Basic science to clinical trials in non-alcoholic fatty liver disease and alcohol-related liver disease: collaboration with industry.
Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are highly prevalent forms of chronic liver diseases globally, associated with rising all-cause morbidity and mortality. While distinct diseases, NAFLD and ALD share several similarities; both can result in fatty liver disease, steatohepatitis, associated hepatic fibrosis and cirrhosis-related complications, including hepatocellular carcinoma (HCC). Our understanding of the pathophysiology and manifestations of these diseases has advanced significantly, which has established a new foundation to identify therapeutic targets and test new treatments. This review underscores emerging pathogenic pathways that establish a template for target identification and clinical trials. Success is critically dependent upon productive interactions between academic investigators and industry to address unmet therapeutic needs in NAFLD and ALD.


Role of health insurance in financing vaccinations for children and adolescents in the United States.
The goal was to elicit perspectives of selected health insurance plan medical or quality improvement directors regarding factors related to coverage and reimbursement and perceptions of financing as a barrier to child and adolescent immunization. Medical or quality improvement directors from 20 plans selected by America's Health Insurance Plans were invited to complete an online survey in July 2007. Respondents who agreed to follow-up interviews were invited to participate in telephone interviews conducted by Centers for Disease Control and Prevention staff members in August 2007. Fifteen plans (representing >67 million enrollees) responded to the online survey. All respondents covered all Advisory Committee on Immunization Practices-recommended child and adolescent vaccines in all or most products. Advisory Committee on Immunization Practices recommendations were the most commonly cited criteria for coverage decisions (86.7%) and coverage modifications (100%). Factors affecting reimbursement that were cited most often were manufacturer's vaccine price (80%) and physician feedback (53.3%). In follow-up interviews with 10 self-selected respondents, manufacturer's price (7 of 10 plans) and physician feedback (4 of 10 plans) were identified as the most-important factors affecting reimbursement. Respondents said that reimbursement delays were most commonly attributable to providers' claim submission errors or patient ineligibility. Some respondents thought that vaccine financing was a barrier (4 of 10 plans) or somewhat a barrier (2 of 10 plans) to providing immunizations; others (4 of 10 plans) did not. Although these data suggest that health insurance coverage for recommended vaccines is high, coverage is not universal across all products offered.


Feature-based groupwise registration by hierarchical anatomical correspondence detection.
Groupwise registration has been widely investigated in recent years due to its importance in analyzing population data in many clinical applications. To our best knowledge, most of the groupwise registration algorithms only utilize the intensity information. However, it is well known that using intensity only is not sufficient to achieve the anatomically sound correspondences in medical image registration. In this article, we propose a novel feature-based groupwise registration algorithm to establish the anatomical correspondence across subjects by using the attribute vector that is defined as the morphological signature for each voxel. Similar to most of the state-of-the-art groupwise registration algorithms, which simultaneously estimate the transformation fields for all subjects, we develop an energy function to minimize the intersubject discrepancies on anatomical structures and drive all subjects toward the hidden common space. To make the algorithm efficient and robust, we decouple the complex groupwise registration problem into two easy-to-solve subproblems, namely (1) robust correspondence detection and (2) dense transformation field estimation, which are systematically integrated into a unified framework. To achieve the robust correspondences in the step (1), several strategies are adopted. First, the procedure of feature matching is evaluated within a neighborhood, rather than only on a single voxel. Second, the driving voxels with distinctive image features are designed to drive the transformations of other nondriving voxels. Third, we take advantage of soft correspondence assignment not only in the spatial domain but also across the population of subjects. Specifically, multiple correspondences are allowed to alleviate the ambiguity in establishing correspondences w.r.t. a particular subject and also the contributions from different subjects are dynamically controlled throughout the registration. Eventually in the step (2), based on the correspondences established for the driving voxels, thin-plate spline is used to propagate correspondences on the driving voxels to other locations in the image. By iteratively repeating correspondence detection and dense deformation estimation, all the subjects will be aligned onto the common space. Our feature-based groupwise registration algorithm has been extensively evaluated over 18 elderly brains, 16 brains from NIREP (with 32 manually delineated labels), 40 brains from LONI LPBA40 (with 54 manually delineated labels), and 12 pairs of normal controls and simulated atrophic brain images. In all experiments, our algorithm achieves more robust and accurate registration results, compared with another groupwise algorithm and a pairwise registration method.


"In vitro" evaluation of the bacterivore potential of three Cladoceran species occurring in tropical and subtropical regions.
Cladocerans occupy an important position among the bacterial consumers in freshwater food webs, being relatively non-selective filter feeders that can exert a strong impact on microbial populations. We evaluated the bacterivory potential of three cladocerans species of subtropical and tropical occurrence (Ceriodaphnia silvestrii, Daphnia gessneri and Ceriodaphnia cornuta) at different life stages, by scanning electron microscopy (SEM) and by the quantification of their bacterial consumption rates using fluorescently labeled bacteria (FLB). All species showed filter mesh sizes sufficiently narrow to retain bacteria. The largest distance between setules was found in primiparous C. cornuta, and the smallest in neonate D. gessneri. The lowest ingestion (IR) and removal (RR) rates were observed in primiparous C. silvestrii and the highest values were observed in adults of D. gessneri. We conclude that bacteria may be considered an important food supplement, particularly for neonates who presented smaller intersetular distances and higher filtration rates than the other life stages.


A systematic review of titles and abstracts of experimental studies in medical education: many informative elements missing.
Informative titles and abstracts facilitate reading and searching the literature. To evaluate the quality of titles and abstracts of full-length reports of experimental studies in medical education. We used a random sample of 110 articles (of 185 eligible articles) describing education experiments. Articles were published in 2003 and 2004 in Academic Medicine, Advances in Health Sciences Education, American Journal of Surgery, Journal of General Internal Medicine, Medical Education and Teaching and Learning in Medicine. Titles were categorised as informative, indicative, neither, or both. Abstracts were evaluated for the presence of a rationale, objective, descriptions of study design, setting, participants, study intervention and comparison group, main outcomes, results and conclusions. Of the 105 articles suitable for review, 86 (82%) had an indicative title and 10 (10%) had a title that was both indicative and informative. A rationale was present in 66 abstracts (63%), objectives were present in 84 (80%), descriptions of study design in 20 (19%), setting in 29 (28%), and number and stage of training of participants in 42 (40%). The study intervention was defined in 55 (52%) abstracts. Among the 48 studies with a control or comparison group, this group was defined in 21 abstracts (44%). Study outcomes were defined in 64 abstracts (61%). Data were presented in 48 (46%) abstracts. Conclusions were presented in 97 abstracts (92%). Reports of experimental studies in medical education frequently lack the essential elements of informative titles and abstracts. More informative reporting is needed.


Native American genetic ancestry and pigmentation allele contributions to skin color in a Caribbean population.
Our interest in the genetic basis of skin color variation between populations led us to seek a Native American population with genetically African admixture but low frequency of European light skin alleles. Analysis of 458 genomes from individuals residing in the Kalinago Territory of the Commonwealth of Dominica showed approximately 55% Native American, 32% African, and 12% European genetic ancestry, the highest Native American genetic ancestry among Caribbean populations to date. Skin pigmentation ranged from 20 to 80 melanin units, averaging 46. Three albino individuals were determined to be homozygous for a causative multi-nucleotide polymorphism OCA2NW273KV contained within a haplotype of African origin; its allele frequency was 0.03 and single allele effect size was -8 melanin units. Derived allele frequencies of SLC24A5A111T and SLC45A2L374F were 0.14 and 0.06, with single allele effect sizes of -6 and -4, respectively. Native American genetic ancestry by itself reduced pigmentation by more than 20 melanin units (range 24-29). The responsible hypopigmenting genetic variants remain to be identified, since none of the published polymorphisms predicted in prior literature to affect skin color in Native Americans caused detectable hypopigmentation in the Kalinago.


Alternatives to allogeneic platelet transfusion.
Allogeneic platelet transfusions are widely used for the prevention and treatment of bleeding in thrombocytopenia. Recent evidence suggests platelet transfusions have limited efficacy and are associated with uncertain immunomodulatory risks and concerns about viral or bacterial transmission. Alternatives to transfusion are a well-recognised tenet of Patient Blood Management, but there has been less focus on different strategies to reduce bleeding risk by comparison to platelet transfusion. Direct alternatives to platelet transfusion include agents to stimulate endogenous platelet production (thrombopoietin mimetics), optimising platelet adhesion to endothelium by treating anaemia or increasing von Willebrand factor levels (desmopressin), increasing formation of cross-linked fibrinogen (activated recombinant factor VII, fibrinogen concentrate or recombinant factor XIII), decreasing fibrinolysis (tranexamic acid or epsilon aminocaproic acid) or using artificial or modified platelets (cryopreserved platelets, lyophilised platelets, haemostatic particles, liposomes, engineered nanoparticles or infusible platelet membranes). The evidence base to support the use of these alternatives is variable, but an area of active research. Much of the current randomised controlled trial focus is on evaluation of the use of thrombopoietin mimetics and anti-fibrinolytics. It is also recognised that one alternative strategy to platelet transfusion is choosing not to transfuse at all.


A Systematic Literature Review on e-Mental Health Solutions to Assist Health Care Workers During COVID-19.
Background: e-Mental health is an established field of exploiting information and communication technologies for mental health care. It offers different solutions and has shown effectiveness in managing many psychological issues. Introduction: The coronavirus disease 2019 (COVID-19) pandemic has critically influenced health care systems and health care workers (HCWs). HCWs are working under hard conditions, and are suffering from different psychological issues, including anxiety, stress, and depression. Consequently, there is an undeniable need of mental care interventions for HCWs. Under the circumstances caused by COVID-19, e-health interventions can be used as tools to assist HCWs with their mental health. These solutions can provide mental health care support remotely, respecting the recommended safety measures. Materials and Methods: This study aims to identify e-mental health interventions, reported in the literature, that are developed for HCWs during the COVID-19 pandemic. A systematic literature review was conducted following the PRISMA protocol by searching the following digital libraries: IEEE, ACM, ScienceDirect, Scopus, and PubMed. Results and Discussion: Eleven publications were selected. The identified e-mental health interventions consisted of social media platforms, e-learning content, online resources and mobile applications. Only 27% of the studies included empirical evaluation of the reported interventions, 55% listed challenges and limitations related to the adoption of the reported interventions. And 45% presented interventions developed specifically for HCWs in China. The overall feedback on the identified interventions was positive, yet a lack of empirical evaluation was identified, especially regarding qualitative evidence. Conclusions: The COVID-19 pandemic has highlighted the importance and need for e-mental health solutions for HCWs.


