Normal dogs than HAC. HSD17B2 facilities metabolism of sex steroids. A SNP region was identified on chromosome 5 in proximity to HSD17B2 that correlated with increased serum ALP. ST in this study with increased ALP had a normal pituitary-adrenal axis in relationship to glucocorticoids and luteinizing hormone. We speculate the identified SNP and HSD17B2 gene may have a role in the pathogenesis of elevated sex steroids and ALP in ST.


Determination of in vitro activities of polymyxin B and rifampin in combination with ampicillin/sulbactam or cefoperazone/sulbactam against multidrug-resistant Acinetobacter baumannii by the E-test and checkerboard methods.
The aim of this study was to investigate the in vitro activities of polymyxin B (PB) and rifampin (RIF) in combination with ampicillin/sulbactam (AS) or cefoperazone/sulbactam (CS) against 20 multidrug-resistant Acinetobacter baumannii (MDR-AB) isolates by the checkerboard and E-test methods. Fractional inhibitory concentration index (FICI) values were defined as synergy, FICI ≤ 0.5; additivity, 0.5 < FICI ≤ 1.0, indifference, 1.0 < FICI < 4.0; and antagonism, FICI ≥ 4. Synergistic interaction was detected only for the RIF + AS and RIF + CS combinations. While the most frequently detected interaction type for PB + AS or PB + CS combinations was indifference, some showed antagonistic interactions. The detection rate of synergy was significantly higher by the checkerboard than by the E-test method, and the detection rate of indifference was significantly higher by the E-test than by the checkerboard method for RIF + AS combination (P ≤ 0.0001). In addition, no statistically significant difference was detected between the checkerboard and E-test methods for the detection rates of interaction types for any of the other combinations (P > 0.05), except for PB + CS combination for the detection of additivity (P = 0.018). Owing to the high percentage of synergistic interactions between RIF and AS, we considered this combination as an effective therapeutic option for MDR-AB infections.


Effect of virtual reality aggression prevention training for forensic psychiatric patients (VRAPT): study protocol of a multi-center RCT.
Many patients residing in forensic psychiatric centers have difficulties regulating their aggression in an adequate manner. Therefore, they are frequently involved in conflicts. Evidenced-based aggression therapies in forensic psychiatry are scarce, and due to the highly secured environment, it is hard to practice real-life provocations. We have developed a Virtual Reality aggression prevention training (VRAPT), providing safe virtual environments, in which patients can practice controlling their aggressive behaviors in an adequate way. The main objective of this study is to examine whether VRAPT is effective in reducing aggression among forensic psychiatric inpatients. Four forensic psychiatric centers in the Netherlands are participating in this study. Participants will be randomly assigned to either VRAPT or a waiting list. The two groups will be compared at several different time points: baseline (12 weeks before intervention), pre-intervention, post-intervention and at 12 weeks follow-up. After follow-up measurements are completed, participants from the waiting list will also receive VRAPT. The primary outcome is level of aggressive behavior, consisting of staff-reported and self-reported measures. Secondary outcomes are self-report questionnaires on e.g., anger, impulsivity and aggression. To the best of our knowledge this is the first study to examine the effectiveness of a VR aggression prevention training in forensic psychiatric centers. Further details on the methodological issues are discussed in this paper. Dutch Trial Register ( NTR, TC = 6340 ). Retrospectively registered 14-04-2017.


In vitro and in vivo efficacy of non-psychoactive cannabidiol in neuroblastoma.
Neuroblastoma (nbl) is one of the most common solid cancers in children. Prognosis in advanced nbl is still poor despite aggressive multimodality therapy. Furthermore, survivors experience severe long-term multi-organ sequelae. Hence, the identification of new therapeutic strategies is of utmost importance. Cannabinoids and their derivatives have been used for years in folk medicine and later in the field of palliative care. Recently, they were found to show pharmacologic activity in cancer, including cytostatic, apoptotic, and antiangiogenic effects. We investigated, in vitro and in vivo, the anti-nbl effect of the most active compounds in Cannabis, Δ(9)-tetrahydrocannabinol (thc) and cannabidiol (cbd). We set out to experimentally determine the effects of those compounds on viability, invasiveness, cell cycle distribution, and programmed cell death in human nbl SK-N-SH cells. Both compounds have antitumourigenic activity in vitro and impeded the growth of tumour xenografts in vivo. Of the two cannabinoids tested, cbd was the more active. Treatment with cbd reduced the viability and invasiveness of treated tumour cells in vitro and induced apoptosis (as demonstrated by morphology changes, sub-G1 cell accumulation, and annexin V assay). Moreover, cbd elicited an increase in activated caspase 3 in treated cells and tumour xenografts. Our results demonstrate the antitumourigenic action of cbd on nbl cells. Because cbd is a nonpsychoactive cannabinoid that appears to be devoid of side effects, our results support its exploitation as an effective anticancer drug in the management of nbl.


Stochastic facilitation of artificial tactile sensation in primates.
Artificial sensation via electrical or optical stimulation of brain sensory areas offers a promising treatment for sensory deficits. For a brain-machine-brain interface, such artificial sensation conveys feedback signals from a sensorized prosthetic limb. The ways neural tissue can be stimulated to evoke artificial sensation and the parameter space of such stimulation, however, remain largely unexplored. Here we investigated whether stochastic facilitation (SF) could enhance an artificial tactile sensation produced by intracortical microstimulation (ICMS). Two rhesus monkeys learned to use a virtual hand, which they moved with a joystick, to explore virtual objects on a computer screen. They sought an object associated with a particular artificial texture (AT) signaled by a periodic ICMS pattern delivered to the primary somatosensory cortex (S1) through a pair of implanted electrodes. During each behavioral trial, aperiodic ICMS (i.e., noise) of randomly chosen amplitude was delivered to S1 through another electrode pair implanted 1 mm away from the site of AT delivery. Whereas high-amplitude noise worsened AT detection, moderate noise clearly improved the detection of weak signals, significantly raising the proportion of correct trials. These findings suggest that SF could be used to enhance prosthetic sensation.


The physical health of British adults with intellectual disability: cross sectional study.
Adults with intellectual disability have poorer health than their non-disabled peers. However, little is known about the health of the 'hidden majority' of adults with primarily mild intellectual disability who do not use intellectual disability services. The aims of the present study were: to estimate the physical health status of a population-based sample of British adults with and without mild intellectual disability while controlling for any potentially confounding effects resulting from between-group differences in gender, age, socio-economic disadvantage and neighborhood social capital. Secondary analysis of data from Understanding Society, a new longitudinal study focusing on the life experiences of UK citizens. We identified 299 participants aged 16-49 (1.2 % of the unweighted age-restricted sample) as having intellectual disability, and 22,927 as not having intellectual disability. Multivariate logistic regression was used to investigate between group differences adjusting for potential confounding personal characteristics (e.g., gender). Unadjusted comparisons indicated that British adults with intellectual disability have markedly poorer health than their non-disabled peers on the majority of indicators investigated including self-rated health, multiple morbidity, arthritis, cancer, diabetes, obesity, measured grip strength, measured lung function and polypharmacy. Adjusting for between-group differences in age and gender had a marginal impact on these estimates. Further adjusting for between-group differences in socio-economic disadvantage and neighborhood quality had a more marked impact on estimates with the number of statistically significant differences reducing from 13 to 8 and statistically significant attenuation of odds on three indicators (self-rated health, SF-12 physical component and multiple morbidity). The 'hidden majority' of adults with primarily mild intellectual disability who do not use intellectual disability services have significantly poorer health than their non-disabled peers. This may, in part, reflect their increased risk of exposure to well established 'social determinants' of poorer health.


