Peripheral neuropathy in metachromatic leukodystrophy: current status and future perspective.
Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited metabolic disease characterized by deficient activity of the lysosomal enzyme arylsulfatase A. Its deficiency results in accumulation of sulfatides in neural and visceral tissues, and causes demyelination of the central and peripheral nervous system. This leads to a broad range of neurological symptoms and eventually premature death. In asymptomatic patients with juvenile and adult MLD, treatment with allogeneic hematopoietic stem cell transplantation (HCT) provides a symptomatic and survival benefit. However, this treatment mainly impacts brain white matter, whereas the peripheral neuropathy shows no or only limited response. Data about the impact of peripheral neuropathy in MLD patients are currently lacking, although in our experience peripheral neuropathy causes significant morbidity due to neuropathic pain, foot deformities and neurogenic bladder disturbances. Besides, the reasons for residual and often progressive peripheral neuropathy after HCT are not fully understood. Preliminary studies suggest that peripheral neuropathy might respond better to gene therapy due to higher enzyme levels achieved than with HCT. However, histopathological and clinical findings also suggest a role of neuroinflammation in the pathology of peripheral neuropathy in MLD. In this literature review, we discuss clinical aspects, pathological findings, distribution of mutations, and treatment approaches in MLD with particular emphasis on peripheral neuropathy. We believe that future therapies need more emphasis on the management of peripheral neuropathy, and additional research is needed to optimize care strategies.


Trends and Insights from Transportation Congestion Pricing Policy Research: A Bibliometric Analysis.
Toll-based congestion pricing (CP) policies are increasingly implemented globally for alleviating road traffic congestion. Several interconnected factors affecting or induced by CP implementation include air quality/emissions, travel time, and road user safety. We sought to examine and characterize research output and patterns across several domains (e.g., health, policy acceptability) surrounding toll-based CP policies, in order to identify where research has focused and where gaps exist. We conducted a structured review and identified 2333 relevant publications, using semi-supervised and machine learning strategies combined with manual review. Annual publication counts peaked in 2015 (n = 122). Themes identified from title and abstract terms included policy implementation characteristics, advanced transportation modeling methods and approaches, and public perception and acceptability. Authorship networks indicated a lack of interdisciplinary research. Country analyses identified the US, China, and the UK as the most frequently represented countries, and underrepresentation from low-income countries. Findings indicate that research focused on specific road user types (e.g., pedestrians) and safety impacts, and equity considerations were relatively sparse compared to other topics (e.g., policy economics, public perception). Additional research on these critical topics is necessary to ensure that such policies are designed to promote positive and equitable effects on road user health and safety.


Retinoic Acid Inducible Gene I and Protein Kinase R, but Not Stress Granules, Mediate the Proinflammatory Response to Yellow Fever Virus.
Yellow fever virus (YFV) is an RNA virus primarily targeting the liver. Severe YF cases are responsible for hemorrhagic fever, plausibly precipitated by excessive proinflammatory cytokine response. Pathogen recognition receptors (PRRs), such as the cytoplasmic retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), and the viral RNA sensor protein kinase R (PKR), are known to initiate a proinflammatory response upon recognition of viral genomes. Here, we sought to reveal the main determinants responsible for the acute cytokine expression occurring in human hepatocytes following YFV infection. Using a RIG-I-defective human hepatoma cell line, we found that RIG-I largely contributes to cytokine secretion upon YFV infection. In infected RIG-I-proficient hepatoma cells, RIG-I was localized in stress granules. These granules are large aggregates of stalled translation preinitiation complexes known to concentrate RLRs and PKR and are so far recognized as hubs orchestrating RNA virus sensing. Stable knockdown of PKR in hepatoma cells revealed that PKR contributes to both stress granule formation and cytokine induction upon YFV infection. However, stress granule disruption did not affect the cytokine response to YFV infection, as assessed by small interfering RNA (siRNA)-knockdown-mediated inhibition of stress granule assembly. Finally, no viral RNA was detected in stress granules using a fluorescence in situ hybridization approach coupled with immunofluorescence. Our findings suggest that both RIG-I and PKR mediate proinflammatory cytokine induction in YFV-infected hepatocytes, in a stress granule-independent manner. Therefore, by showing the uncoupling of the cytokine response from the stress granule formation, our model challenges the current view in which stress granules are required for the mounting of the acute antiviral response.IMPORTANCE Yellow fever is a mosquito-borne acute hemorrhagic disease caused by yellow fever virus (YFV). The mechanisms responsible for its pathogenesis remain largely unknown, although increased inflammation has been linked to worsened outcome. YFV targets the liver, where it primarily infects hepatocytes. We found that two RNA-sensing proteins, RIG-I and PKR, participate in the induction of proinflammatory mediators in human hepatocytes infected with YFV. We show that YFV infection promotes the formation of cytoplasmic structures, termed stress granules, in a PKR- but not RIG-I-dependent manner. While stress granules were previously postulated to be essential platforms for immune activation, we found that they are not required for the production of proinflammatory mediators upon YFV infection. Collectively, our work uncovered molecular events triggered by the replication of YFV, which could prove instrumental in clarifying the pathogenesis of the disease, with possible repercussions for disease management.


Computational redesign of a mononuclear zinc metalloenzyme for organophosphate hydrolysis.
The ability to redesign enzymes to catalyze noncognate chemical transformations would have wide-ranging applications. We developed a computational method for repurposing the reactivity of metalloenzyme active site functional groups to catalyze new reactions. Using this method, we engineered a zinc-containing mouse adenosine deaminase to catalyze the hydrolysis of a model organophosphate with a catalytic efficiency (k(cat)/K(m)) of ~10(4) M(-1) s(-1) after directed evolution. In the high-resolution crystal structure of the enzyme, all but one of the designed residues adopt the designed conformation. The designed enzyme efficiently catalyzes the hydrolysis of the R(P) isomer of a coumarinyl analog of the nerve agent cyclosarin, and it shows marked substrate selectivity for coumarinyl leaving groups. Computational redesign of native enzyme active sites complements directed evolution methods and offers a general approach for exploring their untapped catalytic potential for new reactivities.


Agreement and Repeatability of Two Biometers to Measure Anterior Segment Components: Refractive Error Effect.
BACKGROUND To assess the repeatability and agreement between a new high-resolution optical coherence tomographer (OCT) and a Scheimpflug topographer. MATERIAL AND METHODS Sixty phakic and healthy participants were measured in this study, and one eye per participant was analyzed. Depending on their refractive error, each participant was allocated into a myopic, hyperopic, or emmetropic group. The Cirrus HD-OCT 5000 (Carl Zeiss Meditec, Jena, Germany), and the Sirius Scheimpflug topographer (Costruzione Strumenti Oftalmici, Florence, Italy) were used to take all measurements. RESULTS The repeatability of these instruments to measure the anterior chamber depth, angle-to-angle, thinnest pachymetry, and both nasal and temporal angles was smaller than 0.15 mm, 0.40 mm, 10 µm, and 10 degrees, respectively. However, the repeatability of the Scheimpflug instrument to measure the apex pachymetry was about 15 µm, and for the OCT, it was about 4 µm for all groups. On average, the Sirius Scheimpflug instrument measured shallower anterior chamber depth (about 0.10 mm), shorter angle-to-angle (about 0.5 mm), thinner corneas (approximately 10 µm), and narrower angles (around 5 degrees) for all refractive groups. CONCLUSIONS The repeatability of the Cirrus OCT and Sirius Scheimpflug instrument was good and independent of the refractive error. Nevertheless, to judge whether these instruments could be used interchangeable, clinical criteria are needed.


Modelling low pathogenic avian influenza introduction into the commercial poultry industry.
Outbreaks of highly pathogenic avian influenza (HPAI) in commercial poultry flocks are rare but highly disruptive to the industry. There is evidence that low pathogenic avian influenza (LPAI) can transfer from wild birds to domestic flocks, where it may mutate to HPAI, and the industry is concerned that an increasing demand for free-range produce may affect the risk of LPAI and HPAI outbreaks. In this paper we focus on LPAI introduction and establishment, and formulate a branching process model to compare risk between sectors and their contribution to overall industry-level risk. Our aim is to determine how heterogeneity in avian influenza viruses and the distinct population structures of each sector - caged, barn and free-range, meat and layer - interact with a continuous risk of virus introduction to affect outbreak probabilities. We show that free-range access is the most influential driver of LPAI outbreaks, with production cycle length having relatively little effect. We demonstrate that variation in virus transmission rates is particularly important when modelling avian influenza introduction to domestic poultry. Virus-free status is of interest for biosecurity and we distinguish how it differs from the usual probability of extinction, and discuss how production cycle length affects this difference. We also use the nonlinear relationship between shed size and risk to identify conditions for which shed size is most influential.


Computerised cognitive assessment of concussed Australian Rules footballers.
"Paper and pencil" neuropsychological tests play an important role in the management of sports related concussions. They provide objective information on the athlete's cognitive function and thus facilitate decisions on safe return to sport. It has been proposed that computerised cognitive tests have many advantages over such conventional tests, but their role in this domain is yet to be established. To measure cognitive impairment after concussion in a case series of concussed Australian Rules footballers, using both computerised and paper and pencil neuropsychological tests. To investigate the role of computerised cognitive tests in the assessment and follow up of sports related concussions. Baseline measures on the Digit Symbol Substitution Test (DSST), Trail Making Test-Part B (TMT), and a simple reaction time (SRT) test from a computerised cognitive test battery (CogState) were obtained in 240 players. Tests were repeated in players who had sustained a concussive injury. A group of non-injured players were used as matched controls. Six concussions were observed over a period of nine weeks. At the follow up, DSST and TMT scores did not significantly differ from baseline scores in both control and concussed groups. However, analysis of the SRT data showed an increase in response variability and latency after concussion in the injured athletes. This was in contrast with a decrease in response variability and no change in latency on follow up of the control players (p<0.02). Increased variability in response time may be an important cognitive deficit after concussion. This has implications for consistency of an athlete's performance after injury, as well as for tests used in clinical assessment and follow up of head injuries.