Age-related changes in local and global visual perception.
Over the past 40 years, research has addressed the impact of the aging process on various aspects of visual function. Most studies have focused on age-related visual impairment in low-level local features of visual objects, such as orientation, contrast sensitivity and spatial frequency. However, whether there are lifespan changes in global visual perception is still unclear. To suitably frame this question, we defined global visual patterns by a topological approach, and local visual patterns were manipulated with different levels of geometrical invariants in descending order of structural stability from projective, affine, and then Euclidean features. Using the Configural Superiority Effect, we investigated the influence of aging on local and global visual perception through a comparison of young and old adults in Experiment 1; moreover, we provided continuous-aging data from 21 to 78 years of age to investigate age-related changes in visual perception in Experiment 2. We found a large perceptual decline across increasing age groups in local geometrical perception: for example, Euclidean (orientation), affine (parallelism), and projective (collinearity) discrimination. Moreover, the study provides a counterintuitive finding that global topological perception resists the aging process and remains constant throughout adult lifespan. These findings highlight the possibility that for humans, global topology may be a stable and fundamental component by which visual systems represent and characterize objects.


[Autism, depression and risk of suicide].
Autism is a neurodevelopmental disorder characterized by a qualitative alteration in social interaction and communication, associated with restricted interests and stereotyped behaviors. People with autism are four times more likely to develop depression, than the general population, it is even considered as the most common mental health condition in people with autism spectrum disorders (ASD). One of the challenges is to recognize the manifestations related to depression in people with ASD, in whom, in general, it is expressed differently in relation to those with typical development. Depression in people with autism can manifest itself with restlessness and insomnia and not with feelings of sadness, so it is essential to be attentive and not justify all behavioral problems to autism. Young adults with ASD have higher baseline levels of almost all the depression characteristics listed in the DSM-5, which can lead to overdiagnosis or underreporting of depression. On the other hand, adults with autism have an increased risk of experiencing suicidal thoughts, planning suicide, carrying it out and even dying from suicide. Many of them have a history of depression, harassment and loneliness. It is essential the early detection of depression, develop appropriate tools for diagnosis in autism as well as generate awareness of the risk of ideation or suicide, a problem that only in recent years has been addressed with greater depth. In this paper I analyze depression in autism, the risk of suicidal ideation and suicide, prioritizing clinical aspects, their evaluation and risk factors.


Polycomb represses a gene network controlling puberty via modulation of histone demethylase Kdm6b expression.
Female puberty is subject to Polycomb Group (PcG)-dependent transcriptional repression. Kiss1, a puberty-activating gene, is a key target of this silencing mechanism. Using a gain-of-function approach and a systems biology strategy we now show that EED, an essential PcG component, acts in the arcuate nucleus of the hypothalamus to alter the functional organization of a gene network involved in the stimulatory control of puberty. A central node of this network is Kdm6b, which encodes an enzyme that erases the PcG-dependent histone modification H3K27me3. Kiss1 is a first neighbor in the network; genes encoding glutamatergic receptors and potassium channels are second neighbors. By repressing Kdm6b expression, EED increases H3K27me3 abundance at these gene promoters, reducing gene expression throughout a gene network controlling puberty activation. These results indicate that Kdm6b repression is a basic mechanism used by PcG to modulate the biological output of puberty-activating gene networks.


Physiological mechanisms used by fish to cope with salinity stress.
Salinity represents a critical environmental factor for all aquatic organisms, including fishes. Environments of stable salinity are inhabited by stenohaline fishes having narrow salinity tolerance ranges. Environments of variable salinity are inhabited by euryhaline fishes having wide salinity tolerance ranges. Euryhaline fishes harbor mechanisms that control dynamic changes in osmoregulatory strategy from active salt absorption to salt secretion and from water excretion to water retention. These mechanisms of dynamic control of osmoregulatory strategy include the ability to perceive changes in environmental salinity that perturb body water and salt homeostasis (osmosensing), signaling networks that encode information about the direction and magnitude of salinity change, and epithelial transport and permeability effectors. These mechanisms of euryhalinity likely arose by mosaic evolution involving ancestral and derived protein functions. Most proteins necessary for euryhalinity are also critical for other biological functions and are preserved even in stenohaline fish. Only a few proteins have evolved functions specific to euryhaline fish and they may vary in different fish taxa because of multiple independent phylogenetic origins of euryhalinity in fish. Moreover, proteins involved in combinatorial osmosensing are likely interchangeable. Most euryhaline fishes have an upper salinity tolerance limit of approximately 2× seawater (60 g kg(-1)). However, some species tolerate up to 130 g kg(-1) salinity and they may be able to do so by switching their adaptive strategy when the salinity exceeds 60 g kg(-1). The superior salinity stress tolerance of euryhaline fishes represents an evolutionary advantage favoring their expansion and adaptive radiation in a climate of rapidly changing and pulsatory fluctuating salinity. Because such a climate scenario has been predicted, it is intriguing to mechanistically understand euryhalinity and how this complex physiological phenotype evolves under high selection pressure.


A Case Series of Children With 2019 Novel Coronavirus Infection: Clinical and Epidemiological Features.
We first described the 2019 novel coronavirus infection in 10 children occurring in areas other than Wuhan. The coronavirus diseases in children are usually mild and epidemiological exposure is a key clue to recognize pediatric case. Prolonged virus shedding is observed in respiratory tract and feces at the convalescent stage.


Pharmacotherapy for smoking cessation: current advances and research topics.
Promoting smoking cessation is among the key medical interventions aimed at reducing worldwide morbidity and mortality in this century. Both behavioural counselling and pharmacotherapy have been shown to significantly increase long-term abstinence rates, and combining the two treatment modalities is recommended. This article provides an update on pharmacotherapy for smoking cessation in the general population. Current first-line agents used to support quit attempts are nicotine replacement therapy (NRT), bupropion and varenicline. Research suggests that abstinence rates can be increased by combining different forms of NRT or simultaneously administering NRT and non-nicotine medications. New treatments targeting the nicotinic acetylcholine receptor as well as other pathophysiological pathways involved in nicotine addiction are being developed, with nicotine vaccines now being tested in phase III clinical trials. Among the numerous research topics currently addressed, pharmacogenetics and tailoring therapy to specific groups of smokers look most promising. However, substantial progress is unlikely to be made unless social gradients impeding effective treatment of all smokers are overcome. In addition, public smoking bans and reimbursement of medication costs are crucial in reducing the future burden of disease caused by smoking on a global level.


Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model.
Individuals with 22q11.2 microdeletions show behavioral and cognitive deficits and are at high risk of developing schizophrenia. We analyzed an engineered mouse strain carrying a chromosomal deficiency spanning a segment syntenic to the human 22q11.2 locus. We uncovered a previously unknown alteration in the biogenesis of microRNAs (miRNAs) and identified a subset of brain miRNAs affected by the microdeletion. We provide evidence that the abnormal miRNA biogenesis emerges because of haploinsufficiency of the Dgcr8 gene, which encodes an RNA-binding moiety of the 'microprocessor' complex and contributes to the behavioral and neuronal deficits associated with the 22q11.2 microdeletion.


Effects of chronic inhalation of electronic cigarettes containing nicotine on glial glutamate transporters and α-7 nicotinic acetylcholine receptor in female CD-1 mice.
Alteration in glutamate neurotransmission has been found to mediate the development of drug dependence, including nicotine. We and others, through using western blotting, have reported that exposure to drugs of abuse reduced the expression of glutamate transporter-1 (GLT-1) as well as cystine/glutamate antiporter (xCT), which consequently increased extracellular glutamate concentrations in the mesocorticolimbic area. However, our previous studies did not reveal any changes in glutamate/aspartate transporter (GLAST) following exposure to drugs of abuse. In the present study, for the first time, we investigated the effect of chronic exposure to electronic (e)-cigarette vapor containing nicotine, for one hour daily for six months, on GLT-1, xCT, and GLAST expression in frontal cortex (FC), striatum (STR), and hippocampus (HIP) in outbred female CD1 mice. In this study, we also investigated the expression of alpha-7 nicotinic acetylcholine receptor (α-7 nAChR), a major pre-synaptic nicotinic receptor in the glutamatergic neurons, which regulates glutamate release. We found that inhalation of e-cigarette vapor for six months increased α-7 nAChR expression in both FC and STR, but not in the HIP. In addition, chronic e-cigarette exposure reduced GLT-1 expression only in STR. Moreover, e-cigarette vapor inhalation induced downregulation of xCT in both the STR and HIP. We did not find any significant changes in GLAST expression in any brain region. Finally, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques, we detected high concentrations of nicotine and cotinine, a major metabolite of nicotine, in the FC tissues of e-cigarette exposed mice. These data provide novel evidence about the effects of chronic nicotine inhalation on the expression of key glial glutamate transporters as well as α-7 nAChR. Our work may suggest that nicotine exposure via chronic inhalation of e-cigarette vapor may be mediated in part by alterations in the glutamatergic system.


Role of tumor necrosis factor-alpha in neuronal and glial apoptosis after spinal cord injury.
We investigated the role of tumor necrosis factor (TNF)-alpha in the onset of neuronal and glial apoptosis after traumatic spinal cord crush injury in rats. A few TUNEL-positive cells were first observed within and surrounding the lesion area 4 h after injury, with the largest number observed 24-48 h after injury. Double-labeling of cells using cell type-specific markers revealed that TUNEL-positive cells were either neurons or oligodendrocytes. One hour after injury, an intense immunoreactivity to TNF-alpha was observed in neurons and glial cells in the lesion area, but also seen in cells several mm from the lesion site rostrally and caudally. The level of nitric oxide (NO) also significantly increased in the spinal cord 4 h after injury. The injection of a neutralizing antibody against TNF-alpha into the lesion site several min after injury significantly reduced both the level of NO observed 4 h thereafter as well as the number of apoptotic cells observed 24 h after spinal cord trauma. An inhibitor of nitric oxide synthase (NOS), N(G)-monomethyl-l-arginine acetate (l-NMMA), also reduced the number of apoptotic cells. This reduction of apoptotic cells was associated with a decrease in DNA laddering on agarose gel electrophoresis. These results suggest that: (i) TNF-alpha may function as an external signal initiating apoptosis in neurons and oligodendrocytes after spinal cord injury; and (ii) TNF-alpha-initiated apoptosis may be mediated in part by NO as produced by a NOS expressed in response to TNF-alpha.