Development of SPAWM: selection program for available watershed models.
A selection program for available watershed models (also known as SPAWM) was developed. Thirty-three commonly used watershed models were analyzed in depth and classified in accordance to their attributes. These attributes consist of: (1) land use; (2) event or continuous; (3) time steps; (4) water quality; (5) distributed or lumped; (6) subsurface; (7) overland sediment; and (8) best management practices. Each of these attributes was further classified into sub-attributes. Based on user selected sub-attributes, the most appropriate watershed model is selected from the library of watershed models. SPAWM is implemented using Excel Visual Basic and is designed for use by novices as well as by experts on watershed modeling. It ensures that the necessary sub-attributes required by the user are captured and made available in the selected watershed model.


Expression of CD39 on FoxP3+ T regulatory cells correlates with progression of HBV infection.
Although it is known that regulatory T cells (Tregs) can suppress the function of effector T cells, and may contribute to impaired immune response, the precise role of Tregs during the course of hepatitis B virus (HBV) infection remains to be elucidated. A newly identified subset of the CD4+Foxp3+ Tregs, the CD39+ Tregs, has been associated with viral infections and autoimmune diseases. Therefore, we hypothesized that this discrete Treg subset may contribute to the chronic infection of HBV. Initial characterization studies of healthy peripheral CD39+FoxP3+CD4+ T cells revealed that the majority were CD45RA- Treg cells. Subsequent analysis of HBV-infected patients (38 asymptomatic HBV carriers (AsCs), 37 chronic active hepatitis B (CAH), 29 HBV-associated acute-on-chronic liver failure (ACLF)) and healthy individuals (25 controls) was conducted to assess association with HBV copy number and the liver injury marker alanine aminotransferase (ALT). A higher percentage of CD39+ Tregs was detected within the population of FoxP3+CD4+ T cells in peripheral blood of AsCs patients. Moreover, the percentage of CD39+ Tregs was significantly less in CAH and ACLF patients. The increased proportions of circulating CD39+ Tregs were positively correlated with serum viral load, but inversely correlated with serum ALT level. These findings not only suggest that CD39+ Treg cells may be involved in HBV disease progression but also identify CD39+ Tregs as a dynamic immune regulatory cell population that may represent a new target of immunomodulatory therapeutic interventions.


Hearing loss alters serotonergic modulation of intrinsic excitability in auditory cortex.
Sensorineural hearing loss during early childhood alters auditory cortical evoked potentials in humans and profoundly changes auditory processing in hearing-impaired animals. Multiple mechanisms underlie the early postnatal establishment of cortical circuits, but one important set of developmental mechanisms relies on the neuromodulator serotonin (5-hydroxytryptamine [5-HT]). On the other hand, early sensory activity may also regulate the establishment of adultlike 5-HT receptor expression and function. We examined the role of 5-HT in auditory cortex by first investigating how 5-HT neurotransmission and 5-HT(2) receptors influence the intrinsic excitability of layer II/III pyramidal neurons in brain slices of primary auditory cortex (A1). A brief application of 5-HT (50 μM) transiently and reversibly decreased firing rates, input resistance, and spike rate adaptation in normal postnatal day 12 (P12) to P21 rats. Compared with sham-operated animals, cochlear ablation increased excitability at P12-P21, but all the effects of 5-HT, except for the decrease in adaptation, were eliminated in both sham-operated and cochlear-ablated rats. At P30-P35, cochlear ablation did not increase intrinsic excitability compared with shams, but it did prevent a pronounced decrease in excitability that appeared 10 min after 5-HT application. We also tested whether the effects on excitability were mediated by 5-HT(2) receptors. In the presence of the 5-HT(2)-receptor antagonist, ketanserin, 5-HT significantly decreased excitability compared with 5-HT or ketanserin alone in both sham-operated and cochlear-ablated P12-P21 rats. However, at P30-P35, ketanserin had no effect in sham-operated and only a modest effect cochlear-ablated animals. The 5-HT(2)-specific agonist 5-methoxy-N,N-dimethyltryptamine also had no effect at P12-P21. These results suggest that 5-HT likely regulates pyramidal cell excitability via multiple receptor subtypes with opposing effects. These data also show that early sensorineural hearing loss affects the ability of 5-HT receptor activation to modulate A1 pyramidal cell excitability.


Selection of cell lines with enhanced invasive phenotype from xenografts of the human prostate cancer cell line WPE1-NB26.
Prostate cancer is a leading cause of death from cancer in American men and metastasis the main cause of death. To better understand the disease and accelerate development of new therapies, in vivo models that reflect different disease stages are needed. A family of cell lines that mimics multiple steps in cancer development and tumor progression has been developed in our laboratory from the parent, non-tumorigenic, RWPE-1 cell line by transformation with N-methyl-N-nitrosourea (MNU). The MNU cell lines mimic multiple steps in tumor progression where WPE1-NB26 is the most malignant cell line. WPE1-NB26 cells form metastases in the lungs of athymic, male, nude mice after intravenous injection. Two new cell lines, WPE1-NB26-64 and WPE1-NB26-65, showing more malignant characteristics than the parent WPE1-NB26 cell line, were derived from tumors after subcutaneous injection of WPE1-NB26 cells into nude mice. The WPE1-NB26-64 and WPE1-NB26-65 cell lines show an increase in anchorage-dependent growth and invasive ability as compared to the parent WPE1-NB26 cells. While the parent WPE1-NB26 cells express barely detectable levels, the new cell lines produce high levels of matrix metalloproteinase MMP-2 and detectable levels of MMP-9. By immunostaining, all three cell lines were positive for cytokeratins CK18 and CK5/14. These cell lines, having the same lineage, represent additional steps in the multi-step process of tumor progression and provide novel and useful cell models for studies on tumor progression and for drug development for the treatment of prostate cancer.


Human genetic variation in HIV disease: beyond genome-wide association studies.
Rapid expansion of genomic technologies has resulted in an unprecedented ability to interrogate the impact of human genetic variation on disease. HIV-1 infection is a unique model for studying this impact because host genetic variation influences both clinical outcome and the genetic sequence and evolution of the pathogen itself. Several candidate gene studies have proposed novel associations with HIV acquisition and/or disease progression; however, many of these are not supported by larger genome-wide association studies. Thus, controversy remains as to which host and viral genetic factors truly impact HIV infection. Novel methods for assessing the genetic (viral and host) component of disease progression are becoming important areas of investigation. To fully understand the impact of human genetic variation in HIV disease, the field will need to come together to set a standard for discovery of new genes. Additionally, novel avenues of investigation such as sequencing studies (to define the role of rare variants), studies of epistasis and host/viral genome interaction will be of great value.


Magnetic enzyme carrier for effective biofouling control in the membrane bioreactor based on enzymatic quorum quenching.
Quorum quenching, enzymatic quenching of bacterial quorum sensing, has recently proven its potential as a novel approach of biofouling control in the membrane bioreactor (MBR) for advanced wastewater treatment. However, the short catalytic lifetime and difficulty in recovering free enzyme hamper the successful application of the quorum quenching technique in the MBR under a long-term continuous operation. In this study, a magnetic enzyme carrier (MEC) was prepared by immobilizing the quorum quenching enzyme (acylase) on magnetic particles to overcome the technical limitations of free enzyme. The MEC showed no activity decrease under both continuous shaking for 14 days and 29 iterative cycles of reuse. Furthermore, the comparison of the MEC with free enzyme in a batch type MBR showed that the MEC efficiently alleviated the membrane biofouling and showed a great advantage over free enzyme in terms of recycled use and stability in mixed liquor. When the MEC was applied to the lab scale MBR in a continuous operation, it also enhanced the membrane permeability to a large extent compared with a conventional MBR with no enzyme.