[Updated Argentine consensus on chronic obstructive pulmonary disease].
Due to the increase in morbidity and mortality from Chronic Obstructive Pulmonary Disease (COPD), a group of chest physicians updates the basic knowledge on COPD since the last Consensus in 1994 in order to prepare guidelines for its diagnosis, prevention and treatment. The authors review the definition of COPD together with the most recent information on its pathophysiology. The clinical presentation is summarized together with functional evaluation and imaging. Early diagnosis by means of functional testing (i.e., spirometry) is stressed, emphasizing smoking cessation as the only measure that has been shown to alter the outcome of the disease. Smoking cessation strategies are described as well as pharmacological and non-pharmacological treatment. In the pharmacological section, the use of inhaled bronchodilators (anticholinergic, beta 2 adrenergic agonists or both) is considered the first option for treatment. Long acting bronchodilators improve patient compliance and treatment effectiveness. Inhaled corticosteroids are indicated for patients with severe airways obstruction and known response to corticosteroids. These agents can diminish the number of exacerbations. Annual influenza vaccination is recommended in all patients. In the non-pharmacological section, surgery for emphysema is suggested in particular cases. Rehabilitation, including exercise training, kinesitherapy and nutrition, is a useful tool for patients who are physically disabled. Long-term oxygen therapy at home improves survival in patients with severe chronic hypoxemia. Other therapeutic interventions such as non-invasive home ventilation have specific indications. Acute exacerbations must be aggressively treated with oxygen, corticosteroids, antibiotics, combination of bronchodilators, and eventually respiratory support. The role of public education of the patients and their families is essential in the prevention and treatment of the disease.


Identification card and codification of the chemical and morphological characteristics of 14 dental implant surfaces.
Dental implants are commonly used in daily practice; however, most surgeons do not really know the characteristics of these biomedical devices they are placing in their patients. The objective of this work is to describe the chemical and morphological characteristics of 14 implant surfaces available on the market and to establish a simple and clear identification (ID) card for all of them, following the classification procedure developed in the Dohan Ehrenfest et al (2010) Codification (DEC) system. Fourteen implant surfaces were characterized: TiUnite (Nobel Biocare), Ospol (Ospol), Kohno HRPS (Sweden & Martina), Osseospeed (AstraTech), Ankylos (Dentsply Friadent), MTX (Zimmer), Promote (Camlog), BTI Interna (Biotechnology Institute), EVL Plus (SERF), Twinkon Ref (Tekka), Ossean (Intra-Lock), NanoTite (Biomet 3I), SLActive (ITI Straumann), Integra-CP/NanoTite (Bicon). Three samples of each implant were analyzed. Superficial chemical composition was analyzed using X-ray photoelectron spectroscopy/electron spectroscopy for chemical analysis, and the 100 nm in-depth profile was established using Auger electron spectroscopy. The microtopography was quantified using light interferometry. The general morphology and nanotopography were evaluated using a field emission-scanning electron microscope. Finally, the characterization code of each surface was established using the DEC system, and the main characteristics of each surface were summarized in a reader-friendly ID card. From a chemical standpoint, of the 14 different surfaces, 10 were based on a commercially pure titanium (grade 2 or 4), 3 on a titanium-aluminum alloy (grade 5 titanium), and one on a calcium phosphate core. Nine surfaces presented different forms of chemical impregnation or discontinuous coating of the titanium core, and 3 surfaces were covered with residual aluminablasting particles. Twelve surfaces presented different degrees of inorganic pollutions, and 2 presented a severe organic pollution overcoat. Only 2 surfaces presented no pollution (Osseospeed and Ossean). From a morphological standpoint, 2 surfaces were microporous (anodization) and 12 were microrough, with different microtopographical aspects and values. Ten surfaces were smooth on the nanoscale, and therefore presented no significant and repetitive nanostructures. Four implants were nanomodified: 2 implants were nanorough (Osseospeed and Ossean), and 2 were covered with nanoparticles (NanoTite and SLActive). TiUnite and Kohno HRPS were covered with extended cracks all over the surface. Only 8 surfaces could be considered homogeneous. This systematic approach allowed the main characteristics of these commercially available products to be gathered in a single ID card. It can be used as an experimental tool or a method for controlling industrial implant productions. The DEC system could be an interesting basis for the development of a clear and simple ISO standard for dental implant surfaces and other implantable devices.


[Survival and disability in stroke by stroke subtype based on computed tomographic findings in three rural Japanese communities].
We conducted an epidemiological study of survival and disability in stroke in three Japanese communities to seek community strategies for improvement in survival and disability. A total of 297 first-ever strokes were identified between 1988 and 1992 in three rural communities (total population = 47,000) located in Akita and Ibaraki. We analyzed survival rates and activity of daily living by sex, age-group and stroke subtypes. Successful review of computed tomography (CT) for 84 percent of the strokes (249 out of 297) was possible and the data were used for subtype analyses. For all strokes (n = 297) survival rates were 85% for 30 day, 70% for one year, 62% for three year. The rates tended to be lower in women than in men. The rates were lowest in ages less than 60 at thirty day, and in ages 80 and older at the end of the first and third year. Intracerebral hemorrhage with ventricular rupture, subarachnoid hemorrhage and cortical cerebral infarction had lower survival rates than intracerebral hemorrhage without ventricular rupture and lacunar infarction. Based on Cox's proportional hazard model, risk ratio for death was 2.07 in ages 70-79, and 3.80 in ages 80 and older compared with ages 60-69. The risk ratio was 3.46 for intracerebral hemorrhage with ventricular rupture, 3.38 for subarachnoid hemorrhage and 2.46 for cortical cerebral infarction compared with lacunar infarction. The proportion of stroke survivors who need assistance from others in the first and third years tended to be higher in women than in men. The proportion was higher in older patients than in the younger, and higher for intracerebral hemorrhage with ventricular rupture and cortical cerebral infarction than in other subtypes of stroke. From logistic regression analysis, the odds ratio for disability in the first year was 6.55 for ages 80 and older compared with ages 60-69. The odds ratio was 5.61 for intracerebral hemorrhage with ventricular rupture, 4.53 for cortical cerebral infarction compared with lacunar infarction. In the third year the odds ratio was significant for ages 70-79, and decreased for intracerebral hemorrhage with ventricular rupture (odds ratio = 2.98), and increased for cortical cerebral infarction (odds ratio = 6.06). Survival and disability in stroke depended on age and stroke subtypes. Even after age adjustment, stroke subtypes with large cerebral involvement had worse prognosis than stroke subtypes. Community-based hypertension control programs are important to prevent any subtypes of stroke. Stroke subtypes as well as age should be taken into account to develop effective care and medical treatments for strokes.


Stellate transformation of invasive trophoblast: a distinct phenotype of trophoblast that is involved in decidual vascular remodelling and controlled invasion during pregnancy.
Successful implantation relies on the tightly regulated invasion of extravillous trophoblasts (EVTs). However, little is known about their phenotypic differentiation and relevant motile behaviour. Furthermore, the cell-cell interactions between EVTs and decidual arterioles during physiological transformation are also poorly understood. A total of 128 decidual specimens from early and late gestations containing components of EVTs and spiral arterioles were investigated using immunohistochemistry and periodic acid-Schiff reaction. Unipolar, tadpole-like EVTs are observed throughout the interstitial area, with a tendency to decrease along the invasive pathway. The stellate differentiation of the EVTs is identified around and inside decidual arterioles or in the third-trimester myometrium. Furthermore, stellate transformation of EVTs precedes its interactions with the decidual arteriole. These specialized stellate trophoblasts invade and infiltrate the tunica media, accompanying lacuna formation inside the vessel wall and perturbation of actin fibre alignment of the tunica media. Stellate transformation of trophoblasts may explain controlled invasion of EVTs and probably plays a key role in initiating cell-cell interaction in decidual vascular remodelling.


Mortality and Hospitalizations in Intensive Dialysis: A Systematic Review and Meta-Analysis.
Survival and hospitalization are critically important outcomes considered when choosing between intensive hemodialysis (HD), conventional HD, and peritoneal dialysis (PD). However, the comparative effectiveness of these modalities is unclear. We had the following aims: (1) to compare the association of mortality and hospitalization in patients undergoing intensive HD, compared with conventional HD or PD and (2) to appraise the methodological quality of the supporting evidence. MEDLINE, Embase, ISI Web of Science, CENTRAL, and nephrology conference abstracts. We included cohort studies with comparator arm, and randomized controlled trials (RCTs) with >50% of adult patients (≥18 years) comparing any form of intensive HD (>4 sessions/wk or >5.5 h/session) with any form of chronic dialysis (PD, HD ≤4 sessions/wk or ≤5.5 h/session), that reported at least 1 predefined outcome (mortality or hospitalization). We used the GRADE approach to systematic reviews and quality appraisal. Two reviewers screened citations and full-text articles, and extracted study-level data independently, with discrepancies resolved by consensus. We pooled effect estimates of randomized and observational studies separately using generic inverse variance with random effects models, and used fixed-effects models when only 2 studies were available for pooling. Predefined subgroups for the intensive HD cohorts were classified by nocturnal versus short daily HD and home versus in-center HD. Twenty-three studies with a total of 70 506 patients were included. Of the observational studies, compared with PD, intensive HD had a significantly lower mortality risk (hazard ratio [HR]: 0.67; 95% confidence interval [CI]: 0.53-0.84; I2 = 91%). Compared with conventional HD, home nocturnal (HR: 0.46; 95% CI: 0.38-0.55; I2 = 0%), in-center nocturnal (HR: 0.73; 95% CI: 0.60-0.90; I2 = 57%) and home short daily (HR: 0.54; 95% CI: 0.31-0.95; I2 = 82%) intensive regimens had lower mortality. Of the 2 RCTs assessing mortality, in-center short daily HD had lower mortality (HR: 0.54; 95% CI: 0.31-0.93), while home nocturnal HD had higher mortality (HR: 3.88; 95% CI: 1.27-11.79) in long-term observational follow-up. Hospitalization days per patient-year (mean difference: -1.98; 95% CI: -2.37 to -1.59; I2 = 6%) were lower in nocturnal compared with conventional HD. Quality of evidence was similarly low or very low in RCTs (due to imprecision) and observational studies (due to residual confounding and selection bias). The overall quality of evidence was low or very low for critical outcomes. Outcomes such as quality of life, transplantation, and vascular access outcomes were not included in our review. Intensive HD regimens may be associated with reduced mortality and hospitalization compared with conventional HD or PD. As the quality of supporting evidence is low, patients who place a high value on survival must be adequately advised and counseled of risks and benefits when choosing intensive dialysis. Practice guidelines that promote shared decision-making are likely to be helpful.