The prevalence of lithium-associated hyperparathyroidism in a large Swedish population attending psychiatric outpatient units.
This retrospective study determined the prevalence of lithium-associated hyperparathyroidism (LHPT) in 2 geographically defined, equivalent populations in Sweden, with no other selection bias. The medical journals of all patients receiving lithium treatment were examined specifically regarding their biochemistry: calcium, parathyroid hormone (PTH), creatinine, and vitamin D. The condition LHPT was defined biochemically. All patient data were noted, and the prevalence of the condition could thereby be calculated. A total of 423 patients were included (251 women and 172 men; 3:2), treated over a mean of 13.5 years (range, 1-46 years), aged 19 to 92. 77 patients (18%) were identified with LHTP whose median serum calcium was 2.55 mmol/L and PTH was 99 ng/L. A further 21% showed tendencies toward hypercalcemia. Forty-three percent had vitamin D insufficiency. Five patients (approximately 1%) had undergone parathyroidectomy. The prevalence of LHPT is high and often goes undetected. Vitamin D insufficiency is common as is polypharmacy. Surgery, for unclear reasons, has not been performed extensively, possibly because of limited knowledge of the underlying pathophysiology or surgery's significance. We present standard recommendations on patient management and suggest continual, specific follow-up including the monitoring of calcium, PTH, and vitamin D at least annually. Surgery should be considered with intention to improve psychiatric well-being and provide multiorgan protection.


Purification of hepatic polymorphic arylamine N-acetyltransferase from homozygous rapid acetylator inbred hamster: identity with polymorphic N-hydroxyarylamine-O-acetyltransferase.
The polymorphic acetyltransferase isozyme expressed in homozygous rapid acetylator inbred hamster liver cytosol was purified over 2000-fold by sequential Q-Sepharose fast-flow anion-exchange chromatography, Sephacryl S-200 high-resolution size-exclusion chromatography, Mono Q anion-exchange fast-protein liquid chromatography, and preparative polyacrylamide gel electrophoresis. The isozyme migrated as a single homogeneous monomer following both preparative and sodium dodecyl sulfate-polyacrylamide electrophoresis. The molecular weight was estimated at 34,170 following elution via size-exclusion chromatography and 35,467 following migration via sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The homogeneous polymorphic acetyltransferase exhibited a broad substrate specificity; it catalyzed the acetyl coenzyme A-dependent N-acetylation of p-aminobenzoic acid, carbocyclic arylamine carcinogens such as 2-aminofluorene, 4-aminobiphenyl and beta-naphthylamine, and heterocyclic arylamine carcinogens such as 2-aminodipyrido[1,2-a:3'2'd]imidazole and 3-amino-1-methyl-5H-pyrido[4,3-b]indole. It also readily catalyzed the acetyl coenzyme A-dependent metabolic activation (via O-acetylation) of N-hydroxy-2-aminofluorene to DNA adducts but not the metabolic activation (via intramolecular, N,O-acetyltransfer) of N-hydroxy-2-acetylaminofluorene or N-hydroxy-4-acetylaminobiphenyl to DNA adducts. Conversely, the partially purified monomorphic acetyltransferase isozyme from the same hamsters readily catalyzed the metabolic activation of N-hydroxy-2-acetylaminofluorene and N-hydroxy-4-acetylaminobiphenyl, and rates of metabolic activation of these substrates did not differ between homozygous rapid and slow acetylator liver, intestine, kidney, and lung cytosols. Heat inactivation rates for the purified polymorphic acetyltransferase isozyme were first order and indistinguishable for the acetyl coenzyme A-dependent N-acetylation and O-acetylation activities. The results strongly suggest the expression of a single polymorphic acetyltransferase product of the hamster polymorphic acetyltransferase gene that catalyzes both acetyl coenzyme A-dependent N-acetylation and O-acetylation of arylamine and N-hydroxyarylamine carcinogens but not the metabolic activation of N-hydroxy-N-acetylarylamines (arylhydroxamic acids) via intramolecular N,O-acetyltransfer. Consequently, acetylator genotype-dependent metabolic activation of N-hydroxyarylamines to a DNA adduct in hamster is catalyzed by direct O-acetylation of the hydroxyl group and not via sequential N-acetylation followed by N,O-acetyltransfer.


Coincident alcohol dependence and depression increases risk of suicidal ideation among Army National Guard soldiers.
Suicide rates among military service members have risen dramatically, while drivers remain poorly understood. We examined the relationship between coincident alcohol dependence and depression in shaping risk of suicidal ideation among National Guard forces. We performed a longitudinal analysis using a randomly selected, population-based sample of Ohio Army National Guard soldiers. Telephone-based surveys of 1582 soldiers who participated in both wave 1 (2008-2009) and wave 2 (2009-2010) were analyzed. Odds ratios (ORs) for suicidal ideation among those with versus without alcohol dependence were similar among nondepressed (OR = 3.85 [95% confidence intervals (CIs) = 1.18-12.52]) and depressed individuals (OR = 3.13 [95% CI = 0.88-11.14]); multiplicative interaction was not observed. In contrast, the risk differences (RDs) among those with versus without alcohol dependence diverged for those without depression (RD = 0.04 [95% CI = 0.02-0.07]) compared with those with depression (RD = 0.11 [95% CI = 0.06-0.18]); strong evidence of additive interaction was observed. We found that alcohol dependence and depression interact statistically in shaping risk for incident suicidal ideation among Army National Guard service members. A high-risk prevention approach including population-based screening for suicidality among patients with alcohol dependence, depression, and particularly those with both conditions is warranted in military populations.


The effect of an orientation-to-treatment group on the retention of alcoholics in outpatient treatment.
Seventy-five poor inner city alcoholics were exposed to a 1/2-hour videotape orienting them to treatment. When compared to a similar group that did not see the videotape, the orientation group attended more clinic sessions in the following month. A greater percentage of them made more than 10 visits, were still active after the month, and went on to inpatient rehabilitation. The orientation group is an effective, cost efficient way of increasing patient follow through with treatment.


Experimental human endotoxemia as a model of systemic inflammation.
Systemic inflammation plays a pivotal role in a multitude of conditions, including sepsis, trauma, major surgery and burns. However, comprehensive analysis of the pathophysiology underlying this systemic inflammatory response is greatly complicated by variations in the immune response observed in critically ill patients, which is a result of inter-individual differences in comorbidity, comedication, source of infection, causative pathogen, and onset of the inflammatory response. During experimental human endotoxemia, human subjects are challenged with purified endotoxin (lipopolysaccharide) intravenously which induces a short-lived, well-tolerated and controlled systemic inflammatory response, similar to that observed during sepsis. The human endotoxemia model can be conducted in a highly standardized and reproducible manner, using a carefully selected homogenous study population. As such, the experimental human endotoxemia model does not share the aforementioned clinical limitations and enables us to investigate both the mechanisms of systemic inflammation, as well as to evaluate novel (pharmacological) interventions in humans in vivo. The present review provides a detailed overview of the various designs, organ-specific changes, and strengths and limitations of the experimental human endotoxemia model, with the main focus on its use as a translational model for sepsis research.


Understanding common human driving semantics for autonomous vehicles.
Autonomous vehicles will share roads with human-driven vehicles until the transition to fully autonomous transport systems is complete. The critical challenge of improving mutual understanding between both vehicle types cannot be addressed only by feeding extensive driving data into data-driven models but by enabling autonomous vehicles to understand and apply common driving behaviors analogous to human drivers. Therefore, we designed and conducted two electroencephalography experiments for comparing the cerebral activities of human linguistics and driving understanding. The results showed that driving activates hierarchical neural functions in the auditory cortex, which is analogous to abstraction in linguistic understanding. Subsequently, we proposed a neural-informed, semantics-driven framework to understand common human driving behavior in a brain-inspired manner. This study highlights the pathway of fusing neuroscience into complex human behavior understanding tasks and provides a computational neural model to understand human driving behaviors, which will enable autonomous vehicles to perceive and think like human drivers.


Climate change and future challenges to the sustainable management of the Iraqi marshlands.
The application of restoration plans for the Iraqi marshlands is encountering significant challenges due to water scarcity and the impacts of climate change. This paper assesses the impact of water scarcity on the possibility of continuing the application of restoration and sustainable management plans for the main marshlands in Iraq. This assessment was conducted based on the available data and expected situation of available water resources under climate change conditions until the year 2035. Additionally, a satellite image-based index model was prepared and applied for the period 2009-2020 to obtain the spatiotemporal distribution of the restored marshlands. The results show that the shortage in water resources and insufficient inundation rates prevented the adequate application of the restoration plans. Also, applying the scenarios of distributing the deficit equally over all water demand sectors (S1) and according to the percentage of demand for each sector (S2) shows that the expected deficit in available water for the three marshes by the years 2025 and 2035 will be approximately 25% and 32% for S1 and 9% for S2. Consequently, the considered marshes are expected to lose approximately 20 to 33% of their eligible restoration areas. Accordingly, looking for suitable alternatives to support the water resources of these marshes became a very urgent matter and/or recourse to reduce the areas targeted by inundation and being satisfied with the areas that can be sustainable and maintain the current status of the rest of the regions as an emerging ecosystem characterized by lands that are inundated every few years. Accordingly, steps must be urged to develop plans and programs to maintain the sustainability of these emerging ecosystems within the frameworks of climate change and the conditions of scarcity of water resources and water and air pollution to ensure that they are not lost in the future.


[Diagnostic significance of ferritin assay in peritoneal fluid and gastric juice].
Ferritin was assayed by immunoradiometrical procedure in peritoneal fluid (26 patients with various ovarian pathologies) and gastric juice (18 patients with stomach cancer and 28 cases of gastric ulcer disease). It was found that diagnostic significance of ferritin measurements in peritoneal fluid in ovarian pathology is compromised by inflammation. Therefore, this marker cannot be used to differentiate between malignant and benign ovarian tumor. Single measurements of ferritin for detecting stomach ulcers were also diagnostically irrelevant since the data for stomach cancer and gastric ulcer exacerbation showed no significant difference.