Using actigraphy feedback to improve sleep in soldiers: an exploratory trial.
The objective of this study was to assess the impact of wearing an actigraph and receiving personalized feedback on the sleep of a high-risk occupational group: United States soldiers recently returned from a combat deployment. Following a baseline survey with a full sample, a subsample of soldiers wore an actigraph, received feedback, and completed a brief survey. Two months later, the full sample completed a follow-up survey. The actigraph intervention involved wearing an actigraph for 3 weeks and then receiving a personalized report about sleep patterns and an algorithm-based estimate of cognitive functioning derived from individual sleep patterns. Propensity score matching with a genetic search algorithm revealed that subjects in the actigraph condition (n=43) reported fewer sleep problems (t value = -2.55, P<.01) and getting more sleep hours (t value =1.97, P<.05) at follow-up than those in a matched comparison condition (n=43, weighted). There were no significant differences in functioning, somatic symptoms, and mental health outcomes (posttraumatic stress disorder symptoms and depression). A significant interaction indicated that the actigraph had a more beneficial effect on those with more somatic symptoms at baseline but not those with more sleep problems. Most participants rated the personalized report as helpful. Actigraphs combined with personalized reports may offer a useful, simple intervention to improve the sleep patterns of large, high-risk occupational groups.


Pericytes/vessel-associated mural cells (VAMCs) are the major source of key epithelial-mesenchymal transition (EMT) factors SLUG and TWIST in human glioma.
Epithelial-to-mesenchymal transition (EMT) is supposed to be responsible for increased invasion and metastases in epithelial cancer cells. The activation of EMT genes has further been proposed to be important in the process of malignant transformation of primary CNS tumors. Since the cellular source and clinical impact of EMT factors in primary CNS tumors still remain unclear, we aimed at deciphering their distribution in vivo and clinico-pathological relevance in human gliomas. We investigated 350 glioma patients for the expression of the key EMT factors SLUG and TWIST by immunohistochemistry and immunofluorescence related to morpho-genetic alterations such as EGFR-amplification, IDH-1 (R132H) mutation and 1p/19q LOH. Furthermore, transcriptional cluster and survival analyses were performed. Our data illustrate that SLUG and TWIST are overexpressed in gliomas showing vascular proliferation such as pilocytic astrocytomas and glioblastomas. EMT factors are exclusively expressed by non-neoplastic pericytes/vessel-associated mural cells (VAMCs). They are not associated with patient survival but correlate with pericytic/VAMC genes in glioblastoma cluster analysis. In summary, the upregulation of EMT genes in pilocytic astrocytomas and glioblastomas reflects the level of activation of pericytes/VAMCs in newly formed blood vessels. Our results underscore that the negative prognostic potential of the EMT signature in the group of diffuse gliomas of WHO grade II-IV does most likely not derive from glioma cells but rather reflects the degree of proliferating mural cells thereby constituting a potential target for future alternative treatment approaches.


The clinical presentation caused by truncating CHD8 variants.
Variants in the chromodomain helicase DNA-binding protein 8 (CHD8) have been associated with intellectual disability (ID), autism spectrum disorders (ASDs) and overgrowth and CHD8 is one of the causative genes for OGID (overgrowth and ID). We investigated 25 individuals with CHD8 protein truncating variants (PTVs), including 10 previously unreported patients and found a male to female ratio of 2.7:1 (19:7) and a pattern of common features: macrocephaly (62.5%), tall stature (47%), developmental delay and/or intellectual disability (81%), ASDs (84%), sleep difficulties (50%), gastrointestinal problems (40%), and distinct facial features. Most of the individuals in this cohort had moderate-to-severe ID, some had regression of speech (37%), seizures (27%) and hypotonia (27%) and two individuals were non-ambulant. Our study shows that haploinsufficiency of CHD8 is associated with a distinctive OGID syndrome with pronounced autistic traits and supports a sex-dependent penetrance of CHD8 PTVs in humans.


Temporal discounting of reward and the cost of time in motor control.
Why do movements take a characteristic amount of time, and why do diseases that affect the reward system alter control of movements? Suppose that the purpose of any movement is to position our body in a more rewarding state. People and other animals discount future reward as a hyperbolic function of time. Here, we show that across populations of people and monkeys there is a correlation between discounting of reward and control of movements. We consider saccadic eye movements and hypothesize that duration of a movement is equivalent to a delay of reward. The hyperbolic cost of this delay not only accounts for kinematics of saccades in adults, it also accounts for the faster saccades of children, who temporally discount reward more steeply. Our theory explains why saccade velocities increase when reward is elevated, and why disorders in the encoding of reward, for example in Parkinson's disease and schizophrenia, produce changes in saccade. We show that delay of reward elevates the cost of saccades, reducing velocities. Finally, we consider coordinated movements that include motion of eyes and head and find that their kinematics is also consistent with a hyperbolic, reward-dependent cost of time. Therefore, each voluntary movement carries a cost because its duration delays acquisition of reward. The cost depends on the value that the brain assigns to stimuli, and the rate at which it discounts this value in time. The motor commands that move our eyes reflect this cost of time.


The role of soluble fiber intake in patients under highly effective lipid-lowering therapy.
It has been demonstrated that statins can increase intestinal sterol absorption. Augments in phytosterolemia seems related to cardiovascular disease. We examined the role of soluble fiber intake in endogenous cholesterol synthesis and in sterol absorption among subjects under highly effective lipid-lowering therapy. In an open label, randomized, parallel-design study with blinded endpoints, subjects with primary hypercholesterolemia (n = 116) were assigned to receive during 12 weeks, a daily dose of 25 g of fiber (corresponding to 6 g of soluble fibers) plus rosuvastatin 40 mg (n = 28), rosuvastatin 40 mg alone (n = 30), sinvastatin 40 mg plus ezetimibe 10 mg plus 25 g of fiber (n = 28), or sinvastatin 40 mg plus ezetimibe 10 mg (n = 30) alone. The four assigned therapies produced similar changes in total cholesterol, LDL-cholesterol, and triglycerides (p < 0.001 vs. baseline) and did not change HDL-cholesterol. Fiber intake decreased plasma campesterol (p < 0.001 vs. baseline), particularly among those patients receiving ezetimibe (p < 0.05 vs. other groups), and β-sitosterol (p = 0.03 vs. baseline), with a trend for lower levels in the group receiving fiber plus ezetimibe (p = 0.07). Treatment with rosuvastatin alone or combined with soluble fiber was associated with decreased levels of desmosterol (p = 0.003 vs. other groups). Compared to non-fiber supplemented individuals, those treated with fibers had weight loss (p = 0.04), reduced body mass index (p = 0.002) and blood glucose (p = 0.047). Among subjects treated with highly effective lipid-lowering therapy, the intake of 25 g of fibers added favorable effects, mainly by reducing phytosterolemia. Additional benefits include improvement in blood glucose and anthropometric parameters.