Prediction of death and prolonged mechanical ventilation in acute lung injury.
Prediction of death and prolonged mechanical ventilation is important in terms of projecting resource utilization and in establishing protocols for clinical studies of acute lung injury (ALI). We aimed to identify risk factors for a combined end-point of death and/or prolonged ventilator dependence and developed an ALI-specific prediction model. In this retrospective analysis of three multicenter clinical studies, we identified predictors of death or ventilator dependence from variables prospectively recorded during the first three days of mechanical ventilation. After the prediction model was derived in an international cohort of patients with ALI, it was validated in two independent samples of patients enrolled in a clinical trial involving 17 academic centers and a North American population-based cohort. A combined end-point of death and/or ventilator dependence at 14 days or later occurred in 68% of patients in the international cohort, 60% of patients in the clinical trial, and 59% of patients in the population-based cohort. In the derivation cohort, a model based on age, oxygenation index on day 3, and cardiovascular failure on day 3 predicted death and/or ventilator dependence. The prediction model performed better in the clinical trial validation cohort (area under the receiver operating curve 0.81, 95% confidence interval 0.77 to 0.84) than in the population-based validation cohort (0.71, 95% confidence interval 0.65 to 0.76). A model based on age and cardiopulmonary function three days after the intubation is able to predict, moderately well, a combined end-point of death and/or prolonged mechanical ventilation in patients with ALI.


Gene expression associated with white syndromes in a reef building coral, Acropora hyacinthus.
Corals are capable of launching diverse immune defenses at the site of direct contact with pathogens, but the molecular mechanisms of this activity and the colony-wide effects of such stressors remain poorly understood. Here we compared gene expression profiles in eight healthy Acropora hyacinthus colonies against eight colonies exhibiting tissue loss commonly associated with white syndromes, all collected from a natural reef environment near Palau. Two types of tissues were sampled from diseased corals: visibly affected and apparently healthy. Tag-based RNA-Seq followed by weighted gene co-expression network analysis identified groups of co-regulated differentially expressed genes between all health states (disease lesion, apparently healthy tissues of diseased colonies, and fully healthy). Differences between healthy and diseased tissues indicate activation of several innate immunity and tissue repair pathways accompanied by reduced calcification and the switch towards metabolic reliance on stored lipids. Unaffected parts of diseased colonies, although displaying a trend towards these changes, were not significantly different from fully healthy samples. Still, network analysis identified a group of genes, suggestive of altered immunity state, that were specifically up-regulated in unaffected parts of diseased colonies. Similarity of fully healthy samples to apparently healthy parts of diseased colonies indicates that systemic effects of white syndromes on A. hyacinthus are weak, which implies that the coral colony is largely able to sustain its physiological performance despite disease. The genes specifically up-regulated in unaffected parts of diseased colonies, instead of being the consequence of disease, might be related to the originally higher susceptibility of these colonies to naturally occurring white syndromes.


Probasin promoter (ARR(2)PB)-driven, prostate-specific expression of the human sodium iodide symporter (h-NIS) for targeted radioiodine therapy of prostate cancer.
Prostate cancer is one of the most promising candidates for sodium iodide symporter (NIS)-mediated gene therapy. Adenovirus-mediated expression of NIS that is driven by prostate-specific promoters induces generous radioiodine accumulation in prostate cancer cells that may be used for therapy with (131)I. We have recently developed a replication-deficient adenovirus carrying the human NIS cDNA linked to a composite probasin promoter, ARR(2)PB, aiming toward specific expression of the human NIS gene (h-NIS) in prostate tissue for targeted radioactive iodide therapy of prostate cancer (Ad-ARR(2)PB/hNIS). The ability of Ad-ARR(2)PB/hNIS to cause NIS expression in tumor cells was characterized by iodide uptake assay and compared with Ad-CMV/hNIS in which the h-NIS expression is driven by the cytomegalovirus (CMV) promoter. Androgen-dependent prostate cancer cell lines (LNCaP) and non-prostate origin tumor cell lines (SNU449, MCF-7, HCT116, OVCAR-3, and Panc-1) were infected with the viral constructs, and perchlorate-sensitive (125)I uptake and NIS protein expression were measured. Ad-ARR(2)PB/hNIS-infected LNCaP cells showed androgen-dependent and perchlorate-sensitive iodide uptake. Iodide accumulation in LNCaP cells infected with Ad-ARR(2)PB/hNIS, followed by incubation with synthetic androgen, was 5.3-fold increased compared with those coincubated with perchlorate (15,184 +/- 1,173 cpm versus 2,837 +/- 187 cpm). Ad-ARR(2)PB/hNIS-infected LNCaP cells revealed a 3.2-fold increase of iodide accumulation compared with those infected with Ad-CMV/hNIS (multiplicity of infection = 30). Iodide uptake in a panel of non-prostate tumor cell lines infected with Ad-ARR(2)PB/hNIS was no more than 2,500 cpm, demonstrating the tissue specificity of this construct. These results indicate that Ad-ARR(2)PB/hNIS can be used to achieve high-magnitude and tissue-specific expression of h-NIS in prostate tissue and is a promising candidate for cancer gene therapy of prostate cancer.


Relationship between Dermatoglyphics, Cheiloscopy, Rugoscopy, and Dental Caries: A Cross-sectional Study in Bengaluru, Karnataka.
Early detection of susceptibility to dental caries by studying its genetic basis by effectively utilizing noninvasive, less expensive, and effective tools is gaining popularity. Cariogenesis is affected by a combination of environmental and behavioral factors. The aim of this study was to compare the reliability of dermatoglyphic, cheiloscopic, and rugoscopic patterns for assessing the risk of dental caries in children. The study included 100 children aged 3-7 years who were divided into two groups based on their decayed, missing and filled teeth (DMFT/deft) index. Fingerprints, lip prints, and rugae patterns were recorded and analyzed. The most common fingerprints patterns in the children with higher deft scores were loop pattern (52%), followed by whorls (32%) and arches (16%). The branched pattern of lip prints was found to be the most prevalent in all children irrespective of their caries status. Among palatal rugae shapes, wavy was found to be the most prevalent (54%) one in our study population, irrespective of the deft scores. Considering the palatal rugae unifications, it was found that converging type was significantly (P = 0.032) more prevalent in children with less deft scores (32%) compared to those with high deft caries (14%). Palatal rugae unifications have proved to be a good marker of dental caries. Among the various genes that may be playing a role in caries formation, BCOR and BCORL1 genes may also be playing a role in the development of palate and the rugae patterns and also in the development of enamel, which is known to be the most vulnerable dental tissue to dental caries.


Changing motivations during migration: linking movement speed to reproductive status in a migratory large mammal.
A challenge in animal ecology is to link animal movement to demography. In general, reproducing and non-reproducing animals may show different movement patterns. Dramatic changes in reproductive status, such as the loss of an offspring during the course of migration, might also affect movement. Studies linking movement speed to reproductive status require individual monitoring of life-history events and hence are rare. Here, we link movement data from 98 GPS-collared female moose (Alces alces) to field observations of reproductive status and calf survival. We show that reproductive females move more quickly during migration than non-reproductive females. Further, the loss of a calf over the course of migration triggered a decrease in speed of the female. This is in contrast to what might be expected for females no longer constrained by an accompanying offspring. The observed patterns demonstrate that females of different reproductive status may have distinct movement patterns, and that the underlying motivation to move may be altered by a change in reproductive status during migration.


Identification and expression profiling of microRNAs in the brain, liver and gonads of marine medaka (Oryzias melastigma) and in response to hypoxia.
The marine medaka (Oryzias melastigma) has been increasingly used as a fish model for detecting environmental stresses and chemical contaminants in the marine environment. Recent mammalian studies have shown that environmental stresses can alter the expression profiles of microRNAs (miRNAs), leading to transgenerational effects. Here, we use high-throughput Illumina RNA sequencing (RNA-Seq) for miRNA transcriptome analysis of brain, liver, and gonads from sexually mature male and female marine medaka. A total of 128,883,806 filtered sequence reads were generated from six small RNA libraries, identifying a total of 2,125,663 non-redundant sequences. These sequences were aligned and annotated to known animal miRNAs (miRBase) using the BLAST method. A total of 223 distinct miRNA types were identified, with the greatest number expressed in brain tissue. Our data suggested that 55 miRNA types from 34 families are common to all tested tissues, while some of the miRNAs are tissue-enriched or sex-enriched. Quantitative real-time PCR analysis further demonstrated that let-7a, miR-122, and miR-9-3p were downregulated in hypoxic female medaka, while miR-2184 was specifically upregulated in the testis of hypoxic male fish. This is the first study to identify miRNAs in O. melastigma using small RNA deep sequencing technology. Because miRNA expression is highly conserved between marine medaka and other vertebrates, marine medaka may serve as a good model for studies on the functional roles of miRNAs in hypoxia stress response and signaling in marine fish.