Vascular endothelial growth factor-loaded poly(lactic-co-glycolic acid) microspheres-induced lateral axonal sprouting into the vein graft bridging two healthy nerves: nerve graft prefabrication using controlled release system.
The most commonly used surgical technique for repairing segmental nerve defects is autogenous nerve grafting; however, this method causes donor site morbidity. In this study, we sought to produce prefabricated nerve grafts that can serve as a conduit instead of autologous nerve using a controlled release system created with vascular endothelial growth factor (VEGF)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres. The study was performed in vitro and in vivo. For the in vitro studies, VEGF-loaded PLGA microspheres were prepared. Thirty rats were used for the in vivo studies. Vein grafts were sutured between the tibial and peroneal nerves in all animals. Three groups were created, and an epineural window, partial incision, and microsphere application were performed, respectively. Walking track analysis, morphologic, and electron microscopic assessment were performed at the end of the eight weeks. Microspheres were produced in spherical shapes as required. Controlled release of VEGF was achieved during a 30-days period. Although signs of nerve injury occurred initially in the partial incision groups according to the indexes of peroneal and tibial function, it improved gradually. The index values were not affected in the other groups. There were many myelinated fibers with large diameters in the partial incision and controlled release groups, while a few myelinated fibers that passed through vein graft in the epineural window group. Thereby, prefabrication was carried out for the second and third groups. It was demonstrated that nerve graft can be prefabricated by the controlled delivery of VEGF.


Association of the insertion/deletion gene polymorphism of the apolipoprotein B signal peptide with myocardial infarction in Tunisian patients.
Numerous polymorphisms of the apolipoprotein B (APOB) gene have been described. Particularly, the insertion/deletion (Ins/Del) polymorphism located in the coding part of the signal peptide of apoB, associated with modification of lipid concentrations and the risk of coronary artery disease and/or myocardial infarction (MI), has been reported in the general population. Moreover, conflicting results emerge from the literature and suggest that the effect is context-dependent. In the present study, the first investigation of the Ins/Del polymorphism of the APOB gene in Tunisian patients with MI, we examined a possible association between this polymorphism and MI in a subgroup of the Tunisian population. A total of 318 Tunisian patients with MI and 368 healthy controls were included in the study. Genomic DNA was extracted from white blood cells, and the Ins/Del polymorphism was determined by electrophoresis in polyacrylamide gels after PCR amplification. A binary logistic regression analysis was performed to test how the association between MI and Ins/Del polymorphism is independent from confounding factors. A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with MI had a frequency of 7.2% for the Del/Del genotype, 39.6% for the Ins/Del genotype, and 53.1% for the Ins/Ins genotype. Controls had a frequency of 3.0% for the Del/Del, 32.1% for the Ins/Del and 64.9% for the Ins/Ins genotype (chi2=12.93, p=0.002). The MI patient group showed a significantly higher frequency of the Del allele compared to controls (27.1% vs. 19.1%; chi2=12.50, p=0.0004). In comparison to the Ins/Ins homozygotes, the odds ratio (95% confidence interval) for MI was 1.51 (1.09-2.07) for Ins/Del heterozygotes and 2.95 (1.40-6.22) for Del/Del homozygotes. In multivariate analysis, age (p=0.001), smoking (p<0.001), hypertension (p=0.001), diabetes mellitus (p<0.001), and dyslipidemia (p=0.01) were independent correlates of the presence of MI, whereas the Ins/Del polymorphism (p=0.330) was not an independent predictor of MI. The present study shows a significant but not independent association between the Ins/Del polymorphism of the APOB gene and MI in the Tunisian population.


Kaposi's varicelliform eruption.
Kaposi's varicelliform eruption (eczema herpeticum) is the name given to a distinct cutaneous eruption caused by herpes simplex and certain other viruses that infect persons with preexisting dermatosis. Most commonly it is associated with atopic dermatitis. We report a case of a three-year-old atopic child who presented with extensive vesicular eruption suggestive of Kaposi's varicelliform eruption. There was history of fever, malaise and extensive vesicular eruptions. Diagnosis was made based on clinical features and Tzanck smear examination. Patient responded adequately to oral acyclovir therapy.


Possible association between dysfunction of vitamin D binding protein (GC Globulin) and migraine attacks.
To identify the genetic causality of migraine and acute, severe melalgia, we performed a linkage analysis and exome sequencing in a family with four affected individuals. We identified a variant (R21L) in exon 2 of the GC globulin gene, which is involved in the transportation of vitamin D metabolites and acts as a chemotaxic factor; this variant was co-segregated within the family. To investigate the relationship between GC globulin and melalgia, we investigated the cytokine levels in serum samples from the patients and control subjects using a cytokine antibody array. GC globulin can bind to both MCP-1 and RANTES in human serum but has a higher affinity to MCP-1. In cell culture systems, MCP-1 was able to bind to overexpressed wild-type GC globulin but not to the GC globulin variant, and the GC globulin binding affinity to MCP-1 was significantly lower in sera from the patients than in sera from control subjects. A higher concentration of MCP-1 was also observed in sera from the patients. Thus, the dysfunctional GC globulin affected cytokine release, especially the release of MCP-1, and MCP-1 might play important roles in melalgia and migraine.


Plasmonic interconnects versus conventional interconnects: a comparison of latency, crosstalk and energy costs.
The continued scaling of integrated circuits will require advances in intra-chip interconnect technology to minimize delay, density of energy dissipation and cross-talk. We present the first quantitative comparison between the performance of metal wire interconnects, operated in the traditional manner by electric charge and discharge, versus the performance of metal wires operated as surface plasmon waveguides. Surface plasmon wire waveguides have the potential to reduce signal delay, but the high confinement required for low cross-talk amongst high density plasmon wire interconnects significantly increases energy dissipation per transmitted bit, above and beyond that required for electric charge/discharge interconnects at the same density.


Insect-resistant GM rice in farmers' fields: assessing productivity and health effects in China.
Although no country to date has released a major genetically modified (GM) food grain crop, China is on the threshold of commercializing GM rice. This paper studies two of the four GM varieties that are now in farm-level preproduction trials, the last step before commercialization. Farm surveys of randomly selected farm households that are cultivating the insect-resistant GM rice varieties, without the aid of experimental station technicians, demonstrate that when compared with households cultivating non-GM rice, small and poor farm households benefit from adopting GM rice by both higher crop yields and reduced use of pesticides, which also contribute to improved health.


[Anti-ulcer effect of extract from phellodendri cortex].
In chinese medicine, Phellodendri Cortex (Phellodendron amurense Ruprecht) has been used to treat the patient who suffers from gastroenteritis, abdominal pain or diarrhea. Berberine has been identified as a major component in this plant, and it has biological activities, such as bactericidal activity, anti-cholera toxin effect, anti-inflammatory effect, stimulative effect of bile secretion or bilirubin discharge. In the previous study, we have shown the presence of anti-inflammatory activity in the berberine-free fraction of the extract from this plant. In the present study, we also found anti-ulcer activity in the fraction. The fraction significantly inhibited the formation of ethanol-induced ulcer, aspirin-induced ulcer (s.c., p.o.), pylorus-ligated ulcer (p.o., i.d.) in rats, as well as that of stress ulcer in restrained and water-immersed mice (p.o.). In addition, gastric acid secretion was significantly reduced in pylorus-ligated rats by subcutaneous or intraduodenal administration of the fraction, but not by oral administration. These findings suggest that the suppression of ulcer formation may be due to the additive effect of the cytoprotection effect and the reduction of gastric acid secretion by administration of the berberine-free fraction.


Morin (3,5,7,2',4'-pentahydroxyflavone) exhibits potent inhibitory actions on urate transport by the human urate anion transporter (hURAT1) expressed in human embryonic kidney cells.
In allopurinol-allergic patients, uricosuric agents are often used in the treatment of hyperuricemia. The existing uricosuric agents are not without problems and the availability of better and safer alternatives is highly desirable. Our previous study (J Pharmacol Exp Ther (2006) 316:169-175) has demonstrated that morin (3,5,7,2',4'-pentahydroxyflavone), which occurs in the twigs of Morus alba L. documented in traditional Chinese medicinal literature for treatment of conditions akin to gout, is a potent inhibitor of urate uptake in rat renal brush-border membrane vesicles. It is also effective in lowering uric acid level in a hyperuricemic rat model in vivo. Whether morin is an equally effective uricosuric agent in human requires verification. The human urate anion transporter (hURAT1) has recently been cloned and identified to be the organic anion transporter that mediates renal urate reabsorption in the human kidney. In the present investigation, human embryonic kidney cells were transfected with hURAT1 and the expression was validated by reverse transcription-polymerase chain reaction and subcellular distribution of the exogenously introduced transporter by confocal microscopy. The inhibitory actions of morin on human renal urate reabsorption were demonstrated using this system. The IC50 value of the inhibition by morin was determined to be 2.0 microM, compared with 50 microM for probenecid, 100 microM for sulfinpyrazone, and 0.3 microM for benzbromarone. Kinetic analysis of the uptake inhibition by morin indicates that this compound is a competitive inhibitor of urate uptake on the human urate transporter with a K(i) value of 5.74 microM.


High-performance liquid chromatography-mass spectrometry profiling of phenolic compounds for evaluation of olive oil bitterness and pungency.
Bitterness and pungency are important parameters for olive oil quality. Therefore, two instrumental methods for evaluation of these taste attributes were developed. The first one is based on the photometric measurement of total phenolic compounds content, whereas the second one is based on the semiquantitative evaluation of hydrophilic compounds by high-performance liquid chromatography-mass spectrometry (HPLC-MS). Evaluation of total phenolic compounds content was performed by a modified method for the determination of the K(225) value using a more specific detection based on the pH value dependency of absorbance coefficients of phenols at λ = 274 nm. The latter method was not suitable for correct prediction, because no significant correlation between bitterness/pungency and total phenolic compounds content could be found. For the second method, areas of 25 peaks detected in 54 olive oil samples by a HPLC-MS profiling method were correlated with the bitterness and pungency by partial least-squares regression. Six compounds (oleuropein aglycon, ligstroside aglycon, decarboxymethyl oleuropein aglycon, decarboxymethyl ligstroside aglycon, elenolic acid, and elenolic acid methyl ester) show high correlations to bitterness and pungency. The computed model using these six compounds was able to predict bitterness and pungency of olive oil in the error margin of the sensory evaluation (±0.5) for most of the samples.