Photolysis of inorganic chloramines and efficiency of trichloramine abatement by UV treatment of swimming pool water.
Trichloramine, one of the three inorganic chloramines (mono-, di- and trichloramine), is a problematic disinfection by-product in recreational pool water since it causes skin and eye irritations as well as irritations of the respiratory tract. The most commonly used chloramine mitigation strategy in pool water is UV treatment. Experiments with membrane inlet mass spectrometry (MIMS) confirmed that inorganic chloramines are effectively degraded by UV irradiation with low-pressure (LP) and medium-pressure (MP) mercury lamps (apparent quantum yields (QY): NH2Cl = 0.50 (LP) and 0.31 (MP) mol einstein(-1), NHCl2: 1.06 (LP) and 0.85 (MP) mol einstein(-1)). Trichloramine showed the fastest depletion with a quantum yield slightly above 2 mol einstein(-1) in purified (LP and MP) and pool water (MP). This high quantum yield can partly be explained by reactions involving OH radicals (purified water) and the reaction of trichloramine with moieties formed during UV irradiation of pool water. The presence of free chlorine affects trichloramine degradation (QY: ∼1.5 mol einstein(-1)) since it scavenges OH radicals and competes with trichloramine for reactive species (e.g. organic amines). Measurements in a pool facility revealed that the installed UV reactors degraded trichloramine by 40-50% as expected from laboratory experiments. However, trichloramine reduction in the pools was less pronounced than in the UV reactors. Model calculations combining pool hydraulics with formation/abatement of trichloramine showed that there was a fast trichloramine formation in the pool from the residual chlorine and nitrogenous precursors. The main factors influencing trichloramine concentrations in pool water are the free chlorine concentration and the UV treatment in combination with the recirculation rate through the water treatment system.


Mechanisms of nutritive endocytosis. I. Phagocytic versatility and cellular recognition in Chlorohydra digestive cells, a scanning electron microscope study.
The quantity of surface membrane internalized during phagocytosis by Chlorohydra digestive cells was estimated for a range of particle types. Challenge with 2 of these particles, freshly isolated symbiotic algae (FIS) and latex spheres (LS), resulted in a greater (2.5 X) quantity of surface membrane interiorized than with heat-treated symbiotic algae (HTS) and free living algae (FA), Chlorella vulgaris. This discriminatory process was investigated further by a scanning electron microscope (SEM) and transmission electron microscope (TEM) comparison of the surface events associated with phagocytosis of each of these 4 particles. Those particles that were avidly phagocytized, FIS and LS, were both enveloped by a tightly fitting extension of digestive-cell surface, and obtained a prominent surface coating after their injection into the gut of Chlorohydra. Phagocytic challenge with FIS resulted, furthermore, in the rapid formation of a dense microvillar cover on digestive-cell surfaces. HTS and FA, on the other hand, were enveloped by a less closely fitting extension of digestive-cell surface, did not obtain a prominent surface coating, and did not induce the formation of microvilli. In addition, SEM revealed that at least 3 morphologically distinct phagocytic modes were utilized by the versatile nutritive phagocyte of Chlorohydra: (I) envelopment by the progressive movement of numerous, overlapping tubular protrusions (microvilli) over the particle (FIS) surface, forming first a network of tubular interlocking members, and finally a continuous but rough enclosing surface; (2) envelopment by a single, smooth-surfaced, funnel-like extension of digestive-cell surface (FIS, LS, HTS, FA); and (3) envelopment by multiple, broad folds, often of unequal size, and with overlapping margins (Artemia particles).


Removal of contaminants and pathogens from secondary effluents using intermittent sand filters.
Intermittent infiltration percolation of wastewater through unsaturated sand bed is an extensive treatment technique aimed at eliminating organic matter, oxidizing ammonium and removing pathogens. The main purpose of this study was to determine the depuration efficiencies of a sand filter to remove contaminants from secondary wastewater effluents. Elimination of pathogenic bacteria (total and faecal coliforms, streptococci) and their relationship with the filter depth were investigated. Results showed a high capacity of infiltration percolation process to treat secondary effluents. Total elimination of suspended solids was obtained. Mean removal rate of BOD(5) and COD was more than 97 and more than 81%, respectively. Other water quality parameters such as NH(4)-N, TKN and PO(4)-P showed significant reduction except NO(3)-N which increased significantly in the filtered water. Efficiency of pathogenic bacteria removal was shown to mainly depend on the filter depth. Average reductions of 2.35 log total coliforms, 2.47 log faecal coliforms and 2.11 log faecal streptococci were obtained. The experimental study has shown the influence of the temperature on the output purification of infiltration percolation process.


Distinct signal codes generate dendritic cell functional plasticity.
Our adaptive immune system induces distinct responses to different pathogens because of the functional plasticity of dendritic cells (DCs); however, how DCs program unique responses remains unclear. Here, we found that the cytokine thymic stromal lymphopoietin (TSLP) potently transduced a unique T helper type 2 (T(H)2)-inducing compound signal in DCs. Whereas activation of nuclear factor kappaB (predominantly p50) drove DCs to produce OX40L to induce T(H)2 differentiation, the activation of signal transducer and activator of transcription 6 (STAT6) triggered DCs to secrete chemokines necessary for the recruitment of T(H)2 cells. In addition, TSLP signaling limited the activation of STAT4 and interferon regulatory factor 8 (IRF-8), which are essential factors for the production of the T(H)1-polarizing cytokine interleukin-12 (IL-12). By contrast, Toll-like receptor ligands and CD40 ligand did not activate STAT6 in myeloid DCs, but instead increased the abundance of STAT4 and IRF-8 to induce T(H)1 responses through the production of IL-12. Therefore, we propose that the functional plasticity of DCs relies on elaborate signal codes that are generated by different stimuli.


"Family Matters": A Systematic Review of the Evidence For Family Psychoeducation For Major Depressive Disorder.
The first aim of this systematic review was to evaluate the evidence for family psychoeducation (FPE) interventions for major depressive disorder (MDD). A second aim was to compare the efficacy of different modes of delivering face-to-face FPE interventions. Ten studies (based on nine distinct samples) were identified comprising four single-family studies, four multifamily studies, one single versus multifamily comparative study, and one peer-led, mixed-diagnosis study. Seven studies measured patient functioning and six reported positive outcomes. Six studies measured carer's well-being and four reported positive outcomes. Results provide preliminary evidence that FPE leads to improved outcomes for patient functioning and family-carer's well-being for persons with depression. The implications for future development and delivery of FPE interventions for MDD are discussed.


Ataxin-3 is subject to autolytic cleavage.
The protein ataxin-3 is responsible for spinocerebellar ataxia type 3, a neurodegenerative disease triggered when the length of a stretch of consecutive glutamines exceeds a critical threshold. Different physiologic roles have been suggested for this protein. More specifically, recent papers have shown that the highly conserved N-terminal Josephin domain of ataxin-3 binds ubiquitin and has ubiquitin hydrolase activity, thanks to a catalytic device specific to cysteine proteases. This article shows that the protein also has autoproteolytic activity, sustained by the same residues responsible for the ubiquitin hydrolase activity. The autolytic activity was abolished when these residues, i.e. Cys14 and His119, were replaced by noncatalytic ones. Furthermore, we found that pretreatment of the protein with tosyl l-phenylalanine chloromethyl ketone also abolished this activity, and that this site-specific reagent covalently bound His119, findings supported by MS experiments. MS also allowed us to establish that the attack was aspecific, as cleavage sites were observed at the carboxyl side of apolar, acidic and polar uncharged residues, clustered in the C-terminal, unstructured domain of the protein. In contrast, the Josephin domain was preserved from attack. We propose that the autolytic activity reported here may play a role in pathogenesis, as fragments carrying expanded polyglutamines are thought to be significantly more toxic than the whole protein.