Oral rivaroxaban for the treatment of symptomatic pulmonary embolism.
A fixed-dose regimen of rivaroxaban, an oral factor Xa inhibitor, has been shown to be as effective as standard anticoagulant therapy for the treatment of deep-vein thrombosis, without the need for laboratory monitoring. This approach may also simplify the treatment of pulmonary embolism. In a randomized, open-label, event-driven, noninferiority trial involving 4832 patients who had acute symptomatic pulmonary embolism with or without deep-vein thrombosis, we compared rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with standard therapy with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or clinically relevant nonmajor bleeding. Rivaroxaban was noninferior to standard therapy (noninferiority margin, 2.0; P=0.003) for the primary efficacy outcome, with 50 events in the rivaroxaban group (2.1%) versus 44 events in the standard-therapy group (1.8%) (hazard ratio, 1.12; 95% confidence interval [CI], 0.75 to 1.68). The principal safety outcome occurred in 10.3% of patients in the rivaroxaban group and 11.4% of those in the standard-therapy group (hazard ratio, 0.90; 95% CI, 0.76 to 1.07; P=0.23). Major bleeding was observed in 26 patients (1.1%) in the rivaroxaban group and 52 patients (2.2%) in the standard-therapy group (hazard ratio, 0.49; 95% CI, 0.31 to 0.79; P=0.003). Rates of other adverse events were similar in the two groups. A fixed-dose regimen of rivaroxaban alone was noninferior to standard therapy for the initial and long-term treatment of pulmonary embolism and had a potentially improved benefit-risk profile. (Funded by Bayer HealthCare and Janssen Pharmaceuticals; EINSTEIN-PE ClinicalTrials.gov number, NCT00439777.).


Liquid Biopsies for Ovarian Carcinoma: How Blood Tests May Improve the Clinical Management of a Deadly Disease.
Ovarian cancers (OvC) are frequent, with more than 22,000 new cases each year for 14,000 deaths in the United States. Except for patients with BRCA1 or BRCA2 mutations, diagnostic methods, prognostic tools, and therapeutic strategies have not much improved in the last two decades. High throughput tumor molecular analyses have identified important alterations involved in ovarian carcinoma growth and spreading. However, these data have not modified the clinical management of most of patients. Moreover, tumor sample collection requires invasive procedures not adapted to objectives, such as the screening, prediction, or assessment of treatment efficacy, monitoring of residual disease, and early diagnosis of relapse. In recent years, circulating tumor biomarkers (also known as "liquid biopsies") such as circulating tumor cells, circulating nucleotides (DNA or miRNA), or extracellular vesicles, have been massively explored through various indications, platforms, and goals, but their use has not yet been validated in routine practice. This review describes the methods of analysis and results related to liquid biopsies for ovarian epithelial cancer. The different settings that a patient can go through during her journey with OvC are explored: screening and early diagnosis, prognosis, prediction of response to systemic therapies for advanced stages, and monitoring of residual subclinical disease.


Gold nanoparticles impair autophagy flux through shape-dependent endocytosis and lysosomal dysfunction.
The physicochemical properties of nanoparticles have been tuned via various synthetic methods to improve their diagnostic or curative capability. However, systematic understanding of the relationship between their physicochemical properties and biological effects is still not well established. Particularly, the latent ability of nanomaterials to regulate autophagy has already drawn more attention. In this report, by comparing cellular interactions, uptakes, and autophagic effects of gold nanoparticles with different shapes, we reveal that gold nanoparticles could modulate autophagy in a shape-dependent manner. Western blot assays and confocal images confirm that nanospheres cause more autophagosome accumulation than nanorods, which are highly correlated with the difference in cellular uptakes. With biological TEM, we observe remarkable lysosome swelling and clearly identify the engulfed gold nanoparticles together with undegraded organelles in autolysosomes. Additionally, monitoring of the lysosomal activity and p62 degradation indicates an autophagy flux decrease induced by the impairment of lysosomes after treatment with nanoparticles. Our study not only reveals the effects of nanostructure morphology on autophagy, but also provides an alternative strategy to modulate autophagy, which would contribute to the guidelines for further biomedical applications of various nanomaterials.


A longitudinal twin study of personality and major depression in women.
To elucidate the nature of the etiologic relationship between personality and major depression in women. A longitudinal twin design in which twins completed a time 1 questionnaire and, 15 months later, were personally interviewed for the occurrence of major depression during the last year and completed a time 2-questionnaire. Both questionnaires contained short forms assessing neuroticism and extraversion. 1733 twins from female-female pairs ascertained from the population-based Virginia Twin Registry. Extraversion was unrelated to lifetime or 1-year prevalence of major depression. Neuroticism was strongly related to lifetime prevalence of major depression and robustly predicted the prospective 1-year prevalence of major depression in those who, at time 1, denied previous depressive episodes. However, controlling for levels of neuroticism at time 1, levels of neuroticism at time 2 were moderately elevated in those who had had an episode of major depression between times 1 and 2 ("scar" effect) and substantially elevated in those experiencing an episode of major depression at time 2 ("state" effect). In those who developed major depression, levels of neuroticism did not predict time to onset. In the best-fit longitudinal twin model, the proportion of the observed correlation between neuroticism and the liability to major depression that is due to shared genetic risk factors was estimated at around 70%, that due to shared environmental risk factors at around 20%, and that due to a direct causal effect of major depression on neuroticism (via both "scar" and "state" effects) at around 10%. Approximately 55% of the genetic liability of major depression appeared to be shared with neuroticism, while 45% was unique to major depression. In women, the relationship between neuroticism and the liability to major depression is substantial and largely the result of genetic factors that predispose to both neuroticism and major depression.


Human peripheral blood CD4+ and CD8+ T cells express Th1-like cytokine mRNA and proteins following in vitro stimulation with heat-inactivated Brucella abortus.
Defining the pattern of lymphokine production associated with Brucella abortus is critical for advancing the development of B. abortus as a vaccine carrier. In the present study we investigated the ability of heat-inactivated B. abortus or lipopolysaccharide from B. abortus to induce lymphokine production from purified human T cells in vitro. Gamma interferon (IFN-gamma), interleukin-2 (IL-2), IL-4, and IL-5 induction was assayed by mRNA-specific PCR and by enzyme-linked immunosorbent assay and bioassay for protein production. Following depletion of monocytes and B cells, B. abortus increased IFN-gamma and IL-2 mRNA expression in purified T cells compared with expression in unstimulated cells. In contrast, no IL-5 mRNA expression and only transient low-level IL-4 mRNA expression and no IL-4 protein secretion were detected. Phytohemagglutinin or phorbol myristate acetate plus ionomycin induced mRNA and protein for all these cytokines. Similar results were obtained with LPS purified from B. abortus. Removal of NK cells did not reduce lymphokine production, and enriched NK cells did not express IFN-gamma mRNA or secrete IFN-gamma protein in response to B. abortus, indicating that NK cells were not the responding population. Both CD4+ and CD8+ populations produced IFN-gamma and IL-2 in response to B. abortus. Preincubation of resting T cells with B. abortus or LPS from B. abortus for 7 days induced their differentiation into Th1-like cells as judged by their subsequent lymphokine response to phorbol myristate acetate plus ionomycin. These results suggest that B. abortus can induce differentiation of Th0 into Th1-type cells.


Nonsurgical management of congenital eyelid malpositions using hyaluronic Acid gel.
To report our preliminary experience using hyaluronic acid gel fillers as a nonsurgical alternative in the management of congenital eyelid malpositions. In this retrospective interventional case series, 5 patients (10 eyes) with congenital eyelid malpositions, including eyelid retraction, ectropion, euryblepharon, epiblepharon, and abnormalities associated with a shallow orbit, with resultant lagophthalmos and/or keratopathy and tearing were evaluated before and after injection with hyaluronic acid gel (Restylane) in the pretarsal and/or septal regions of the affected eyelid(s). Pretreatment, posttreatment, and follow-up photographs were analyzed for eyelid position and degree of eyelid closure and lagophthalmos, and slit-lamp evaluation of the degree of keratopathy. All 5 patients demonstrated significant improvement of eyelid position and degree of keratopathy. The mean improvement in lagophthalmos was 4.5 mm (range, 2-7 mm). The average volume of hyaluronic acid gel used was 0.5 ml per eyelid. Complications were minor, including transient edema and ecchymosis at the sites of injection. Of the 10 eyelids injected, only one had increased astigmatism after injection. Hyaluronic acid gel shows promise as a safe and effective nonsurgical treatment for the management of certain eyelid malpositions, disorders traditionally requiring surgical intervention if aggressive ocular lubrication fails. This treatment is particularly useful in such patients who are commonly premature with poor general health and serves as a temporizing measure by allowing the much needed tissue expansion to take effect over time.


Genetic characterisation of the emerging invasive Neisseria meningitidis serogroup Y in Sweden, 2000 to 2010.
Neisseria meningitidis serogroups B and C have been responsible for the majority of invasive meningococcal disease in Europe. Recently, an increase of N. meningitidis disease due to serogroup Y has been noted in Sweden (in 2010, the proportion was 39%, with an incidence of 0.23 per 100,000 population), as well as in other northern European countries. We aimed to investigate the clonal pattern of the emerging serogroup Y in Sweden during 2000 to 2010. The serogroup Y isolates identified during this time (n=85) were characterised by multilocus sequence typing and sequencing of the fetA, fHbp, penA, porA and porB genes. The most frequent clone (comprising 28 isolates) with identical allele combinations of the investigated genes, was partly responsible for the observed increased number of N. meningitidis serogroup Y isolates. It was sulfadiazine resistant, with genosubtype P1.5-2,10-1,36-2, sequence type 23, clonal complex 23, porB allele 3-36, fetA allele F4-1, fHbp allele 25 and penA allele 22. The first case with disease due to this clone was identified in 2002: there was a further case in 2004, six during 2006 to 2007, eight during 2008 to 2009, with a peak of 12 cases in 2010. An unusual increase of invasive disease in young adults (aged 20–29 years) caused by this clone was shown, but no increase in mortality rate was observed.


Noninvasive Molecular Imaging of Mouse Atherosclerosis.
Molecular imaging offers great potential for noninvasive visualization and quantitation of the cellular and molecular components involved in atherosclerotic plaque stability. In this chapter, we review emerging molecular imaging modalities and approaches for quantitative, noninvasive detection of early biological processes in atherogenesis, including vascular endothelial permeability, endothelial adhesion molecule up-regulation, and macrophage accumulation, with special emphasis on mouse models. We also highlight a number of targeted imaging nanomaterials for assessment of advanced atherosclerotic plaques, including extracellular matrix degradation, proteolytic enzyme activity, and activated platelets using mouse models of atherosclerosis. The potential for clinical translation of molecular imaging nanomaterials for assessment of atherosclerotic plaque biology, together with multimodal approaches is also discussed.