Development of a biosensor platform based on ITO sheets modified with 3-glycidoxypropyltrimethoxysilane for early detection of TRAP1.
The aim of this research was to design an electrochemical immunosensor for determination of tumour necrosis factor receptor-associated protein-1(TRAP1) antigen, a heat shock protein linked to tumour necrosis factor. The indium-tin oxide covered polyethylene terephthalate (ITO-PET) electrode surface was cleaned and was prepared for the introduction of hydroxyl groups on its surface by using NH4 OH/H2 O2 /H2 O. As a silanization agent for covalent attachment of anti-TRAP1 on the surface of the ITO working electrode, 3-glycidoxypropyltrimethoxysilane (3-GOPS) was used. Cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS) were used to characterize the immobilization steps. A variety of parameters, 3-GOPS and anti-TRAP1 concentrations, and anti-TRAP1 and TRAP1 incubation durations were optimized. After determining the optimum conditions, characterization studies such as repeatability, reproducibility, regeneration, square wave voltammetry, and single frequency impedance were performed. The electrochemical immunosensor has presented an extremely wide determination range for TRAP1 from 0.1 pg/mL to 100 pg/mL.


Needs assessment survey to justify establishing a reproductive health clinic at a comprehensive cancer center.
Reproductive health problems, including sexual dysfunction and impaired fertility, are distressing and persistent after cancer treatment. However, recent reports suggest that reproductive health remains neglected in oncology settings. We conducted a survey to ascertain the prevalence of reproductive health problems in men and women treated in a comprehensive cancer center, and to estimate potential usage of clinical services to preserve fertility or to treat postcancer infertility and sexual dysfunction. We mailed 800 questionnaires to men and women treated for cancer at our institution 1 to 5 years previously. Cancer sites and ages were chosen to maximize the risk of reproductive problems. We stratified the sample by living distance from our institution, to see if travel affected service utlilization. To provide a self-selected sample for comparison, another 200 questionnaires were made available in outpatient areas. Self-report questionnaire. The return rate for the combined surveys was 29% for men and 26% for women. Cancer sites for self-selected respondents were almost identical to those in the postal cohort. Prevalence and types of sexual dysfunction were typical for surveys of cancer survivors, with 49% of men reporting new erection problems after cancer treatment and 45% of women noting loss of desire for sex and vaginal dryness. About a third of patients aged less than 50 years would have liked a fertility consultation before cancer treatment. Twenty to thirty percent wanted more information about premature ovarian failure or health risks for their children. Twenty-four percent of men and 21% of women would definitely want to visit a reproductive health clinic in the next year. Factors associated with wanting an appointment included self-selection to complete the survey and, for men, having less education. It should be feasible to establish a multidisciplinary reproductive health center in a comprehensive cancer center.


[Surgical treatment of chronic occlusions of the carotid bifurcation (author's transl)].
Optimal protection of the brain during carotid endarterectomy is of great importance and is guaranteed by general anaesthesia with maintenance of normal blood-pressure and a normal CO2-level, routine use of internal shunts and heparinization. Operation of "asymptomatic" patients has to be seriously considered. Patients with acute occlusions of the carotid artery should not have surgery as emergency procedures, unless the operation can be done immediately after the onset of symptoms. In chronic occlusion of the internal carotid artery endarterectomy may be considered if the shiphon is patent and in good condition.


BCG skin reactions by 2 months of age are associated with better survival in infancy: a prospective observational study from Guinea-Bissau.
Receiving Bacille Calmette-Guérin (BCG)-Denmark vaccine at birth has been associated with ~40% reductions in all-cause neonatal mortality. We evaluated determinants of BCG skin reaction characteristics by age 2 months and tested the association with subsequent mortality. Prospective observational study amalgamating five trials providing BCG-at-birth that were conducted between 2002 and 2018 in Guinea-Bissau. The reaction status and size were evaluated at home-visits by 2 months of age among 6012 neonates; mortality from 2 to 12 months was assessed at subsequent visits. Reaction determinants were evaluated by binomial regression providing risk ratios (RRs). In Cox-models providing adjusted mortality rate ratios (aMRRs), we assessed the association between (1) having a 2-month reaction (yes/no) and (2) reaction size tertiles and subsequent all-cause mortality risk. A subgroup had their BCG reaction evaluated and were bled at age 4 weeks; their samples underwent in vitro analysis for specific and non-specific cytokine responses. The BCG strain was the main determinant for developing a 2-month reaction and the reaction size: the BCG-Russia/BCG-Denmark RR for large-reaction was 0.38 (0.30-0.47) and the BCG-Russia/BCG-Japan RR was 0.61 (0.51-0.72). 5804 infants (96.5%) were reactors by age 2 months; 208 (3.5%) were non-reactors. The 2-12 months mortality risk was 4.8% (10/208) for non-reactors, 2.9% (64/2213) for small reactors, 1.8% (30/1710) for medium reactors and 0.8% (15/1881) for large reactors. The reactor/non-reactor aMRR was 0.49 (0.26-0.95) and there was a linear trend of decreasing mortality with increasing reaction size (p for trend <0.001). BCG reactors had higher 4-week specific and non-specific cytokine responses, responses that were highest among those with large reactions. Among BCG-vaccinated infants, having a BCG skin reaction by age 2 months was associated with markedly better survival, as was the reaction size. Our findings thus support that BCG has substantial effects on all-cause mortality. Emphasising at-birth vaccination with immunogenic BCG strains and revaccinating non-reactors and small reactors could have major public health benefits. NCT00146302, NCT00168610, NCT00625482, NCT01989026 and NCT02447536.


A molecular survey of vector-borne pathogens and haemoplasmas in owned cats across Italy.
Feline vector-borne pathogens (FeVBPs) have been increasingly investigated for their impact on cat health and their zoonotic potential. The aim of the present study was to assess the prevalence of FeVBPs and haemoplasmas in cats across Italy and to identify potential risk factors linked to their occurrence. Blood samples from 958 owned cats living in the North (n = 556), Centre (n = 173) and South (n = 229) of Italy were tested for Babesia spp., Hepatozoon spp., Ehrlichia spp., Anaplasma spp. and filarioids by conventional PCR (cPCR) and for haemoplasmas and Bartonella spp. by SYBR green real-time PCR. Cats included in the study represent a sub-sample from a larger number of animals enrolled in a previous study, which were selected based on the geographical origin. Data on cats' positivity for Leishmania infantum, feline leukaemia virus (FeLV) and for feline immunodeficiency virus (FIV), available from the previous study, were included and examined. Potential risk factors for pathogen infection were assessed in relationship to categorical variables including sex, geographical origin, breed, neutering status and age of cats. Out of the 958 cats, 194 (20.2%) were positive for at least one of the tested pathogens, 89 (16%) from the North, 32 (18.5%) from the Centre and 73 (31.9%) from the South of Italy. A high prevalence of FeVBPs was detected in male cats (n = 125, 27.8%), living in the southern part of the country (n = 73, 31.9%), younger than 18 months of age (n = 24, 22.4%) and not neutered (n = 39; 27.5%). In particular, 24 cats (2.5%) tested PCR-positive for Bartonella spp., of which 1.6% for B. henselae and 0.9% for B. clarridgeiae. A total of 111 cats scored PCR-positive for haemoplasmas (11.6%), specifically "Candidatus Mycoplasma haemominutum" (n = 95, 9.9%), M. haemofelis (n = 14, 1.5%) and "Candidatus Mycoplasma turicensis" (n = 2, 0.2%). Moreover, 39, 31 and 8 cats were positive for FeLV (4.1%), L. infantum (3.2%) and FIV (0.8%), respectively. Co-infections were registered for 19 (9.8%) cats. These results confirm the occurrence of haemoplasmas and FeVBPs throughout Italy. Preventive measures to protect both animal and human health should be carried out also for owned cats, even if no health status of animals has been assessed in this study.


Diversity-oriented combinatorial biosynthesis of benzenediol lactone scaffolds by subunit shuffling of fungal polyketide synthases.
Combinatorial biosynthesis aspires to exploit the promiscuity of microbial anabolic pathways to engineer the synthesis of new chemical entities. Fungal benzenediol lactone (BDL) polyketides are important pharmacophores with wide-ranging bioactivities, including heat shock response and immune system modulatory effects. Their biosynthesis on a pair of sequentially acting iterative polyketide synthases (iPKSs) offers a test case for the modularization of secondary metabolic pathways into "build-couple-pair" combinatorial synthetic schemes. Expression of random pairs of iPKS subunits from four BDL model systems in a yeast heterologous host created a diverse library of BDL congeners, including a polyketide with an unnatural skeleton and heat shock response-inducing activity. Pairwise heterocombinations of the iPKS subunits also helped to illuminate the innate, idiosyncratic programming of these enzymes. Even in combinatorial contexts, these biosynthetic programs remained largely unchanged, so that the iPKSs built their cognate biosynthons, coupled these building blocks into chimeric polyketide intermediates, and catalyzed intramolecular pairing to release macrocycles or α-pyrones. However, some heterocombinations also provoked stuttering, i.e., the relaxation of iPKSs chain length control to assemble larger homologous products. The success of such a plug and play approach to biosynthesize novel chemical diversity bodes well for bioprospecting unnatural polyketides for drug discovery.


Xenoestrogens impact brain estrogen receptor signaling during the female lifespan: A precursor to neurological disease?
Xenoestrogens, foreign synthetic chemicals mimicking estrogens, are lurking in our surroundings. Climate change may alter their toxicity and bioavailability. Since xenoestrogens have extremely high lipid solubility and are structurally similar to natural endogenous estrogens, they can bind to estrogen receptors (ERs) -alpha (ER-α) and -beta (ER-β). Scientific evidence accumulated over the past decades have suggested that natural 17β-estradiol (E2; a potent estrogen), via activation of its receptors, plays a pivotal role in regulation of brain development, differentiation, metabolism, synaptic plasticity, neuroprotection, cognition, anxiety, body temperature, feeding and sexual behavior. In the brain, ER-β is predominantly expressed in the various regions, including cerebral cortex and hippocampus, that have been shown to play a key role in cognition. Therefore, disturbances in function of ER-β mediated E2 signaling by xenoestrogens can lead to deleterious effects that potentiate a variety of neurological diseases starting from prenatal to post-menopause in women. The goal of this review is to identify the possible neurological effects of xenoestrogens that can alter estrogen receptor-mediated signaling in the brain during different stages of the female lifespan.