A unified diabatic description for electron transfer reactions, isomerization reactions, proton transfer reactions, and aromaticity.
While diabatic approaches are ubiquitous for the understanding of electron-transfer reactions and have been mooted as being of general relevance, alternate applications have not been able to unify the same wide range of observed spectroscopic and kinetic properties. The cause of this is identified as the fundamentally different orbital configurations involved: charge-transfer phenomena involve typically either 1 or 3 electrons in two orbitals whereas most reactions are typically closed shell. As a result, two vibrationally coupled electronic states depict charge-transfer scenarios whereas three coupled states arise for closed-shell reactions of non-degenerate molecules and seven states for the reactions implicated in the aromaticity of benzene. Previous diabatic treatments of closed-shell processes have considered only two arbitrarily chosen states as being critical, mapping these states to those for electron transfer. We show that such effective two-state diabatic models are feasible but involve renormalized electronic coupling and vibrational coupling parameters, with this renormalization being property dependent. With this caveat, diabatic models are shown to provide excellent descriptions of the spectroscopy and kinetics of the ammonia inversion reaction, proton transfer in N2H7(+), and aromaticity in benzene. This allows for the development of a single simple theory that can semi-quantitatively describe all of these chemical phenomena, as well as of course electron-transfer reactions. It forms a basis for understanding many technologically relevant aspects of chemical reactions, condensed-matter physics, chemical quantum entanglement, nanotechnology, and natural or artificial solar energy capture and conversion.


Socioenvironmental factors associated with heat and cold-related mortality in Vadu HDSS, western India: a population-based case-crossover study.
Ambient temperatures (heat and cold) are associated with mortality, but limited research is available about groups most vulnerable to these effects in rural populations. We estimated the effects of heat and cold on daily mortality among different sociodemographic groups in the Vadu HDSS area, western India. We studied all deaths in the Vadu HDSS area during 2004-2013. A conditional logistic regression model in a case-crossover design was used. Separate analyses were carried out for summer and winter season. Odds ratios (OR) and 95% confidence intervals (CI) were estimated for total mortality and population subgroups. Temperature above a threshold of 31 °C was associated with total mortality (OR 1.48, CI = 1.05-2.09) per 1 °C increase in daily mean temperature. Odds ratios were higher among females (OR 1.93; CI = 1.07-3.47), those with low education (OR 1.65; CI = 1.00-2.75), those owing larger agricultural land (OR 2.18; CI = 0.99-4.79), and farmers (OR 1.70; CI = 1.02-2.81). In winter, per 1 °C decrease in mean temperature, OR for total mortality was 1.06 (CI = 1.00-1.12) in lag 0-13 days. High risk of cold-related mortality was observed among people occupied in housework (OR = 1.09; CI = 1.00-1.19). Our study suggests that both heat and cold have an impact on mortality particularly heat, but also, to a smaller degree, cold have an impact. The effects may differ partly by sex, education, and occupation. These findings might have important policy implications in preventing heat and cold effects on particularly vulnerable groups of the rural populations in low and middle-income countries with hot semi-arid climate.


Fluoride for the treatment of postmenopausal osteoporotic fractures: a meta-analysis.
We conducted an effectiveness meta-analysis to determine the efficacy of fluoride therapy on bone loss, vertebral and nonvertebral fractures and side effects in postmenopausal women. A literature search was conducted on MEDLINE, Current Contents and the Cochrane Controlled Trial Registry. Two independent reviewers selected randomized controlled trials which met predetermined inclusion criteria. They independently extracted data using predetermined forms and assessed the methodologic quality of the trials using a validated scale. For dichotomous outcomes, the relative risk (RR) was calculated, and for continuous outcomes, the weighted mean difference (WMD) of percentage change from baseline was calculated. Where heterogeneity existed (determined by a chi-square test) a random effects model was used. Eleven studies (1429 subjects) met the inclusion criteria. The increase in lumbar spine bone mineral density (BMD) was found to be higher in the treatment group than in the control group with a WMD 8.1% (95% CI: 7.15, 9.09) after 2 years of treatment and 16.1% (95% CI: 14.65, 17.5) after 4 years. The RR for new vertebral fractures was not significant at 2 years [0.87 (95% CI: 0.51, 1.46)] or at 4 years [0.9 (95% CI: 0.71, 1.14)]. The RR for new nonvertebral fractures was not significant at 2 years [1.2 (95% CI: 0.68, 2.10)] but was increased at 4 years in the treated group [1.85 (95% CI: 1.36, 2.50)], especially if used at high doses and in a non-slow-release form. The RR for gastrointestinal side effects was not significant at 2 years [2.18 (95% CI: 0.86, 1.21)] but was increased at 4 years in the treated group [2.18 (95% CI: 1.69, 4.57)], especially if fluoride was used at high doses and in a non-slow-release form. The number of withdrawals and dropouts was not different between treated and control groups at 2 and 4 years. Thus, although fluoride has an ability to increase bone mineral density at the lumbar spine, it does not result in a reduction in vertebral fractures. Increasing the dose of fluoride increases the risk of nonvertebral fractures and gastrointestinal side effects without any effect on the vertebral fracture rate.


Changes of mate occur in Schistosoma mansoni.
Male and female schistosomes are generally assumed to form stable monogamous pairs for the whole span of their long existence in the mammalian host. Recent evidence from mixed infections has shown that Schistosoma mansoni males can displace S. intercalatum males from their homologous partners, but no information exists about the existence of similar phenomena within a single schistosome species. Here, we determine whether male S. mansoni can displace males of the same species from pre-formed pairs in vivo. The availability of clear-cut genetic markers of drug resistance in schistosomes was exploited to show that hycanthone sensitive S. mansoni males can displace homospecific hycanthone resistant males from pre-formed pairs and vice versa. The frequency of changes is dependent on the magnitude of the excess single males competing with paired worms. The possible mechanics and the biological significance of mate changing are discussed.


Examining the effect of Withania somnifera supplementation on muscle strength and recovery: a randomized controlled trial.
Withania somnifera (ashwagandha) is a prominent herb in Ayurveda. This study was conducted to examine the possible effects of ashwagandha root extract consumption on muscle mass and strength in healthy young men engaged in resistance training. In this 8-week, randomized, prospective, double-blind, placebo-controlled clinical study, 57 young male subjects (18-50 years old) with little experience in resistance training were randomized into treatment (29 subjects) and placebo (28 subjects) groups. Subjects in the treatment group consumed 300 mg of ashwagandha root extract twice daily, while the control group consumed starch placebos. Following baseline measurements, both groups of subjects underwent resistance training for 8 weeks and measurements were repeated at the end of week 8. The primary efficacy measure was muscle strength. The secondary efficacy measures were muscle size, body composition, serum testosterone levels and muscle recovery. Muscle strength was evaluated using the 1-RM load for the bench press and leg extension exercises. Muscle recovery was evaluated by using serum creatine kinase level as a marker of muscle injury from the effects of exercise. Compared to the placebo subjects, the group treated with ashwagandha had significantly greater increases in muscle strength on the bench-press exercise (Placebo: 26.4 kg, 95% CI, 19.5, 33.3 vs. Ashwagandha: 46.0 kg, 95% CI 36.6, 55.5; p = 0.001) and the leg-extension exercise (Placebo: 9.8 kg, 95% CI, 7.2,12.3 vs. Ashwagandha: 14.5 kg, 95 % CI, 10.8,18.2; p = 0.04), and significantly greater muscle size increase at the arms (Placebo: 5.3 cm(2), 95% CI, 3.3,7.2 vs. Ashwagandha: 8.6 cm(2), 95% CI, 6.9,10.8; p = 0.01) and chest (Placebo: 1.4 cm, 95% CI, 0.8, 2.0 vs. Ashwagandha: 3.3 cm, 95% CI, 2.6, 4.1; p < 0.001). Compared to the placebo subjects, the subjects receiving ashwagandha also had significantly greater reduction of exercise-induced muscle damage as indicated by the stabilization of serum creatine kinase (Placebo: 1307.5 U/L, 95% CI, 1202.8, 1412.1, vs. Ashwagandha: 1462.6 U/L, 95% CI, 1366.2, 1559.1; p = 0.03), significantly greater increase in testosterone level (Placebo: 18.0 ng/dL, 95% CI, -15.8, 51.8 vs. Ashwagandha: 96.2 ng/dL, 95% CI, 54.7, 137.5; p = 0.004), and a significantly greater decrease in body fat percentage (Placebo: 1.5%, 95% CI, 0.4%, 2.6% vs. Ashwagandha: 3.5%, 95% CI, 2.0%, 4.9%; p = 0.03). This study reports that ashwagandha supplementation is associated with significant increases in muscle mass and strength and suggests that ashwagandha supplementation may be useful in conjunction with a resistance training program.