Association between N-terminal pro-brain natriuretic peptide and quality of life in adult patients with congenital heart disease.
Advances in medical treatment have resulted in increased life expectancy in congenital heart disease. Consequently, the focus of management has shifted from reducing mortality to reducing long-term morbidity with the goal of improving quality of life. A predictor of quality of life might be N-terminal pro-brain natriuretic peptide, a well-established marker for heart failure. We aimed to determine the association between N-terminal pro-brain natriuretic peptide and quality of life in patients with congenital heart disease. We collected blood samples from consecutive patients who were initially operated between 1968 and 1980 (47.8% women; mean age 40.2±5.4 years). The 36-item Short-Form Health Survey was completed to assess subjective health status as a measure of quality of life. Analysis was performed for the entire group and for subgroups defined as simple versus complex congenital heart diseases. Median N-terminal pro-brain natriuretic peptide level was 15.2 pmol/L (overall range 1.3-299.3 pmol/L). N-terminal pro-brain natriuretic peptide levels were associated with the subdomain physical functioning (β=-0.074, p=0.031). This association remained significant after adjustment for age and sex (β=-0.071, p=0.038) and after adjustment for age, sex, body mass index, left ventricular function, and renal function (β=-0.069, p=0.048). In complex congenital heart disease, the association between N-terminal pro-brain natriuretic peptide and physical functioning remained significant in multivariable analysis (β=-0.076, p=0.046). No associations were found in the simple congenital heart disease group or on the other health status subdomains. In adults operated for congenital heart disease, N-terminal pro-brain natriuretic peptide is associated with the subdomain physical, primarily in the complex subgroup.


Assessment of Age and Duration of Symptoms on Outcomes of Emergency Scrotal Exploration for Acute Scrotal Pain.
To study the effects of age and duration of symptoms on the outcomes of scrotal explorations for acute scrotal pain at our institution. Case series. Bradford Teaching Hospital NHS Trust, from January 2006 to December 2017. Retrospective data was collected from electronic case records of the patients who required scrotal exploration for suspected torsion of the testis. Group difference between continuous variables (age and duration of symptoms) were assessed by Kruskal Wallis and independent samples Mann-Whitney U-tests. The Fisher Exact and Chisquare tests were used to analyse relationships between categorical data. In total, 502 patients required scrotal exploration. The median age (years) and duration of symptoms (hours) were 16.4 years (1.3 - 77) and 4 hours (1 - 336), respectively. Torsion of the testis was found in 231 (46%), torsion of the testicular appendix in 126 (25%), epididymal inflammation in 46 (9.2%), and no cause identified in 99 (19.7%). Immediate orchidectomy for non-viable testis performed in 34 (14.7% of TT group and 6.8% of the overall cohort). Duration of symptoms was significantly associated with risk of orchidectomy in torsion patients 4 vs. 27 hours (p <0.0001). Overall 47 (9.3%) patients presented after 12 hours, 22 (46.8%) had TT. There were 13 (2.6%) patients older than 40 years and 8 (61.5%) of these had torsion. The most commonest diagnosis for patients presenting with acute scrotal pain was torsion of the testis followed by torsion of appendix testis. Testicular salvage was inversely related to the duration of symptoms. Patient's age did not predict the need for orchidectomy. This data supports the practice of urgent scrotal exploration for acute scrotal pain with a clinical suspicion of torsion regardless of age and duration of symptoms.


Alcoholics Anonymous and 12-Step Facilitation Treatments for Alcohol Use Disorder: A Distillation of a 2020 Cochrane Review for Clinicians and Policy Makers.
A recently completed Cochrane review assessed the effectiveness and cost-benefits of Alcoholics Anonymous (AA) and clinically delivered 12-Step Facilitation (TSF) interventions for alcohol use disorder (AUD). This paper summarizes key findings and discusses implications for practice and policy. Cochrane review methods were followed. Searches were conducted across all major databases (e.g. Cochrane Drugs and Alcohol Group Specialized Register, PubMed, Embase, PsycINFO and ClinicalTrials.gov) from inception to 2 August 2019 and included non-English language studies. Randomized controlled trials (RCTs) and quasi-experiments that compared AA/TSF with other interventions, such as motivational enhancement therapy (MET) or cognitive behavioral therapy (CBT), TSF treatment variants or no treatment, were included. Healthcare cost offset studies were also included. Studies were categorized by design (RCT/quasi-experimental; nonrandomized; economic), degree of manualization (all interventions manualized versus some/none) and comparison intervention type (i.e. whether AA/TSF was compared to an intervention with a different theoretical orientation or an AA/TSF intervention that varied in style or intensity). Random-effects meta-analyses were used to pool effects where possible using standard mean differences (SMD) for continuous outcomes (e.g. percent days abstinent (PDA)) and the relative risk ratios (RRs) for dichotomous. A total of 27 studies (21 RCTs/quasi-experiments, 5 nonrandomized and 1 purely economic study) containing 10,565 participants were included. AA/TSF interventions performed at least as well as established active comparison treatments (e.g. CBT) on all outcomes except for abstinence where it often outperformed other treatments. AA/TSF also demonstrated higher health care cost savings than other AUD treatments. AA/TSF interventions produce similar benefits to other treatments on all drinking-related outcomes except for continuous abstinence and remission, where AA/TSF is superior. AA/TSF also reduces healthcare costs. Clinically implementing one of these proven manualized AA/TSF interventions is likely to enhance outcomes for individuals with AUD while producing health economic benefits.


Feasibility Trial of Tailored Home Modifications: Process Outcomes.
The aim of this study was to conduct a process evaluation to examine the implementation of a randomized controlled trial of home modifications designed to reduce the risk of falls and improve daily activity performance among community-dwelling older adults. A process evaluation was conducted alongside a blinded, randomized sham-controlled trial (n = 92). Participants were followed for 1 yr after intervention. The process evaluation was framed using the Reach, Effectiveness, Adoption, Implementation, and Maintenance framework. The treatment group improved daily activity performance over 12 mo compared with the sham control group (F = 4.13; p = .024). The intervention elements and dose were delivered with greater than 90% accuracy. Participants reported a 91% adherence rate at 12 mo. The complex intervention of home modifications examined in this study is acceptable to older adults, is feasible, and can be delivered with high fidelity for frail, community-dwelling older adults.


Noradrenergic modulation of subthalamic nucleus activity: behavioral and electrophysiological evidence in intact and 6-hydroxydopamine-lesioned rats.
The subthalamic nucleus (STN) plays a key role in the pathophysiology of Parkinson's disease. The modulation of the STN by norepinephrine, however, is unknown. The present study aims at characterizing the effects of systemic administration of noradrenergic agents on locomotor activity and on in vivo extracellularly recorded STN neuronal activity in intact and 6-hydroxydopamine (6-OHDA)-lesioned rats. Using selective agonists and antagonists of alpha1 and alpha2 adrenergic receptors (ARs), we show that STN neurons have functional alpha1- and alpha2-AR controlling STN firing with an impact on locomotor activity. We further demonstrate that those systemic effects are supported, at least in part, by a direct modulation of STN neuronal activity, using patch-clamp recordings of STN neurons in brain slices. These findings support the premise that hypokinesia is associated with an increased STN neuronal activity, and that improvements of parkinsonian motor abnormalities are associated with a decrease in STN activity. Our data challenge assumptions about the role of alpha1-AR and alpha2-AR in the regulation of STN neurons in both intact and 6-OHDA-lesioned rats and further ground the rationale for using alpha2-AR noradrenergic antagonists in Parkinson's disease, albeit via an unexpected mechanism.


Striving to respond to palliative care patients' pain at home: a puzzle for family caregivers.
to describe the types of pain patients in palliative care at home experience and how family caregivers assess them and intervene. qualitative using grounded theory. family caregivers' homes. 24 family caregivers of patients with advanced cancer receiving palliative care at home. semistructured interviews and field notes. Data analysis used Strauss and Corbin's recommendations for open, axial, and selective coding. pain, pain management, family caregivers, palliative care, and home care. caregivers assessed different types of pain and, therefore, were experimenting with different types of interventions. Not all family caregivers were able to distinguish between the different pains afflicting patients, and, consequently, were not selecting the most appropriate interventions. This often led to poorly managed pain and frustrated family caregivers. The accurate assessment of the types of pain the patient is experiencing, coupled with the most appropriate intervention for pain control, is critical for optimal pain relief as well as supporting the confidence and feelings of family caregivers who are undertaking the complex process of cancer pain management. nurses involved with patients receiving palliative care and their family caregivers should be aware of all types of pain experienced by the patient and how caregivers are managing the pain. Nurses should be knowledgeable about different pain relief interventions to help family caregivers obtain accurate information, understand their options, and administer these interventions safely and effectively.


The best friendships of shy/withdrawn children: prevalence, stability, and relationship quality.
The mutual best friendships of shy/withdrawn and control children were examined for prevalence, stability, best friend's characteristics, and friendship quality. Using peer nominations of shy/socially withdrawn and aggressive behaviors, two groups of children were identified from a normative sample of fifth-grade children: shy/withdrawn (n = 169) and control (nonaggressive/nonwithdrawn; n = 163). Friendship nominations, teacher reports, and friendship quality data were gathered. Results revealed that shy/withdrawn children were as likely as control children to have mutual stable best friendships. Withdrawn children's friends were more withdrawn and victimized than were the control children's best friends; further, similarities in social withdrawal and peer victimization were revealed for withdrawn children and their friends. Withdrawn children and their friends reported lower friendship quality than did control children. Results highlight the importance of both quantitative and qualitative measures of friendship when considering relationships as risk and/or protective factors.


Exposure To Harmful Workplace Practices Could Account For Inequality In Life Spans Across Different Demographic Groups.
The existence of important socioeconomic disparities in health and mortality is a well-established fact. Many pathways have been adduced to explain inequality in life spans. In this article we examine one factor that has been somewhat neglected: People with different levels of education get sorted into jobs with different degrees of exposure to workplace attributes that contribute to poor health. We used General Social Survey data to estimate differential exposures to workplace conditions, results from a meta-analysis that estimated the effect of workplace conditions on mortality, and a model that permitted us to estimate the overall effects of workplace practices on health. We conclude that 10-38 percent of the difference in life expectancy across demographic groups can be explained by the different job conditions their members experience.


Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects.
In vitro studies showed that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to 3,4-methylenedioxyamphetamine (MDA). However, the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans is unknown. The effects of genetic variants in these CYP enzymes on the pharmacokinetics and pharmacodynamics of MDMA were characterized in 139 healthy subjects (69 male, 70 female) in a pooled analysis of eight double-blind, placebo-controlled studies. MDMA-MDA conversion was positively associated with genotypes known to convey higher CYP2C19 or CYP2B6 activities. Additionally, CYP2C19 poor metabolizers showed greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes. Furthermore, the maximum concentration of MDA was higher in tobacco smokers that harbored the inducible CYP1A2 rs762551 A/A genotype compared with the non-inducible C-allele carriers. The findings indicate that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may moderate the cardiovascular toxicity of MDMA.


Antibiotic prescribing by single handed general practitioners: secondary analysis of data.
To determine the contribution of various doctor and patient factors on the frequency of antibiotic prescribing. Secondary analyses of data on 155 single handed general practitioners. Three variables explained 25% of variation in antibiotic prescribing. Doctors qualified from the Indian subcontinent issued more antibiotics than U.K.-qualified doctors. Patients from the non-manual social class were issued fewer antibiotics than those from the manual class and the most deprived patients received significantly more antibiotics. Very little of prescribing of antibiotics by doctors is explained by these doctor-patient factors. Prescribing is a complex process and the search for factors must continue in order to address the rising antibiotic resistance.


Process and implementation of participatory ergonomic interventions: a systematic review.
Participatory ergonomic (PE) interventions may vary in implementation. A systematic review was done to determine the evidence regarding context, barriers and facilitators to the implementation of participatory ergonomic interventions in workplaces. In total, 17 electronic databases were searched. Data on PE process and implementation were extracted from documents meeting content and quality criteria and synthesised. The search yielded 2151 references. Of these, 190 documents were relevant and 52 met content and quality criteria. Different ergonomic teams were described in the documents as were the type, duration and content of ergonomic training. PE interventions tended to focus on physical and work process changes and report positive impacts. Resources, programme support, ergonomic training, organisational training and communication were the most often noted facilitators or barriers. Successful PE interventions require the right people to be involved, appropriate ergonomic training and clear responsibilities. Addressing key facilitators and barriers such as programme support, resources, and communication is paramount. STATEMENT OF RELEVANCE: A recent systematic review has suggested that PE has some effect on reducing symptoms, lost days of work and claims. Systematic reviews of effectiveness provide practitioners with the desire to implement but do not provide clear information about how. This article reviews the literature on process and implementation of PE.


Population genomics of picophytoplankton unveils novel chromosome hypervariability.
Tiny photosynthetic microorganisms that form the picoplankton (between 0.3 and 3 μm in diameter) are at the base of the food web in many marine ecosystems, and their adaptability to environmental change hinges on standing genetic variation. Although the genomic and phenotypic diversity of the bacterial component of the oceans has been intensively studied, little is known about the genomic and phenotypic diversity within each of the diverse eukaryotic species present. We report the level of genomic diversity in a natural population of Ostreococcus tauri (Chlorophyta, Mamiellophyceae), the smallest photosynthetic eukaryote. Contrary to the expectations of clonal evolution or cryptic species, the spectrum of genomic polymorphism observed suggests a large panmictic population (an effective population size of 1.2 × 107) with pervasive evidence of sexual reproduction. De novo assemblies of low-coverage chromosomes reveal two large candidate mating-type loci with suppressed recombination, whose origin may pre-date the speciation events in the class Mamiellophyceae. This high genetic diversity is associated with large phenotypic differences between strains. Strikingly, resistance of isolates to large double-stranded DNA viruses, which abound in their natural environment, is positively correlated with the size of a single hypervariable chromosome, which contains 44 to 156 kb of strain-specific sequences. Our findings highlight the role of viruses in shaping genome diversity in marine picoeukaryotes.


Long-Term Consequences of Worsened Poststroke Status in Patients With Premorbid Disability.
Background and Purpose- Patients with premorbid disability, generally defined as modified Rankin Scale (mRS) score ≥2, are often excluded from trials of acute stroke therapies. However, increased disability in such patients will adversely affect long-term outcomes if treatments are withheld in routine practice. We assessed the extent to which increased disability poststroke influences 5-year mortality, institutionalization, and costs in premorbidly disabled patients. Methods- In a population-based, prospective cohort of patients with ischemic stroke (OXVASC [Oxford Vascular Study], 2002-2014), we tracked mortality, institutionalization, and healthcare/social-care costs during follow-up. We compared 5-year mortality and poststroke institutionalization (Cox regressions) and 5-year healthcare/social-care costs (generalized linear model) in 3-month survivors with premorbid mRS of 2 to 4 (excluding extreme disability, mRS=5), based on the degree of change in mRS(ΔmRS) from prestroke to 3 months poststroke, adjusting analyses for age/sex/initial National Institutes of Health Stroke Scale. Results- Among 1607 patients, 530 (33.0%) had premorbid mRS of 2 to 4. Only 2 premorbidly disabled patients received thrombolysis, but 421 (79.4%) were alive at 3 months. ΔmRS was independently associated with 5-year mortality/institutionalization (adjusted hazard ratio for ΔmRS=1 versus 0: 1.59; 95% CI, 1.20-2.11; ΔmRS=2: 2.39; 95% CI, 1.62-3.53; ΔmRS=3: 4.12; 95% CI, 1.98-8.60; P<0.001) and costs (margin for ΔmRS ≥2 versus 0: $30 011, 95% CI, $4222-55 801; P=0.023). Results were similar on examining patients with premorbid mRS of 2, 3, and 4 separately (eg, 5-year mortality/institutionalization adjusted hazard ratio for premorbid mRS=3 with ΔmRS=1 versus 0: 1.60; 95% CI, 1.06-2.42; P=0.027; ΔmRS=2: 3.20; 95% CI, 1.85-5.54; P<0.001). Conclusions- Patients with stroke with premorbid disability have higher mortality, institutionalization, and costs if they accumulate additional disability because of the stroke. These findings highlight the long-term outcomes expected if acute interventions are routinely withheld in patients with mild-moderate premorbid disability and suggest that trials/registries should include such patients.


Diabetes registries in patient-centered medical homes.
Little is known about the effectiveness of a patient registry, an attribute within the patient-centered medical home (PCMH) model, as it relates to diabetes health outcomes. The purpose of this retrospective study was to compare hemoglobin A1c (HbA1c) values for patients (n = 713) from clinics with an established diabetes registry (n = 7) to patients (n = 325) at clinics without a diabetes registry (n = 15), and determine whether HbA1c levels improve significantly more over time at registry clinics compared to nonregistry clinics. Up to 3 most recent sequential HbA1c values, along with demographic variables of age, body mass index (BMI), gender, race, insurance type, marital status, and whether or not the patient lived in the local area around the medical center were extracted from the electronic medical record used throughout the primary health care system. Presence of comorbid conditions of lipid metabolism and hypertension disorders were also collected. Analysis of variance and propensity-score-matched 2-sample analyses were used to examine the association between diabetes registry status HbA1c, controlling for demographic variables. Analyses indicated no evidence that patients in clinics with established diabetes registries had improved HbA1c levels significantly more than patients in clinics without diabetes registries. Patients in clinics with diabetes registry did not have greater overall improvement in HbA1c values than patients in nondiabetes registry clinics. However, patients at all clinics had significantly reduced HbA1c values over time. More research is needed to determine if registries are effective PCMH tools to reduce diabetes morbidity and mortality.


Hammer or crescent wrench? Stone-tool form and function in the Aurignacian of southwest Germany.
The early Upper Paleolithic of Europe is associated with the appearance of blade/bladelet technology (e.g., Aurignacian). These industries include a wider range of formal tool types than seen in the Middle Paleolithic. Greater diversity in tool types is often interpreted as specialized tools created for specific tasks. This, in turn, is said to reflect dramatic behavioral shifts between Neandertals and modern humans. In order to test previous interpretations, it is necessary to have a detailed understanding of early Upper Paleolithic stone-tool function. Toward this end, analyses of microscopic residue and use-wear were undertaken on 109 stone tools from three Aurignacian sites in southwest Germany (Hohle Fels, Geissenklösterle, and Vogelherd). These cave sites evidenced remarkable residue preservation, with approximately 82% of the sample showing some form of functional evidence. Residues observed included hair, feathers, bone/antler, wood, plant tissue, phytoliths, starch grains, and resin. The results suggest that tool typology is not strongly linked to the processing of specific materials. For example, endscrapers from the sample show evidence of processing wood, charred wood, plants, starchy plants, birds, bone/antler, and animals (hair). Hairs are found on tools typologically classified as blades, flakes, borers, pointed blades, and combination tools (nosed endscraper-borer, burin-laterally-retouched blade). In the early Upper Paleolithic of southwest Germany, a wide range of tool types appears to have been used to process a diverse array of materials. These results suggest that the interpretation of behavioral patterns from stone tools must consider more than tool typology.


The brain as part of an enactive system.
The notion of an enactive system requires thinking about the brain in a way that is different from the standard computational-representational models. In evolutionary terms, the brain does what it does and is the way that it is, across some scale of variations, because it is part of a living body with hands that can reach and grasp in certain limited ways, eyes structured to focus, an autonomic system, an upright posture, etc. coping with specific kinds of environments, and with other people. Changes to any of the bodily, environmental, or intersubjective conditions elicit responses from the system as a whole. On this view, rather than representing or computing information, the brain is better conceived as participating in the action.