Effect of handedness on fMRI activation in the medial temporal lobe during an auditory verbal memory task.
Several studies have shown marked differences in the neural localization of language functions in the brains of left-handed individuals when compared with right-handers. Previous experiments involving functional lateralization have demonstrated cerebral blood flow patterns that differ concordantly with subject handedness while performing language-related tasks. The effect of handedness on function in specific stages of memory processing, however, is a largely unexplored area. We used a paired-associates verbal memory task to elicit activation of neural areas related to declarative memory, examining the hypothesis that there are differences in activation in the medial temporal lobe (MTL) between handedness groups. 15 left-handed and 25 right-handed healthy adults were matched for all major demographic and neuropsychological variables. Functional and structural imaging data were acquired and analyzed for group differences within MTL subregions. Our results show that activation of the MTL during declarative memory processing varies with handedness. While both groups showed activation in left and right MTL subregions, the left-handed group showed a statistically significant increase in the left hippocampus and amygdala during both encoding and recall. No increases in activation were found in the right-handed group. This effect was found in the absence of any differences in performance on the verbal memory task, structural volumetric disparities, or functional asymmetries. This provides evidence of functional differences between left-handers and right-handers, which extends to declarative memory processes.


Competitive inhibition of human organic anion transporters 1 (SLC22A6), 3 (SLC22A8) and 4 (SLC22A11) by major components of the medicinal herb Salvia miltiorrhiza (Danshen).
When herbal products are used in combination therapy with drugs, alterations in pharmacokinetics, pharmacodynamics, and toxicity can result. Many active components of herbal products are organic anions, and human organic anion transporter 1 (hOAT1, SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11) have been identified as potential sites of drug-drug interactions. Therefore, we assessed the effects of lithospermic acid (LSA), rosmarinic acid (RMA), salvianolic acid A (SAA), salvianolic acid B (SAB), and tanshinol (TSL), components of the herbal medicine Danshen, on the function of these transporters. Kinetic analysis demonstrated a competitive mechanism of inhibition for all five. K(i) values (µM) were estimated as 20.8 ± 2.1 (LSA), 0.35 ± 0.06 (RMA), 5.6 ± 0.3 (SAA), 22.2 ± 1.9 (SAB), and 40.4 ± 12.9 (TSL) on hOAT1 and as 0.59 ± 0.26 (LSA), 0.55 ± 0.25 (RMA), 0.16 ± 0.03 (SAA), 19.8 ± 8.4 (SAB), and 8.6 ± 3.3 (TSL) on hOAT3. No significant inhibition of hOAT4 activity by TSL was observed. Using published human pharmacokinetic values, unbound C(max)/K(i) ratios were calculated as an indicator of in vivo drug-drug interaction potential. Analysis indicated a strong interaction potential for RMA and TSL on both hOAT1 and hOAT3 and for LSA on hOAT3. Thus, herb-drug interactions may occur in vivo in situations of co-administration of Danshen and clinical therapeutics known to be hOAT1/hOAT3 substrates.


Fast thermal regeneration of fiber Bragg gratings.
In this Letter we report a fast thermal regeneration of Type I fiber Bragg gratings inscribed with a UV laser in up to four different optical fibers: hydrogenated standard fiber, hydrogenated highly Ge-doped fiber, hydrogenated photosensitive fiber, and nonhydrogenated fiber. The thermal treatment consists in directly introducing the optical fiber into a preheated oven. The preheat temperature depends on the type of fiber used and is high enough to erase the grating and regenerate it afterward. The best results are obtained with hydrogenated photosensitive fiber and highly Ge-doped fiber, whereas no satisfactory results were obtained with hydrogenated standard fiber and nonhydrogenated photosensitive fiber. A regenerated grating with only 1.6 dB of loss was obtained in 10 min, reducing the time needed by a factor of 5.7. By adjusting the temperature of the oven, regenerated gratings of 13.7 dB of loss in 31 s and 5.8 dB of loss in 3 min were obtained. The factors of improvement in time are 110.3 and 19, respectively.


Energy expenditure during walking in patients recovering from fractures of the leg.
The oxygen consumption during walking has been studied in 13 patients recovering from fractures of the leg and in 8 control subjects. Oxygen consumption of normal subjects when walking at velocities of 0.5, 1.0 and 1.5 m sec-1 was 8.0, 9.8 and 13.6 ml kg-1 min-1 respectively. For subjects walking on crutches with the leg encased in a Plaster of Paris cast, the oxygen consumption at these velocities was 12.0, 17.5 and 25.3 ml kg-1 min-1 respectively. The energy cost of walking was reduced when the cast was removed, when the crutches were replaced by sticks and when all aides were discarded. When all aids had been discarded the energy expenditure was normal at 0.5 and 1.0 m sec-1 but was still significantly higher at faster velocities.


Endoscopic Skipping of the Terminal Ileum in Pediatric Crohn Disease.
Pediatric small-bowel (SB) Crohn disease (CD) may be missed if the terminal ileum (TI) appears normal at endoscopy and SB imaging is not performed. We sought to estimate the prevalence and clinical characteristics of pediatric patients with CD and endoscopic skipping of the TI-that is, pediatric patients with active SB or upper gut inflammation and an endoscopically normal TI. This retrospective study included pediatric patients with CD who underwent both CT enterography (CTE) or MR enterography (MRE) and ileocolonoscopy within a 30-day period between July 2004 and April 2014. The physician global assessment was used as the reference standard for SB CD activity. Radiologists reviewed the CTE and MRE studies for inflammatory parameters; severity, length, and multifocality of SB inflammation; and the presence of penetrating complications. Of 170 patients who underwent ileal intubation, the TI was macroscopically normal or showed nonspecific inflammation in 73 patients (43%). Nearly half (36/73, 49%) of the patients with normal or nonspecific findings at ileocolonoscopy had radiologically active disease with a median length of SB involvement of 20 cm (range, 1 to > 100 cm). Seventeen (47%) of these patients had multifocal SB involvement and five (14%) had penetrating complications. Overall, endoscopic TI skipping was present in 43 (59%) patients with normal or nonspecific ileocolonoscopic findings: 20 with histologic inflammation (17 with positive imaging findings), 14 with inflammation at imaging only, and nine with proximal disease (upper gut, jejunum, or proximal ileum). There were no significant differences in the clinical parameters of the patients with and those without endoscopic TI skipping. Ileocolonoscopy may miss SB CD in pediatric patients that is due to isolated histologic, intramural, or proximal inflammation. Enterography is complementary to ileocolonoscopy in the evaluation of pediatric CD.


[Recovery from apparently hopeless fresh-water drowning (author's transl)].
Report of 3 cases of drowning (children). 2 patients survived without severe injury, 1 patient died after 13 days. The protective action of hypothermia to the brain and heart in hypothermic drowning is emphasized. Even in apparently hopeless cases resuscitation should be started immediately and should not be discontinued too early. Especially in hypothermic drowning efforts can be successful after more than 60 min. of resuscitation. In cases of drowning an emergency physician should be called immediately (emergency-ambulance, rescue-helicopter). A short survey of pathologic physiology, emergency therapy and intensive care of drowning is given.


Incidence and malignant transformation of glottic precursor lesions in Denmark.
Objectives: Glottic precursor lesion (GPL) is a well-known premalignant condition, but the existing knowledge of incidence and malignant potential is based on subpopulation studies. In this first, nationwide study we report data from all verified cases of GPL in Denmark during a 10-year period with focus on incidence and malignant transformation of GPL.Methods: Patients were identified by a search for GPL in the time period from 01.01.2000 to 31.12.2009 using the Danish Pathology Data Base, Patobank, which is a nationwide source of all cyto- and histopathological data obtained in Denmark. Data were validated and supplemented by medical chart review.Results: A 10-year national cohort of 965 patients (median age 60 years, male-female ratio 2:1) with histologically verified GPL was analyzed. The overall malignant transformation rate was 18.3% (mild dysplasia 7.7%, moderate dysplasia 19.8%, severe dysplasia 28.5%, and carcinoma in situ 40.3%) with a median progression time of 29 months. Eighty-eight percent of patients were active or former smokers. A significantly larger proportion of male patients (24.1%) experienced malignant transformation compared to females (6.6%) (p < .001).Conclusion: This nationwide population-based study of GPL patients confirmed a stable incidence of GPL in Denmark from January 2000 to December 2009 and a considerable malignant potential, correlated to the grading of GPL according to the World Health Organization classification of laryngeal precursor lesions from 2005, WHOC2005. The recent update, WHOC2017, of low-grade versus high-grade lesions may thus contain less nuanced prognostic information than WHOC2005.Level of evidence: 2b retrospective cohort study.


Community and federal collaboration to assess pregnancy outcomes in Alaska Native women, 1997-2005.
The objectives are to report the estimated prevalence of pregnancy complications and adverse pregnancy outcomes in a defined population of Alaska Native women and also examine factors contributing to an intensive and successful collaboration between a tribal health center and the Centers for Disease Control and Prevention. Investigators abstracted medical record data from a random sample of singleton deliveries to residents of the study region occurring between 1997 and 2005. We used descriptive statistics to estimate the prevalence and 95% confidence intervals of selected pregnancy complications and adverse pregnancy outcomes. Records were examined for 505 pregnancies ending in a singleton delivery to 469 women. Pregnancy complication rates were 5.9% (95% CI 4.0, 8.4) for gestational diabetes mellitus, 6.1% (95% CI 4.2, 8.6%) for maternal chronic hypertension and 11.5% (95% CI 8.8, 14.6) for pregnancy associated hypertension, and 22.9% (95% CI 19.2-26.5 %) for anemia. The cesarean section rate was 5.5% (95% CI 3.5, 7.5) and 3.8% (95% CI 2.3, 5.8) of newborns weighed >4,500 g. Few previous studies reported pregnancy outcomes among Alaska Native women in a specific geographic region of Alaska and regarding the health needs in this population. We highlight components of our collaboration that contributed to the success of the study. Studies focusing on special populations such as Alaska Native women are feasible and can provide important information on health indicators at the local level.


