Intestinal obstruction by a pancreatic bezoar: a case report.
Pancreatic pseudocysts are relatively common complications of pancreatitis. A pseudocyst can result from an episode of acute pancreatitis, exacerbation of chronic pancreatitis, or trauma. Treatment is indicated for persistent, symptomatic pseudocysts and in the case of related complications. We describe the case of a 66-year-old man who referred to our department for bowel obstruction caused by a necrotic pancreatic bezoar occurring 16 days after the patient underwent a jejunal-pseudocyst anastomosis performed to treat a post-pancreatitis voluminous pseudocyst obstructing the gastric outlet. In case of intestinal obstruction after a jejunal-pseudocyst anastomosis, pancreatic bezoar should be considered in the armamentarium of the differential diagnosis.


Dialectical behavioral therapy: an update and review of the existing treatment models adapted for adults with eating disorders.
Despite the effectiveness of CBT in reducing shape/weight concerns and dietary restraint, research suggests that patients considered recovered may still exhibit emotional difficulties related to eating disorders (EDs). Dialectical behavior therapy (DBT) has been adapted for a variety of mental disorders characterized by emotion dysregulation and, more recently, for EDs specifically. The current review found that the majority of the research studies employed one of the following three adaptations of DBT for EDs: The Stanford Model, Radically Open-DBT (RO-DBT), or Multidiagnostic ED-DBT (MED-DBT). Therefore, this review sought to review and update the empirical research on each adaptation and (2) offer preliminary recommendations for when and which adaptation of DBT to use when treating adults with EDs. Findings from the empirical literature on DBT and EDs indicate that the Stanford Model has the most rigorous and numerous studies demonstrating efficacy and effectiveness in those diagnosed with binge eating disorder. Fewer studies have been conducted using the Stanford Model with bulimia nervosa; therefore, less strong assertions can be made about DBT with those diagnosed with bulimia. The MED-DBT model has been evaluated in several open trials within higher levels of care with promising results, but the lack of randomized clinically-controlled trials prevents a definitive statement about its efficacy. Finally, research on applying the RO-DBT model to anorexia-nervosa, restricting subtype is in its infancy, prohibiting solid conclusions or recommendations regarding its efficacy or effectiveness.


The human VAV proto-oncogene maps to chromosome region 19p12----19p13.2.
A novel human oncogene, designated VAV, has been recently characterized. This oncogene was generated by a rearrangement within the 5' coding sequences of a normal cellular gene, the VAV proto-oncogene. The normal VAV gene is specifically expressed in hematopoietic cells regardless of their differentiation lineage. We now report that the VAV locus has been localized in the human genome at chromosome 19p12----19p13.2 by analysis of its segregation pattern in rodent-human somatic cell hybrids and by chromosomal in situ hybridization. The VAV locus might be closely linked to the insulin receptor (INSR) locus, as suggested by comigration of INSR and VAV high-molecular-weight DNA fragments after pulsed-field gel electrophoresis. The VAV chromosomal assignment is of interest because chromosome region 19p13 is involved in different karyotypic abnormalities in a variety of malignancies including melanomas and leukemias. The identification of a novel proto-oncogene that maps to that region will enable us to define whether VAV is involved in any of the translocations observed.


Cocaine and the eye: a historical overview.
Cocaine was brought to Europe after the discovery of America. In the 19th century, the active component of coca leaves, named cocaine, was extracted and several researchers started experimenting with the substance, describing many physiological and pathological effects of its action. The first scholar to practically demonstrate the possibility of using cocaine solution in medicine, mostly ophthalmology, was Carl Koller. Following this remarkable achievement cocaine became the substance most frequently applied for different types of anaesthesia. Halsted and Hall reported the first successful nerve block of the interior dental nerve with 4% cocaine solution. In 1892, Schleich published the results of his studies in which he used a 0.1-0.2% solution of cocaine hydrochloride intra- and subcutaneously, introducing the so-called infiltration anaesthesia. At the end of the 19th century it was, however, demonstrated that cocaine possessed many undesirable effects, including addiction, which triggered off interest in other, less toxic, anaesthetics.