RNA polymerase beta-subunit gene (rpoB) sequence analysis for the identification of Bacteroides spp.
Partial rpoB sequences (317 bp) of 11 species of Bacteroides, two Porphyromonas spp. and two Prevotella spp. were compared to delineate the genetic relationships among Bacteroides and closely related anaerobic species. The high level of inter-species sequence dissimilarities (7.6-20.8%) allowed the various Bacteroides spp. to be distinguished. The position of the Bacteroides distasonis and Bacteriodes merdae cluster in the rpoB tree was different from the position in the 16S rRNA gene tree. Based on rpoB sequence similarity and clustering in the rpoB tree, it was possible to correctly re-identify 80 clinical isolates of Bacteroides. In addition to two subgroups, cfiA-negative (division I) and cfiA-positive (division II), of Bacteroides fragilis isolates, two distinct subgroups were also found among Bacteroides ovatus and Bacteroides thetaiotaomicron isolates. Bacteroides genus-specific rpoB PCR and B. fragilis species-specific rpoB PCR allowed Bacteroides spp. to be differentiated from Porphyromonas and Prevotella spp., and also allowed B. fragilis to be differentiated from other non-fragilisBacteroides spp. included in the present study.


Proteomic analysis of NMDA receptor-adhesion protein signaling complexes.
N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.


The Effect of Population Growth on the Environment: Evidence from European Regions.
There is a long-standing dispute on the extent to which population growth causes environmental degradation. Most studies on this link have so far analyzed cross-country data, finding contradictory results. However, these country-level analyses suffer from the high level of dissimilarity between world regions and strong collinearity of population growth, income, and other factors. We argue that regional-level analyses can provide more robust evidence, isolating the population effect from national particularities such as policies or culture. We compile a dataset of 1062 regions within 22 European countries and analyze the effect from population growth on carbon dioxide (CO2) emissions and urban land use change between 1990 and 2006. Data are analyzed using panel regressions, spatial econometric models, and propensity score matching where regions with high population growth are matched to otherwise highly similar regions exhibiting significantly less growth. We find a considerable effect from regional population growth on carbon dioxide (CO2) emissions and urban land use increase in Western Europe. By contrast, in the new member states in the East, other factors appear more important.


Quantitative assessment of the nematode fauna present on Geotrupes dung beetles reveals species-rich communities with a heterogeneous distribution.
Pristionchus spp. nematodes exhibit several traits that might serve as pre-adaptations to parasitism. Under harsh environmental conditions, these nematodes can arrest development and form dauer larvae. In addition, they have been shown to live in necromenic association with a range of beetles, including dung beetles ( Geotrupes stercorosus ) on which, for example, Pristionchus entomophagus is commonly found. It has been argued that the formation of dauer larvae and the association with invertebrates represent intermediate steps towards parasitism. To better understand necromenic associations, and to gain information on Pristionchus spp. abundance and the general species composition on dung beetles, we extracted all the nematode fauna present on 114 individuals of G. stercorosus. By direct sequencing using the 18S SSU, we provide a barcode for all nematodes isolated from the beetle samples. In total, 5,002 dauer-stage nematodes were sequenced, which included Pristionchus spp., Koerneria spp. (Diplogastridae), Pelodera spp. (Rhabditidae), and Strongyloidea as well as Spirurida. Intensities of infection varied from over 1,000 nematodes isolated from a single G. stercorosus to none, with Pelodera spp. being the most abundant group isolated. This study presents the first quantitative data on the Pristionchus spp. infection of beetles.


Parameterization and atomistic simulations of biomimetic membranes.
Biomimetic membranes, designed by combining proteins or protein-mimics with self-assembled block copolymers, are emerging as novel hybrid materials with applications in the next generation of sensing and separation devices. However, designing such membranes requires a fundamental understanding of the atomic-scale interactions between biological channel proteins and their non-native polymeric membrane environment as it affects their stability and function. In principle, all-atom molecular dynamics (MD) simulations are well-suited to probe the atomistic details of channel/membrane interactions, but the absence of interatomic potentials is a major limiting factor in conducting such simulations. To alleviate this, we have developed CHARMM force-field compatible parameters and conducted all-atom explicit-solvent MD simulations of biomimetic membranes composed of block copolymers of poly(butadiene), poly(isoprene), and poly(ethylene oxide). Consistent with scaling laws and literature data, we report measurements on several structural properties that inform on molecular-scale features of chain conformations. Finally, we report simulations of a synthetic transport channel in selected membranes and characterize its functional behavior by measuring the single-channel water permeability. We suggest that the interatomic potentials and membrane models reported here could be useful in studies of other proteins as well as for deriving potentials for coarse-grained models to permit future simulations of large-scale protein/polymer membranes.


Kinesin-13 regulates flagellar, interphase, and mitotic microtubule dynamics in Giardia intestinalis.
Microtubule depolymerization dynamics in the spindle are regulated by kinesin-13, a nonprocessive kinesin motor protein that depolymerizes microtubules at the plus and minus ends. Here we show that a single kinesin-13 homolog regulates flagellar length dynamics, as well as other interphase and mitotic dynamics in Giardia intestinalis, a widespread parasitic diplomonad protist. Both green fluorescent protein-tagged kinesin-13 and EB1 (a plus-end tracking protein) localize to the plus ends of mitotic and interphase microtubules, including a novel localization to the eight flagellar tips, cytoplasmic anterior axonemes, and the median body. The ectopic expression of a kinesin-13 (S280N) rigor mutant construct caused significant elongation of the eight flagella with significant decreases in the median body volume and resulted in mitotic defects. Notably, drugs that disrupt normal interphase and mitotic microtubule dynamics also affected flagellar length in Giardia. Our study extends recent work on interphase and mitotic kinesin-13 functioning in metazoans to include a role in regulating flagellar length dynamics. We suggest that kinesin-13 universally regulates both mitotic and interphase microtubule dynamics in diverse microbial eukaryotes and propose that axonemal microtubules are subject to the same regulation of microtubule dynamics as other dynamic microtubule arrays. Finally, the present study represents the first use of a dominant-negative strategy to disrupt normal protein function in Giardia and provides important insights into giardial microtubule dynamics with relevance to the development of antigiardial compounds that target critical functions of kinesins in the giardial life cycle.


Dividing the self: distinct neural substrates of task-based and automatic self-prioritization after brain damage.
Facial self-awareness is a basic human ability dependent on a distributed bilateral neural network and revealed through prioritized processing of our own over other faces. Using non-prosopagnosic patients we show, for the first time, that facial self-awareness can be fractionated into different component processes. Patients performed two face perception tasks. In a face orientation task, they judged whether their own or others' faces were oriented to the left or right. In the 'cross' experiment, they judged which horizontal or vertical element in a cross was relatively longer while ignoring a task-irrelevant face presented as background. The data indicate that impairments to a distinct task-based prioritization process (when faces had to be attended) were present after brain damage to right superior frontal gyrus, bilateral precuneus, and left middle temporal gyrus. In contrast, impairments to automatic prioritization processes (when faces had to be ignored) were associated only with left hemisphere damage (the cingulate gyrus, superior parietal lobe, and superior temporal gyrus). In addition, both automatic and task-based self-prioritizations were affected by damage to left supramarginal and angular gyrus. The results for the gray matter analyses also extended to the adjacent white matter fiber tracts including the inferior occipital-frontal fasciculus, cingulum, and optic radiation. The data provide the first empirical evidence for separate functional roles of the left and right hemispheres in different aspects of self-face perception and suggest distinct functional processes respectively for paying attention to and for ignoring self-related information.


Adenovirus: Epidemiology, Global Spread of Novel Serotypes, and Advances in Treatment and Prevention.
Adenoviruses (AdVs) are DNA viruses that typically cause mild infections involving the upper or lower respiratory tract, gastrointestinal tract, or conjunctiva. Rare manifestations of AdV infections include hemorrhagic cystitis, hepatitis, hemorrhagic colitis, pancreatitis, nephritis, or meningoencephalitis. AdV infections are more common in young children, due to lack of humoral immunity. Epidemics of AdV infection may occur in healthy children or adults in closed or crowded settings (particularly military recruits). The disease is more severe and dissemination is more likely in patients with impaired immunity (e.g., organ transplant recipients, human immunodeficiency virus infection). Fatality rates for untreated severe AdV pneumonia or disseminated disease may exceed 50%. More than 50 serotypes of AdV have been identified. Different serotypes display different tissue tropisms that correlate with clinical manifestations of infection. The predominant serotypes circulating at a given time differ among countries or regions, and change over time. Transmission of novel strains between countries or across continents and replacement of dominant viruses by new strains may occur. Treatment of AdV infections is controversial, as prospective, randomized therapeutic trials have not been conducted. Cidofovir is the drug of choice for severe AdV infections, but not all patients require treatment. Live oral vaccines are highly efficacious in reducing the risk of respiratory AdV infection and are in routine use in the military in the United States, but currently are not available to civilians.


Association Between Insurance Status and Hospital Length of Stay Following Trauma.
Previous research has demonstrated that nonclinical factors are associated with differences in clinical care, with uninsured patients receiving decreased resource use. Studies on trauma populations have also shown unclear relationships between insurance status and hospital length of stay (LOS), a commonly used metric for evaluating quality of care. The objective of this study is to define the relationship between insurance status and LOS after trauma using the largest available national trauma dataset and controlling for significant confounders. Data from 2007 to 2010 National Trauma Data Bank were used to compare differences in LOS among three insurance groups: privately insured, publically insured, and uninsured trauma patients. Multivariable regression models adjusted for potential confounding due to baseline differences in injury severity and demographic and clinical factors. A total of 884,493 patients met the inclusion criteria. After adjusting for the influence of covariates, uninsured patients had significantly shorter hospital stays (0.3 days) relative to privately insured patients. Publicly insured patients had longer risk-adjusted LOS (0.9 days). Stratified differences in discharge disposition and injury severity significantly altered the relationship between insurance status and LOS. In conclusion, this study elucidates the association between insurance status and hospital LOS, demonstrating that a patient's ability to pay could alter LOS in acute trauma patients. Additional research is needed to examine causes and outcomes from these differences to increase efficiency in the health care system, decrease costs, and shrink disparities in health outcomes.


Long-term T cell memory requires the surface expression of self-peptide/major histocompatibility complex molecules.
How memory T cells are maintained in vivo is poorly understood. To address this problem, a male-specific peptide (H-Y) was identified and used to activate female anti-H-Y T cells in vitro. Anti-H-Y T cells survived in vivo for at least 70 days in the absence of antigen. This persistence was not because of the intrinsic ability of memory T cells to survive in vivo. Instead, the survival and function of adoptively transferred memory cells was found to require transporter of antigen protein 1-dependent expression of self-peptide/major histocompatibility complex class I molecules in recipient animals. Therefore, it appears that the level of T cell receptor engagement provided by transporter of antigen protein 1-dependent, self-peptide/major histocompatibility complexes is sufficient to maintain the long-term survival and functional phenotype of memory cells in the absence of persistent antigen. These data suggest that positive selection plays a role not only in T cell development but also in the maintenance of T cell memory.