Evaluation of load-deflection properties of fiber-reinforced composites and its comparison with stainless steel wires.
The aim of this study was to evaluate the response of common sized fiber-reinforced composites (FRCs) to different deflections due to bending forces and comparing it with stainless steel (SS) wires. In this experimental study, two FRC groups with 0.75 mm and 1.2 mm diameters (Everstick Ortho, Stick Tech, Finland) and three SS groups with 0.016 × 0.022 inch, 0.0215 × 0.028 inch and 0.7 mm diameters (3M Uniteck, Monrovia, California, USA) were tested. Each group contained 10 samples that were tested according to a three point bending test. Each group was tested at deflections of 0.5, 1 and 1.5 mm and the data was analyzed using the repeated measure ANOVA by SPSS software (Statistical Package for the Social Sciences, IBM SPSS, Inc. in Chicago, Illinois, USA). P < 0.05 was considered as significant. The highest recorded load belonged to the 1.2 mm FRC and after that 0.7 mm SS wire, 0.75 mm FRC, 0.0215 × 0.028 inch SS wire and finally 0.016 × 0.022 inch SS wire. The 0.7 mm SS wire and 0.75 mm FRC were compared as retainers and the results showed the 0.7 mm SS wire showed significantly higher load compared with 0.75 mm FRC (P < 0.05). The 1.2 mm FRC had significantly higher load compared to 0.0215 × 0.028 inch and 0.016 × 0.022 inch SS wires (P < 0.05). The results showed that the 1.2 mm FRC group had significantly higher load compared to SS wires and other FRC groups under the 0.5, 1 and 1.5 mm deflections. Therefore, it can be suggested that FRC can be used as an esthetic replacement for SS wires for active and passive purposes in orthodontics.


Constitutively activated receptors for parathyroid hormone and parathyroid hormone-related peptide in Jansen's metaphyseal chondrodysplasia.
An activating mutation of the receptor for parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) was recently found in a patient with Jansens's metaphyseal chondrodysplasia, a rare form of short-limbed dwarfism associated with hypercalcemia and normal or low serum concentrations of the two hormones. To investigate this and other activating mutations and to refine the classification of this unusual disorder, we analyzed genomic DNA from six additional patients with Jansen's disease. Exons encoding the PTH-PTHrP receptor were amplified by the polymerase chain reaction (PCR), and the products were analyzed by gel electrophoresis or direct nucleotide-sequence analysis. Nucleotide changes were confirmed by restriction-enzyme digestion of genomic DNA or the PCR products. The previously reported mutation, which changes a histidine at position 223 to arginine (H223R), was found in genomic DNA from three of the six patients but not in DNA from their healthy relatives or 45 unrelated normal subjects. A novel missense mutation that changes a threonine in the receptor's sixth membrane-spanning region to proline (T410P) was identified in another patient but not in 62 normal subjects. In two patients with radiologic evidence of Jansen's metaphyseal chondrodysplasia but less severe hypercalcemia, no receptor mutations were detected. In COS-7 cels expressing PTH-PTHrP receptors with the T410P or H223R mutation, basal cyclic AMP accumulation was four to six times higher than in cells expressing wild-type receptors. The expression of constitutively active PTH-PTHrp receptors in kidney, bone, and growth-plate chondrocytes provides a plausible genetic explanation for mineral-ion abnormalities and metaphyseal changes in patients with Jansen's disease.


Baseline characteristics of patients enrolled in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).
EXSCEL is a randomized, double-blind, placebo-controlled trial examining the effect of exenatide once-weekly (EQW) versus placebo on time to the primary composite outcome (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) in patients with type 2 diabetes mellitus (DM) and a wide range of cardiovascular (CV) risk. Patients were enrolled at 688 sites in 35 countries. We describe their baseline characteristics according to prior CV event status and compare patients with those enrolled in prior glucagon-like peptide-1 receptor agonist (GLP-1RA) outcomes trials. Of a total of 14,752 participants randomized between June 2010 and September 2015, 6,788 (46.0%) patients were enrolled in Europe; 3,708 (25.1%), North America; 2,727 (18.5%), Latin America; and 1,529 (10.4%), Asia Pacific. Overall, 73% had at least one prior CV event (70% coronary artery disease, 24% peripheral arterial disease, 22% cerebrovascular disease). The median (IQR) age was 63 years (56, 69), 38% were female, median baseline HbA1c was 8.0% (7.3, 8.9) and 16% had a prior history of heart failure. Those without a prior CV event were younger with a shorter duration of diabetes and better renal function than those with at least one prior CV event. Compared with prior GLP-1RA trials, EXSCEL has a larger percentage of patients without a prior CV event and a notable percentage who were taking a dipeptidyl peptidase-4 inhibitor at baseline (15%). EXSCEL is one of the largest global GLP-1RA trials, evaluating the safety and efficacy of EQW with a broad patient population that may extend generalizability compared to prior GLP-1RA trials (ClinicalTrials.gov number, NCT01144338).


Outcomes of Mobilisation of Vulnerable Elders in Ontario (MOVE ON): a multisite interrupted time series evaluation of an implementation intervention to increase patient mobilisation.
older patients admitted to hospitals are at risk for hospital-acquired morbidity related to immobility. The aim of this study was to implement and evaluate an evidence-based intervention targeting staff to promote early mobilisation in older patients admitted to general medical inpatient units. the early mobilisation implementation intervention for staff was multi-component and tailored to local context at 14 academic hospitals in Ontario, Canada. The primary outcome was patient mobilisation. Secondary outcomes included length of stay (LOS), discharge destination, falls and functional status. The targeted patients were aged ≥ 65 years and admitted between January 2012 and December 2013. The intervention was evaluated over three time periods-pre-intervention, during and post-intervention using an interrupted time series design. in total, 12,490 patients (mean age 80.0 years [standard deviation 8.36]) were included in the overall analysis. An increase in mobilisation was observed post-intervention, where significantly more patients were out of bed daily (intercept difference = 10.56%, 95% CI: [4.94, 16.18]; P < 0.001) post-intervention compared to pre-intervention. Hospital median LOS was significantly shorter during the intervention period (intercept difference = -3.45 days, 95% CI: [-6.67,-0.23], P = 0.0356) compared to pre-intervention. It continued to decrease post-intervention with significantly fewer days in hospital (intercept difference= -6.1, 95% CI: [-11,-1.2]; P = 0.015) in the post-intervention period compared to pre-intervention. this is a large-scale study evaluating an implementation strategy for early mobilisation in older, general medical inpatients. The positive outcome of this simple intervention on an important functional goal of getting more patients out of bed is a striking success for improving care for hospitalised older patients.


Chiral aromatase and dual aromatase-steroid sulfatase inhibitors from the letrozole template: synthesis, absolute configuration, and in vitro activity.
To explore aromatase inhibition and to broaden the structural diversity of dual aromatase-sulfatase inhibitors (DASIs), we introduced the steroid sulfatase (STS) inhibitory pharmacophore to letrozole. Letrozole derivatives were prepared bearing bis-sulfamates or mono-sulfamates with or without adjacent substituents. The most potent of the achiral and racemic aromatase inhibitor was 40 (IC 50 = 3.0 nM). Its phenolic precursor 39 was separated by chiral HPLC, and the absolute configuration of each enantiomer was determined using vibrational and electronic circular dichroism in tandem with calculations of the predicted spectra. Of the two enantiomers, ( R)-phenol ( 39a) was the most potent aromatase inhibitor (IC 50 = 0.6 nM, comparable to letrozole), whereas the ( S)-sulfamate, ( 40b) inhibited STS most potently (IC 50 = 553 nM). These results suggest that a new structural class of DASI for potential treatment of hormone-dependent breast cancer has been identified, and this is the first report of STS inhibition by an enantiopure nonsteroidal compound.


Factors associated with variability in management of vascular access ports.
Guidelines and clinical practice recommendations vary on the management of vascular access ports. Traditionally, patient, health system and healthcare professional's factors have been interrelated in studies of clinical practice variability. Understanding variation in the management of vascular access ports and to identify the influence of these factors in the compliance with the most common recommendations of vascular access guidelines, is an important first step for designing targeted improvement interventions. We analysed data from a survey sent to all Spanish outpatient clinics. Overall, 185 units at Spanish outpatients clinics out of a total of 256 completed the survey. Geographical region and unit size are the most common associated factors in the management of vascular access ports and there is a low level of compliance with many of the recommendations given by guidelines. Large outpatient chemotherapy units have been related to higher monitoring of the recommendations. Clinical practice and provided care to patients with vascular access ports are influenced by region and structural and organisational differences in the outpatient chemotherapy units. It is important to identify additional factors that may explain the variability.


Resolved Cerebral Venous Hypertension after Angioplasty of Central Venous Stenosis in a Hemodialysis Patient: A Case Report.
Stenosis of the central veins is a common complication in hemodialysis patients. However, cerebral venous hypertension and neurological symptoms caused by central vein stenosis are relatively rare. We present a rare case of cerebral venous hypertension in a 63-year-old male who showed venous reflux into the dural sinuses due to central venous stenosis on time-of-flight MR angiography. After management for central venous stenosis, the venous reflux disappeared.


Characteristics of Medical Teams in Disaster.
Disasters present unique challenges for teams providing medical assistance to those populations impacted by the event. This scoping review focused on the characteristics of medical teams in disaster and how these characteristics are developed. The scoping review methods of Arksey and O'Malley were followed. An inductive thematic analysis of selected articles was used to identify recurrent themes. A total of 6,521 articles were reviewed from eight databases, yielding 33 articles. Four recurrent theme groups were identified: (1) adaptability, flexibility, and improvisation; (2) creativity and innovation; (3) experience and training; and (4) leadership and command structure. The study highlighted key characteristics identified by responders for effective team functioning and interdependence between the characteristics. It also identified the paucity of literature on the subject. Results from the study can help to guide future research and training development for medical teams in disaster. Oldenburger D , Baumann A , Banfield L . Characteristics of medical teams in disaster. Prehosp Disaster Med. 2017;32(2):195-200.


UV sensitivity of human keratinocyte and Langerhans cell-expressed HLA-DR antigens: a comparison.
HLA-DR expression on human keratinocytes (KC) was induced in vivo by intradermal injection of purified protein derivative of tuberculin (PPD). Neither preceding nor subsequent exposure of the PPD injection site to a dose of approximately 2 MED of UVB radiation abolished KC HLA-DR, though subsequent irradiation caused a slight diminution in the intensity of the antigen expression. By contrast, epidermal Langerhans cell (LC) HLA-DR and T6 expressions in normal epidermis were greatly reduced by an identical dose of UVB. Pemphigus antigen on the surface of KC was not affected by irradiation or PPD injection.