Reconstitution of a MEC1-independent checkpoint in yeast by expression of a novel human fork head cDNA.
A novel human cDNA, CHES1 (checkpoint suppressor 1), has been isolated by suppression of the mec1-1 checkpoint mutation in Saccharomyces cerevisiae. CHES1 suppresses a number of DNA damage-activated checkpoint mutations in S. cerevisiae, including mec1, rad9, rad24, dun1, and rad53. CHES1 suppression of sensitivity to DNA damage is specific for checkpoint-defective strains, in contrast to DNA repair-defective strains. Presence of CHES1 but not a control vector resulted in G2 delay after UV irradiation in checkpoint-defective strains, with kinetics, nuclear morphology, and cycloheximide resistance similar to those of a wild-type strain. CHES1 can also suppress the lethality, UV sensitivity, and G2 checkpoint defect of a mec1 null mutation. In contrast to this activity, CHES1 had no measurable effect on the replication checkpoint as assayed by hydroxyurea sensitivity of a mec1 strain. Sequence analysis demonstrates that CHES1 is a novel member of the fork head/Winged Helix family of transcription factors. Suppression of the checkpoint-defective phenotype requires a 200-amino-acid domain in the carboxy terminus of the protein which is distinct from the DNA binding site. Analysis of CHES1 activity is most consistent with activation of an alternative MEC1-independent checkpoint pathway in budding yeast.


Do scleroderma patients look young?: Evaluation by using facial imaging system.
These days various collagen supplements have widely been marketed. However, it has not been scientifically proved whether increasing collagen can actually prevent skin aging. Systemic sclerosis (SSc) is an autoimmune disease that is characterized by thickening of the skin caused by accumulation of collagen. In this study, we tried to evaluate facial skin characteristics and skin aging of SSc patients by using digital imaging system. As the result, the severity of wrinkles, texture and pores were significantly lower in SSc patients than control subjects. Among them, wrinkles showed better correlation with skin thickness score. Therefore, increased amount of collagen in scleroderma skin may directly affect wrinkles. In conclusion, attempt on collagen induction itself is reasonable and effective strategy in order to keep young appearance, although oral collagen supplementation may not directly reach to the skin.


Habitat modification for mosquito control in the Ilparpa Swamp, Northern Territory, Australia.
Habitat modification is an established method of effective long-term mosquito management, particularly in salt-marsh environments. It is especially pertinent when mosquitoes are known vectors of life-threatening disease and their larval breeding habitat is in close proximity to residential areas. The Ilparpa Swamp is located less than 10 km from Alice Springs, Northern Territory. Wet season rainfall, often followed by effluent discharges to the swamp from the adjacent sewage treatment plant, create ideal sites for the immature stages of the common banded mosquito Culex annulirostris (Skuse), a major vector of Murray Valley encephalitis (MVEV) and Kunjin (KUNV) viruses. Subsequent to increases in notifications of MVEV disease cases in 2000 and 2001, a drainage system was established in the Ilparpa Swamp in early 2002. This paper evaluates the drainage intervention effects. Results indicate a significant reduction in mosquito numbers following habitat modification, which remain low. There have been no seroconversions in sentinel chickens to MVEV or KUNV and no human infections from these viruses in the Alice Springs urban region since the drains were completed. Habitat modification has successfully reduced mosquito numbers and minimized the risk for mosquito-borne disease to residents in Alice Springs urban and surrounding areas, which has never before been documented in Australia.


Long-term follow-up of proximal versus distal laparoscopic gastric bypass for morbid obesity.
Laparoscopic gastric bypass is the 'gold standard' for treatment of morbidly obese patients in many centres. There is debate regarding the optimal length for small bowel limbs. This study aimed to determine whether the proximal or distal approach is better. Twenty-five patients undergoing primary distal gastric bypass in 2000-2002 were randomly matched for age, sex and preoperative body mass index (BMI) with 25 patients having a primary proximal bypass. All distal operations were performed laparoscopically; one proximal procedure was converted to open surgery. Mean operating time was 170 min for proximal and 242 min for distal bypasses (P = 0.004); median hospital stay was similar in the two groups. There were no deaths and the overall complication rate was similar, as was weight loss at 4 years: BMI decreased from 45.9 to 31.7 kg/m2 for the proximal and from 45.8 to 33.1 kg/m2 for the distal approach. Co-morbidities decreased after surgery in both groups; the prevalence of diabetes, arterial hypertension and dyslipidaemia at all time points was similar in the two groups. Proximal and distal laparoscopic gastric bypass operations are feasible and safe, with no differences in weight loss or reduction of co-morbidity in unselected morbidly obese patients.


Multimodality endoscopic optical coherence tomography and fluorescence imaging technology for visualization of layered architecture and subsurface microvasculature.
Endoscopic imaging technologies, such as endoscopic optical coherence tomography (OCT) and near-infrared fluorescence, have been used to investigate vascular and morphological changes as hallmarks of early cancer in the gastrointestinal tract. Here we developed a high-speed multimodality endoscopic OCT and fluorescence imaging system. Using this system, the architectural morphology and vasculature of the rectum wall were obtained simultaneously from a Sprague Dawley rat in vivo. This multimodality imaging strategy in a single imaging system permits the use of a single imaging probe, thereby improving prognosis by early detection and reducing costs.


Prescription practices in the treatment of first-episode schizophrenia spectrum disorders: data from the national RAISE-ETP study.
Treatment guidelines suggest distinctive medication strategies for first-episode and multiepisode patients with schizophrenia. To assess the extent to which community clinicians adjust their usual treatment regimens for first-episode patients, the authors examined prescription patterns and factors associated with prescription choice in a national cohort of early-phase patients. Prescription data at study entry were obtained from 404 participants in the Recovery After an Initial Schizophrenia Episode Project's Early Treatment Program (RAISE-ETP), a nationwide multisite effectiveness study for patients with first-episode schizophrenia spectrum disorders. Treatment with antipsychotics did not exceed 6 months at study entry. The authors identified 159 patients (39.4% of the sample) who might benefit from changes in their psychotropic prescriptions. Of these, 8.8% received prescriptions for recommended antipsychotics at higher than recommended dosages; 32.1% received prescriptions for olanzapine (often at high dosages), 23.3% for more than one antipsychotic, 36.5% for an antipsychotic and also an antidepressant without a clear indication, 10.1% for psychotropic medications without an antipsychotic, and 1.2% for stimulants. Multivariate analysis showed evidence for sex, age, and insurance status effects on prescription practices. Racial and ethnic effects consistent with effects reported in previous studies of multiepisode patients were found in univariate analyses. Despite some regional variations in prescription practices, no region consistently had different practices from the others. Diagnosis had limited and inconsistent effects. Besides prescriber education, policy makers may need to consider not only patient factors but also service delivery factors in efforts to improve prescription practices for first-episode schizophrenia patients.