Evidence for Contemporary Switching of the O-Antigen Gene Cluster between Shiga Toxin-Producing Escherichia coli Strains Colonizing Cattle.
Shiga toxin-producing Escherichia coli (STEC) comprise a group of zoonotic enteric pathogens with ruminants, especially cattle, as the main reservoir. O-antigens are instrumental for host colonization and bacterial niche adaptation. They are highly immunogenic and, therefore, targeted by the adaptive immune system. The O-antigen is one of the most diverse bacterial cell constituents and variation not only exists between different bacterial species, but also between individual isolates/strains within a single species. We recently identified STEC persistently infecting cattle and belonging to the different serotypes O156:H25 (n = 21) and O182:H25 (n = 15) that were of the MLST sequence types ST300 or ST688. These STs differ by a single nucleotide in purA only. Fitness-, virulence-associated genome regions, and CRISPR/CAS (clustered regularly interspaced short palindromic repeats/CRISPR associated sequence) arrays of these STEC O156:H25 and O182:H25 isolates were highly similar, and identical genomic integration sites for the stx converting bacteriophages and the core LEE, identical Shiga toxin converting bacteriophage genes for stx1a, identical complete LEE loci, and identical sets of chemotaxis and flagellar genes were identified. In contrast to this genomic similarity, the nucleotide sequences of the O-antigen gene cluster (O-AGC) regions between galF and gnd and very few flanking genes differed fundamentally and were specific for the respective serotype. Sporadic aEPEC O156:H8 isolates (n = 5) were isolated in temporal and spatial proximity. While the O-AGC and the corresponding 5' and 3' flanking regions of these aEPEC isolates were identical to the respective region in the STEC O156:H25 isolates, the core genome, the virulence associated genome regions and the CRISPR/CAS elements differed profoundly. Our cumulative epidemiological and molecular data suggests a recent switch of the O-AGC between isolates with O156:H8 strains having served as DNA donors. Such O-antigen switches can affect the evaluation of a strain's pathogenic and virulence potential, suggesting that NGS methods might lead to a more reliable risk assessment.


Subcortical connections of the prefrontal cortex in dogs: afferents to the proreal gyrus.
Afferent subcortical connections to the proreal gyrus of the prefrontal cortex (PFC) in the dog were investigated using the horseradish peroxidase retrograde transport method. The afferent projections derive mainly from dorsal-intermediate and caudal regions of the mediodorsal nucleus (MD), from $he ventral as well as from the lateral thalamic nuclei. In the ventral nuclei, the distribution of labeled cells showed a topography correlated with injections localized in the anteroposterior direction. Furthermore, single cells were labeled in midline and intralaminar thalamic nuclei as well as some extrathalamic structures. The data obtained in behavioral and anatomical experiments with dog and monkey are discussed. The distribution of afferent projection from MD and the functional division on particular subfields of PFC seems to be in accordance in both species.


Carisbamate acutely suppresses spasms in a rat model of symptomatic infantile spasms.
Infantile spasms are the signature seizures of West syndrome. The conventional treatments for infantile spasms, such as adrenocorticotropic hormone (ACTH) and vigabatrin, are not always effective, especially in symptomatic infantile spasms (SIS). We tested the efficacy of carisbamate, a novel neurotherapeutic drug, to suppress spasms in the multiple-hit rat model of SIS, and compared it with phenytoin to determine if its effect is via sodium-channel blockade. Sprague-Dawley rats received right intracerebral infusions of doxorubicin and lipopolysaccharide at postnatal day 3 (PN3) and intraperitoneal p-chlorophenylalanine at PN5. A single intraperitoneal injection of carisbamate was administered at PN4, after the onset of spasms, at the following doses: 10 mg/kg (CRS-10), 30 mg/kg (CRS-30), and 60 mg/kg (CRS-60), and was compared to vehicle-injected group (VEH). Video-monitoring of PN6-7 CRS-60 or VEH-injected pups was also done. Carisbamate acutely reduced both behavioral spasms (CRS-30 and CRS-60 groups only) and electroclinical spasms during the first 2-3 postinjection hours, without detectable toxicity or mortality. In contrast, phenytoin (20 or 50 mg/kg) failed to suppress spasms. Our findings provide preclinical evidence that carisbamate displays acute anticonvulsive effect on spasms through a sodium channel-independent mechanism. Because spasms in the multiple-hit rat model are refractory to ACTH and transiently sensitive to vigabatrin, carisbamate may constitute a candidate new therapy for SIS, including the ACTH-refractory spasms. Further confirmation with clinical studies is needed.


Cytotoxic effects of 3,4-methylenedioxy-N-alkylamphetamines, MDMA and its analogues, on isolated rat hepatocytes.
The amphetamine-derived designer drugs have been illegally used worldwide as recreational drugs, some of which are known to be hepatotoxic in humans. To compare their cytotoxic effects, 3,4-methylenedioxy-N-methamphetamine (MDMA) and its related analogues, N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB), 3,4-(methylenedioxyphenyl)-2-butanamine (BDB) and 2-methylamino-1-(3,4-methylenedioxyphenyl)-propane-1-one (methylone) were studied in freshly isolated rat hepatocytes. MBDB caused not only concentration (0-4.0 mM)- and time (0-2 h)-dependent cell death accompanied by the formation of cell blebs, and the loss of cellular ATP and adenine nucleotide pools, and reduced glutathione levels, but also the accumulation of oxidized glutathione. Of the other analogues examined, the cytotoxicity of MBDB and BDB was greater than that of MDMA and methylone, suggesting that hepatotoxicity is generally induced by these drugs. In addition, DNA damage and the induction of reactive oxygen species were greater after the incubation of hepatocytes with MBDB (2 and 4 mM) than after that with MDMA. In isolated liver mitochondria, MBDB/BDB resulted in a greater increase in the rate of state 4 oxygen consumption than did MDMA/methylone, indicating an uncoupling effect and a decrease in the rate of state 3 oxygen consumption in a concentration dependent manner. Furthermore, MBDB resulted in mitochondrial swelling dependent on the mitochondrial permeability transition (MPT); the effect of MDMA was less than that of MBDB. Taken collectively, these results suggest that (1) the onset of cytotoxicity caused by designer drugs such as MBDB and MDMA is linked to mitochondrial failure dependent upon the induction of the MPT accompanied by mitochondrial depolarization and depletion of ATP through uncoupling of oxidative phosphorylation in rat hepatocytes, and (2) MBDB and MDMA elicit DNA damage, suggesting that nuclei as well as mitochondria are target sites of these compounds.


Assessment of professional behaviour--a comparison of self-assessment by first year dental students and assessment by staff.
A study was set up to assess usefulness and acceptability of a method of assessing professional behaviour of undergraduate dental students. The first year preclinical course at the Department of Dentistry and Oral Hygiene, University of Groningen, the Netherlands. A form was developed with an ordinal scale to assess undergraduate professional behaviour. A standard means of carrying out assessment was then undertaken and subsequently used to give feedback to the students at the end of each of three terms. The students' self-assessment was then compared to that of the staff. Descriptive analysis of the results was carried out per term. The response rate was 80-85%. The significant difference which existed between the scores of students and staff at the start of the study was reduced to reasonable agreement over two of the three criteria. The study indicated that the initial difference in assessment of their professional behaviour by first year dental students and by staff, was reduced by the forms and procedure used. This indicates the usefulness of the procedure as a teaching aid. The high participation rate confirms this to be an acceptable means of assessment of dental students' professional behaviour.


Clinical and radiographic characteristics of sacral arteriovenous fistulas: a multicenter experience.
Available data on management of sacral arteriovenous fistulas (sAVFs) are limited to individual case reports and small series. Management includes observation, endovascular embolization, or surgical ligation, with no clear guidelines on the optimal treatment modality. The authors' objective was to report their multiinstitutional experience with management of sAVF patients, including clinical and radiographic characteristics and postprocedural outcomes. The electronic medical records of patients with a diagnosis of spinal arteriovenous fistula treated from January 2004 to December 2019 at the authors' institutions were reviewed, and data were summarized using descriptive statistics, including percentage and count for categorical data, median as a measure of central tendency for continuous variables, and interquartile range (IQR) as a measure of dispersion. A total of 26 patients with sAVFs were included. The median (IQR) age was 65 (57-73) years, and 73% (n = 19) of patients were male. Lower-extremity weakness was the most common presenting symptom (n = 24 [92%]), and half the patients (n = 13 [50%]) reported bowel and bladder sphincter dysfunction. The median (IQR) time from symptom onset to treatment was 12 (5.25-26.25) months. Radiographically, all patients had T2 hyperintensity at the level of the conus medullaris (CM) (n = 26 [100%]). Intradural flow voids were identified in 85% (n = 22) of patients. The majority of the lesions had a single identifiable arterial feeder (n = 19 [73%]). The fistula was located most commonly at the S1 level (n = 13 [50%]). The site where the draining vein connects to the pial venous plexus was seen predominantly at the lumbar level (n = 16 [62%]). In total, 29 procedures were performed: 10 open surgeries and 19 endovascular embolization procedures. Complete occlusion was achieved in 90% (n = 9) of patients after open surgery and 79% (n = 15) after endovascular embolization. Motor improvement was seen in 68% of patients (n = 15), and bladder and bowel function improved in 9 patients (41%). At last follow-up, 73% (n = 16) of patients had either resolution or improvement of the pretreatment intramedullary T2 signal hyperintensity. T2 hyperintensity of the CM and a dilated filum terminale vein are consistent radiographic signs of sAVF, and delayed presentation is common. Complete occlusion was achieved in almost all patients after surgery, and endovascular embolization was effective in 70% of the patients. Further studies are needed to determine the best treatment modality based on case-specific characteristics.