Seroprevalence and risk factors for hepatitis B infection in an adult population in Northeast China.
The prevalence of the hepatitis B virus (HBV) is higher in adults than in children. We determined the seroepidemiology of HBV infection in an adult population in JiLin, China, to guide effective preventive measures. A cross-sectional serosurvey was conducted throughout JiLin, China. A total of 3833 people was selected and demographic and behavioral information gathered. Serum samples were tested for HBV markers and liver enzymes. The prevalence of the hepatitis B surface antigen (HBsAg), the antibody to the hepatitis B surface antigen (anti-HBs), the hepatitis B e antigen (HBeAg), the antibody to HBeAg (anti-HBe), and the antibody to the hepatitis B core antigen (anti-HBc) were 4.38%, 35.66%, 1.38%, 6.65%, and 40.88%, respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were significantly higher among HBsAg (+) than HBsAg (-) subjects. By multivariate logistic regression analysis, independent predictors for chronic HBV infection were smoking, poor sleep quality; occupation as private small-businessmen, laborers, or peasants; male gender; family history of HBV; personal history of vaccination; and older age. Independent predictors for exposure to HBV were large family size, occupation as a private small-businessman, male gender, family history of HBV, personal history of vaccination, and older age. Independent predictors for immunity by vaccination were occupation as a private small-businessman, high income, personal history of vaccination, and young age. Independent predictors for immunity by exposure were drinking, male gender, personal history of vaccination, and older age. The prevalence rate of HBV infection (4.38%) was lower than the previous rate of general HBV vaccination. However, 44.59% of the population remained susceptible to HBV. The prevalence of HBV infection was high in young adults, private small-businessmen, peasants, those with a family history of HBV, and males. Therefore, immunization of the non-immune population is reasonable to reduce hepatitis B transmission between adults.


From radiation-induced chromosome damage to cell death: modelling basic mechanisms and applications to boron neutron capture therapy.
Cell death is a crucial endpoint in radiation-induced biological damage: on one side, cell death is a reference endpoint to characterise the action of radiation in biological targets; on the other side, any cancer therapy aims to kill tumour cells. Starting from Lea's target theory, many models have been proposed to interpret radiation-induced cell killing; after briefly discussing some of these models, in this paper, a mechanistic approach based on an experimentally observed link between chromosome aberrations and cell death was presented. More specifically, a model and a Monte Carlo code originally developed for chromosome aberrations were extended to simulate radiation-induced cell death applying an experimentally observed one-to-one relationship between the average number of 'lethal aberrations' (dicentrics, rings and deletions) per cell and -ln S, S being the fraction of surviving cells. Although such observation was related to X rays, in the present work, the approach was also applied to protons and alpha particles. A good agreement between simulation outcomes and literature data provided a model validation for different radiation types. The same approach was then successfully applied to simulate the survival of cells enriched with boron and irradiated with thermal neutrons at the Triga Mark II reactor in Pavia, to mimic a typical treatment for boron neutron capture therapy.


Gastrointestinal parasites among felids inhabiting the Serra dos Órgãos National Park, Rio de Janeiro, Brazil.
This study aimed to investigate the species of felids that inhabit the Serra dos Órgãos National Park (Parnaso) and gastrointestinal parasites at various stages of their life cycles in the feces of these animals. Between 2013 and 2015, felid feces were collected from trails in Parnaso. The sampling points were georeferenced. A total of 82 fecal samples were processed, of which 79 were collected on the ground, two from captured felids and one from a necropsied animal. All samples underwent coproparasitological techniques. Samples collected from the environment underwent additional trichological analysis. Fur patterns corresponding to Leopardus guttulus, Leopardus pardalis, Leopardus wiedii and Puma yagouaroundi were observed in 32 of the samples collected on the soil. High frequency of potentially parasitic evolving forms (88.6%) was observed in felid feces, particularly eggs of the family Diphyllobothriidae (68.6%). Besides, were also detected, eggs of superfamily Ascaridoidea (42.9%), nematode larvae (28.6%), eggs of order Strongylida (28.6%), Capillaria sp. (8.6%), Trichuris sp. (8.6%), eggs of order Spirurida (2.9%), unsporulated coccidian oocysts (8.6%) and Eimeria sp. (2.9%). Felid feces presented higher frequency of polyparasitism (60%) than monoparasitism (28.6%).


Characterization of a novel subtilisin-like protease myroicolsin from deep sea bacterium Myroides profundi D25 and molecular insight into its collagenolytic mechanism.
Collagen is an insoluble protein that widely distributes in the extracellular matrix of marine animals. Collagen degradation is an important step in the marine nitrogen cycle. However, the mechanism of marine collagen degradation is still largely unknown. Here, a novel subtilisin-like collagenolytic protease, myroicolsin, which is secreted by the deep sea bacterium Myroides profundi D25, was purified and characterized, and its collagenolytic mechanism was studied. Myroicolsin displays low identity (<30%) to previously characterized subtilisin-like proteases, and it contains a novel domain structure. Protein truncation indicated that the Pro secretion system C-terminal sorting domain in the precursor protein is involved in the cleavage of the N-propeptide, and the linker is required for protein folding during myroicolsin maturation. The C-terminal β-jelly roll domain did not bind insoluble collagen fiber, suggesting that myroicolsin may degrade collagen without the assistance of a collagen-binding domain. Myroicolsin had broad specificity for various collagens, especially fish-insoluble collagen. The favored residue at the P1 site was basic arginine. Scanning electron microscopy and atomic force microscopy, together with biochemical analyses, confirmed that collagen fiber degradation by myroicolsin begins with the hydrolysis of proteoglycans and telopeptides in collagen fibers and fibrils. Myroicolsin showed strikingly different cleavage patterns between native and denatured collagens. A collagen degradation model of myroicolsin was proposed based on our results. Our study provides molecular insight into the collagen degradation mechanism and structural characterization of a subtilisin-like collagenolytic protease secreted by a deep sea bacterium, shedding light on the degradation mechanism of deep sea sedimentary organic nitrogen.


HYENA detects oncogenes activated by distal enhancers in cancer.
Somatic structural variations (SVs) in cancer can shuffle DNA content in the genome, relocate regulatory elements, and alter genome organization. Enhancer hijacking occurs when SVs relocate distal enhancers to activate proto-oncogenes. However, most enhancer hijacking studies have only focused on protein-coding genes. Here, we develop a computational algorithm "HYENA" to identify candidate oncogenes (both protein-coding and non-coding) activated by enhancer hijacking based on tumor whole-genome and transcriptome sequencing data. HYENA detects genes whose elevated expression is associated with somatic SVs by using a rank-based regression model. We systematically analyze 1,148 tumors across 25 types of adult tumors and identify a total of 192 candidate oncogenes including many non-coding genes. A long non-coding RNA TOB1-AS1 is activated by various types of SVs in 10% of pancreatic cancers through altered 3-dimension genome structure. We find that high expression of TOB1-AS1 can promote cell invasion and metastasis. Our study highlights the contribution of genetic alterations in non-coding regions to tumorigenesis and tumor progression.


Real-time animal functional magnetic resonance imaging and its application to neuropharmacological studies.
In pharmacological magnetic resonance imaging (phMRI) with anesthetized animals, there is usually only a single time window to observe the dynamic signal change to an acute drug administration since subsequent drug injections are likely to result in altered response properties (e.g., tolerance). Unlike the block-design experiments in which fMRI signal can be elicited with multiple repetitions of a task, these single-event experiments require stable baseline in order to reliably identify drug-induced signal changes. Such factors as subject motion, scanner instability and/or alterations in physiological conditions of the anesthetized animal could confound the baseline signal. The unique feature of such functional MRI (fMRI) studies necessitates a technique that is able to monitor MRI signal in a real-time fashion and to interactively control certain experimental procedures. In the present study, an approach for real-time MRI on a Bruker scanner is presented. The custom software runs on the console computer in parallel with the scanner imaging software, and no additional hardware is required. The utility of this technique is demonstrated in manganese-enhanced MRI (MEMRI) with acute cocaine challenge, in which temporary disruption of the blood-brain barrier (BBB) is a critical step for MEMRI experiments. With the aid of real-time MRI, we were able to assess the outcome of BBB disruption following bolus injection of hyperosmolar mannitol in a near real-time fashion prior to drug administration, improving experimental success rate. It is also shown that this technique can be applied to monitor baseline physiological conditions in conventional fMRI experiments using blood oxygenation level-dependent (BOLD) contrast, further demonstrating the versatility of this technique.


Isocitrate Dehydrogenase Mutations are Better Prognostic Marker than O6-methylguanine-DNA Methyltransferase Promoter Methylation in Glioblastomas - a Retrospective, Single-centre Molecular Genetics Study of Gliomas.
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are a promising prognostic biomarker of gliomas. The purpose of our study was to examine the clinical prognostic properties of IDH1/2 mutations in a glioma patient cohort from the Czech Republic using an improved platform for simple and reliable IDH genotyping. We retrospectively analyzed a group of 145 glioma patients by testing for the three most frequent IDH mutations, IDH1 R132H, IDH1 R132C, and IDH2 R172K, through the competitive amplification of differentially melting amplicons (CADMA) polymerase chain reaction (PCR). O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, copy number of EGFR, p53, RB1, MDM2, CDKN2A genes, and deletions in 1p, 19q and 10p chromosomal regions were also analyzed and correlated with clinical characteristics. Of 145 gliomas, 36 harbored IDH1 R132H mutation and 1 IDH1 R132C mutation. We did not detect any IDH2 R172K mutation. IDH1 mutations were positively associated with MGMT methylation (OR 3.08, 95% CI 1.387-7.282; p = 0.007), 1p/19q co-loss (OR 8.85, 95% CI 2.367-42.786; p = 0.002) and negatively associated with epidermal growth factor receptor amplification (OR 0.12, 95% CI 0.019-0.437; p = 0.006) and 10p loss (OR 0.09, 95% CI 0.005-0.436; p = 0.019). The overall survival of IDH-mutant was 25 months, but only 9 months in IDH-wild type gliomas (p = 0.035); at the same time, survival associated with methylated vs. unmethylated MGMT promoter did not significantly differ (p = 0.166). Despite IDH1 mutations being closely associated with MGMT methylation in glioma patients, IDH1 mutations in glioblastoma patients are stronger marker of overall survival than MGMT methylation and should be the marker of choice, especially when using genotyping by CADMA PCR.Key words: isocitrate dehydrogenase - polymerase chain reaction - glioma - glioblastoma.