Foods, nutrients or whole diets: effects of targeting fish and LCn3PUFA consumption in a 12mo weight loss trial.
There is some evidence in the literature that emphasising fish consumption may assist with weight loss. The aim was to assess the effects of advice to consume 2 fish meals per week in a weight loss diet. A parallel randomised placebo-controlled trial was conducted in 118 obese Australian adults (mean BMI ± SD 31.3 ± 3.5 kg/m2; mean age ± SD 45 ± 10 y; 28% male). Participants received low calorie dietary advice+placebo (1 g olive oil; CONTROL), low calorie dietary advice emphasising fish+placebo (Fish), or low calorie dietary advice emphasising fish diet + LCn3PUFA supplements (Fish+S). Individualised advice targeted 2 MJ energy deficit (30%E fat, 45%E carbohydrate and 25%E protein) with or without two servings (180 g) fatty fish/wk. All groups lost weight at 12 months (CONTROL -4.5 kg vs. Fish -4.3 kg vs. Fish+S -3.3 kg; p<0.001) and percentage body fat ( -1.5% vs. Fish: -1.4% vs. Fish+S: -0.7%; p<0.001) but there were no significant differences between groups. Cardiovascular disease risk factors changed as expected from weight loss. Advice to consume 2 fish meals per week did not enhance the effects on weight loss of a healthy low calorie diet. ACTRN12608000425392.


Mobilizing resources with an investment case to mitigate cross-border malaria transmission and achieve malaria elimination in South Africa.
South Africa's effort to eliminate malaria is significantly challenged by a large number of imported malaria cases, especially from neighbouring Mozambique. The country has a funding gap to achieve its malaria elimination goals (prior to 2019) and is ineligible to receive a national allocation from the Global Fund. The findings of an IC were utilised to successfully mobilise resources for malaria elimination in South Africa in 2018. A five-step resource mobilisation strategy was implemented to highlight financing challenges and leverage the economic evidence from an IC for malaria elimination in South Africa. South Africa's malaria programme implements control and elimination activities in three malaria-endemic provinces (KwaZulu Natal, Limpopo, and Mpumalanga). Driven by the IC findings, the South African government took an unprecedented step and increased total domestic malaria financing by approximately 36%, from the 2018/19 to the 2019/20 financial years through the creation of a new conditional grant for malaria. The IC findings predicted that malaria control in southern Mozambique is a prerequisite to eliminate malaria in South Africa. Based on this, the South African government also allocated funding towards a co-financing mechanism to support malaria control efforts in southern Mozambique. The IC findings assisted the South African National Department of Health to make a convincing case to key government decision-makers to invest in national malaria elimination and maximise economic returns in the long run. The South African government is the first in Southern Africa to mobilise a significant increase in domestic malaria financing to address the financial sustainability of both national and regional malaria elimination efforts. Continued surveillance activities will be required to prevent the re-establishment of malaria transmission even after malaria elimination is achieved in South Africa. Information sharing and close collaboration with provincial and national government officials were key to the successful outcome.


Effect of altered membrane structure on NK cell-mediated cytotoxicity. II. Conversion of NK-resistant tumor cells into NK-sensitive targets upon fusion with liposomes containing NK-sensitive membranes.
There is a large body of evidence that supports the notion that NK cells exert important immune surveillance functions in vivo, against a variety of virus-infected and neoplastic cells. However, certain targets are not susceptible to lysis by NK cells. The exact mechanism by which resistance or sensitivity is conferred on target cells is not known. We investigated whether the selectivity to NK lysis is a property of the membrane of the target cell. This was examined by the application of a recently developed method which is aimed at changing the membrane structure of the target cell by cell-liposome fusion. Our studies demonstrate that NK-resistant tumor cells acquired sensitivity to lysis by NK cells after fusion with reconstituted vesicles which contained membrane components derived from NK-sensitive target cells. The fusion required the presence of Sendai virus envelope glycoproteins and exogenous lipids (soybean lecithin and cholesterol) for maximal efficiency. This finding was demonstrated in both the human system (with U937 and Raji as NK-sensitive and -resistant cell lines, respectively) and the rat/murine system (with YAC-1 as NK-sensitive target and P815 and YAC-asc as NK-resistant targets). Both the 51Cr-release assay and the single cell assay showed lysis of the modified target cells in a 3-hr incubation period. The magnitude of the cytotoxic activity was found to depend on the concentration of reconstituted vesicles used in the fusion step. The effect seen was specific because target cells were not lysed when fused with vesicles which contained membrane constituents derived from either NK-resistant targets or NK-sensitive targets from another species (human vs mouse). The resistance of modified target cells to lysis by xenogeneic NK cells was not due to failure of membrane fusion, as detected by immunofluorescence, or to failure to form conjugates. These results demonstrate the feasibility of converting a resistant NK target to a sensitive target by cell-liposome fusion. Furthermore, the data indicate that susceptibility to lysis by NK cells is a property of the membrane composition of the target cell. The significance of these findings is discussed.


Surrogate markers of infection: interrogation of the immune system.
Infectious diseases remain the greatest causes of morbidity and mortality in global terms. As much of the burden occurs in the developing world, limited access to diagnostic testing has hampered the diagnosis and treatment of these conditions, while, in the developed world, the cost of managing infectious diseases remains considerable. Despite the size of the problem there remains an ongoing need for tests that improve diagnostic sensitivity and specificity, provide more rapid diagnoses, are available for point-of-care testing in remote regions, and can help inform therapeutic decision-making by identifying resistance patterns or patient outcomes. This article discusses the background to biomarker development for infectious diseases, some current assays that are providing useful information regarding the host's response to infection (using examples such as Cytomegalovirus and Mycobacterium tuberculosis), as well as likely future technologies and their limitations.


Microsurgical obliteration of a thoracic spinal perimedullary arteriovenous fistula.
Spinal vascular lesions are rare and may be classified as a) dural arteriovenous fistulas (AVFs), b) arteriovenous malformations, or c) perimedullary AVFs. In this narrated video illustration, we present the case of a 71-year-old woman who presented with progressive bilateral lower extremity weakness and urinary retention who was diagnosed with a thoracic spinal perimedullary arteriovenous fistula. The diagnostic studies included a thoracic MRI and spinal angiogram. A multilevel thoracic laminoplasty was performed for microsurgical obliteration of the AVF. The techniques of intraoperative angiography, thoracic laminoplasty and microsurgical obliteration and resection of the AVF are reviewed. The video can be found here: http://youtu.be/5vVp3oq5sLg.


Dysregulation of the gut-brain axis in schizophrenia and bipolar disorder: probiotic supplementation as a supportive treatment in psychiatric disorders.
Schizophrenia (SCZ) and bipolar disorder are severe mental disorders, both placing a significant burden on individuals' wellbeing and global health generally. The complex interaction of multiple mechanisms, underlying these disorders, still needs further elucidation. Increased activation of components of the immune system may be involved, including alterations in intestinal permeability and gut microbiome. Probiotics, defined as living microorganisms conferring health benefits to the host when administered in adequate amounts, seem to have supportive therapeutic effect in psychiatric disorders. The authors in this review provide an overview of this emerging research field and summarize both the publicated microbiome studies in SCZ and bipolar disorder and the current clinical research using probiotic supplementation in patients diagnosed with these disorders. The current data indicate that there are differences in the microbiome in SCZ and bipolar disorder patients as compared with healthy controls. Part of these differences may be induced by medication use, others by smoking and other lifestyle factors. Correlations between microbiome quantification and symptom severity have been observed in cross-sectional studies, but unfortunately, no replicated findings so far. Probiotic supplementation was shown not only to alleviate gastrointestinal complaints but also reduce symptom severity, rehospitalization rates and cognitive improvement. Replication of improvement of cognition is needed. Differences in microbiome have been shown in both SCZ and bipolar disorder in comparison to healthy controls. Evidence that probiotics can improve psychiatric functioning is still very limited.


A comparison of the behavioural effects of embryonic nigral grafts in the caudate nucleus and in the putamen of marmosets with unilateral 6-OHDA lesions.
The behaviour of marmosets with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle and grafts of embryonic mesencephalon in either the caudate nucleus or the putamen was compared with that of lesion-alone and unoperated controls. The grafts comprised injections of cell suspensions prepared from marmoset ventral mesencephalon (i.e. allografts) targeted at four sites either entirely within the caudate nucleus or entirely within the putamen. Behavioural tests, including measures of amphetamine-induced rotation, neglect and use of each arm to retrieve food from inside tubes, were given before and after the 6-hydroxydopamine lesion and at regular intervals for 6 months after transplantation surgery. Grafts in the caudate nucleus reduced the ipsilateral rotation induced by amphetamine, whereas grafts in the putamen did not. Despite the absence of an effect on rotation, the putamen grafts were effective in reducing lesion-induced deficits on the task in which the marmosets were required to reach into tubes. In this latter task, the caudate grafts were also effective when the monkeys were given a free choice of which hand to use. However, when constrained to use the hand contralateral to the lesion and graft, the performance of the marmosets with caudate grafts was not significantly improved compared with that of lesion-alone controls. Neither the grafts in the caudate nucleus nor the grafts in the putamen abolished the contralateral somatosensory neglect induced by the lesion, although there was a trend for the marmosets with putamen grafts to contact the label on the contralateral side more quickly than those with caudate grafts or the lesion-alone controls. These results demonstrate that the location of embryonic nigral grafts within the primate striatum influences the profile of functional recovery.


Bone tissue engineering with human stem cells.
Treatment of extensive bone defects requires autologous bone grafting or implantation of bone substitute materials. An attractive alternative has been to engineer fully viable, biological bone grafts in vitro by culturing osteogenic cells within three-dimensional scaffolds, under conditions supporting bone formation. Such grafts could be used for implantation, but also as physiologically relevant models in basic and translational studies of bone development, disease and drug discovery. A source of human cells that can be derived in large numbers from a small initial harvest and predictably differentiated into bone forming cells is critically important for engineering human bone grafts. We discuss the characteristics and limitations of various types of human embryonic and adult stem cells, and their utility for bone tissue engineering.


The histone chaperone protein Nucleosome Assembly Protein-1 (hNAP-1) binds HIV-1 Tat and promotes viral transcription.
Despite the large amount of data available on the molecular mechanisms that regulate HIV-1 transcription, crucial information is still lacking about the interplay between chromatin conformation and the events that regulate initiation and elongation of viral transcription. During transcriptional activation, histone acetyltransferases and ATP-dependent chromatin remodeling complexes cooperate with histone chaperones in altering chromatin structure. In particular, human Nucleosome Assembly Protein-1 (hNAP-1) is known to act as a histone chaperone that shuttles histones H2A/H2B into the nucleus, assembles nucleosomes and promotes chromatin fluidity, thereby affecting transcription of several cellular genes. Using a proteomic screening, we identified hNAP-1 as a novel cellular protein interacting with HIV-1 Tat. We observed that Tat specifically binds hNAP1, but not other members of the same family of factors. Binding between the two proteins required the integrity of the basic domain of Tat and of two separable domains of hNAP-1 (aa 162-290 and 290-391). Overexpression of hNAP-1 significantly enhanced Tat-mediated activation of the LTR. Conversely, silencing of the protein decreased viral promoter activity. To explore the effects of hNAP-1 on viral infection, a reporter HIV-1 virus was used to infect cells in which hNAP-1 had been either overexpressed or knocked-down. Consistent with the gene expression results, these two treatments were found to increase and inhibit viral infection, respectively. Finally, we also observed that the overexpression of p300, a known co-activator of both Tat and hNAP-1, enhanced hNAP-1-mediated transcriptional activation as well as its interaction with Tat. Our study reveals that HIV-1 Tat binds the histone chaperone hNAP-1 both in vitro and in vivo and shows that this interaction participates in the regulation of Tat-mediated activation of viral gene expression.


New pathways for evaluating potential acute stroke therapies.
Pharmacological therapy for acute ischemic stroke remains limited to one successful, approved treatment: tissue plasminogen activator within 3 h of stroke onset. Many neuroprotective drugs and a few other thrombolytics were evaluated in clinical trials, but none demonstrated unequivocal success and were approved by regulatory agencies. The development paradigm for such therapies needs to provide convincing evidence of efficacy and safety to obtain approval by the Food and Drug Administration (FDA). The FDA modernization act of 1997 stated that such evidence could be derived from one large phase III trial with a clinical endpoint and supportive evidence. Drugs being developed for acute ischemic stroke can potentially be approved under this act by coupling a major phase III trial with supportive evidence provided by a phase IIB trial demonstrating an effect on a relevant biomarker such as magnetic resonance imaging or computed tomography assessment of ischemic lesion growth. Statistical approaches have been developed to optimize the design of such an imaging-based phase IIB study, for example approaches that modify randomization probabilities to assign larger proportions of patients to the 'winning' strategy (i.e. 'pick the winner' strategies) with an interim assessment to reduce the sample size requirement. Demonstrating a treatment effect on a relevant imaging-based biomarker should provide supportive evidence for a new drug application, if a subsequent phase III trial with a clinical outcome demonstrates a significant treatment effect.


Improving clinical research and cancer care delivery in community settings: evaluating the NCI community cancer centers program.
In this article, we describe the National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) pilot and the evaluation designed to assess its role, function, and relevance to the NCI's research mission. In doing so, we describe the evolution of and rationale for the NCCCP concept, participating sites' characteristics, its multi-faceted aims to enhance clinical research and quality of care in community settings, and the role of strategic partnerships, both within and outside of the NCCCP network, in achieving program objectives. The evaluation of the NCCCP is conceptualized as a mixed method multi-layered assessment of organizational innovation and performance which includes mapping the evolution of site development as a means of understanding the inter- and intra-organizational change in the pilot, and the application of specific evaluation metrics for assessing the implementation, operations, and performance of the NCCCP pilot. The assessment of the cost of the pilot as an additional means of informing the longer-term feasibility and sustainability of the program is also discussed. The NCCCP is a major systems-level set of organizational innovations to enhance clinical research and care delivery in diverse communities across the United States. Assessment of the extent to which the program achieves its aims will depend on a full understanding of how individual, organizational, and environmental factors align (or fail to align) to achieve these improvements, and at what cost.