In-hospital outcomes after emergency or prophylactic veno-arterial extracorporeal membrane oxygenation during transcatheter aortic valve implantation: a comprehensive review of the literature.
Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) has been used to deal with life-threatening complications as well as back-up or active cardiovascular support during high-risk procedures in patients undergoing transcatheter aortic valve implantation (TAVI). PubMed and MEDLINE electronic databases were searched in order to identify studies with emergency or prophylactic V-A ECMO application in association with TAVI procedures. From November 2012 to November 2017, 14 relevant studies were identified that included 5,115 TAVI patients of whom 102 (2%) required V-A ECMO (22 prophylactically, 66 as an emergency and 14 without a reported indication). The reason for emergency V-A ECMO institution was detailed in 64 patients: left ventricle free wall rupture (n = 14), haemodynamic instability (n = 12), ventricular arrhythmias (n = 7), aortic annulus rupture (n = 6), coronary obstruction (n = 6), low left ventricular output (ejection fraction <35%) (n = 5), uncontrollable bleeding (n = 5), severe aortic regurgitation (n = 4), prosthesis embolisation (n = 3), aortic dissection (n = 1) and respiratory failure (n = 1). Femoral arterial and vein cannulation was the most common access technique for V-A ECMO institution. Major bleeding (n = 7) and vascular access complications (n = 7) were reported after ECMO institution. The overall in-hospital survival was 73% (61% in the emergency vs. 100% in the prophylactic group). V-A ECMO support should be available at any centre performing TAVI and provides effective mechanical circulatory support in an emergency setting. We present an algorithm to aid decisions about prophylactic circulatory assistance with V-A ECMO and it should form part of the heart team discussion before a TAVI procedure is undertaken.


Trends in Motor Performance of First Graders: A Comparison of Cohorts from 2006 to 2015.
Motor performance is an important factor for health. Already in childhood, motor performance is associated with, e.g., obesity and risk factors for cardiovascular diseases. It is widely believed that the motor performance of children has declined over recent years. However, this belief is lacking clear evidence. The objective of this study was to examine trends in motor performance of first grade students during a period of 10 years (2006-2015). We examined trends in (a) aerobic fitness, (b) strength, (c) speed, and (d) balance for boys and girls separately and considered body mass index (BMI) as a potential confounder. From 2006 to 2015, we tested 5,001 first graders [50.8% boys; mean age 6.76 (0.56) years] of 18 primary schools in Germany. Each year between 441 and 552 students of the same schools were surveyed. Performance tests were taken from the Motorik-Module Study and the "German Motor Ability Test": "6-min run," "push-ups," "20-m sprint," and "static stand." Linear regression models were conducted for statistical analysis. A slightly negative trend in aerobic fitness performance was revealed in boys (β = -0.050; p = 0.012) but not in girls. In the strength performance test no trend over time was detected. Performance in speed (boys: β = -0.094; girls: β = -0.143; p ≤ 0.001) and balance tests (boys: β = -0.142; girls: β = -0.232; p ≤ 0.001) increased over time for both boys and girls. These findings held true when BMI was considered. This study only partly supported the assumption that motor performance of children has declined: in our study, aerobic fitness declined (only in boys), while strength remained stable and speed and balance even increased in both sexes. Moreover, it seems as if BMI can explain changes in performance only to a small extent. Changed lifestyles might be a substantial cause. Further research on recent trends of motor performance and interacting variables is needed to support the results of our study and to provide more knowledge on causes of these trends.


Noninvasive Diagnosis of Portal Hypertension in Patients With Compensated Advanced Chronic Liver Disease.
We aimed to explore the prevalence of portal hypertension in the most common etiologies of patients with compensated advanced chronic liver disease (cACLD) and develop classification rules, based on liver stiffness measurement (LSM), that could be readily used to diagnose or exclude clinically significant portal hypertension (CSPH) in clinical practice. This is an international cohort study including patients with paired LSM/hepatic venous pressure gradient (HVPG), LSM ≥10 kPa, and no previous decompensation. Portal hypertension was defined by an HVPG >5 mm Hg. A positive predictive value ≥90% was considered to validate LSM cutoffs for CSPH (HVPG ≥10 mm Hg), whereas a negative predictive value ≥90% ruled out CSPH. A total of 836 patients with hepatitis C (n = 358), nonalcoholic steatohepatitis (NASH, n = 248), alcohol use (n = 203), and hepatitis B (n = 27) were evaluated. Portal hypertension prevalence was >90% in all cACLD etiologies, except for patients with NASH (60.9%), being even lower in obese patients with NASH (53.3%); these lower prevalences of portal hypertension in patients with NASH were maintained across different strata of LSM values. LSM ≥25 kPa was the best cutoff to rule in CSPH in alcoholic liver disease, chronic hepatitis B, chronic hepatitis C, and nonobese patients with NASH, whereas in obese NASH patients, the positive predictive value was only 62.8%. A new model for patients with NASH (ANTICIPATE-NASH model) to predict CSPH considering body mass index, LSM, and platelet count was developed, and a nomogram was constructed. LSM ≤15 kPa plus platelets ≥150 × 10/L ruled out CSPH in most etiologies. Patients with cACLD of NASH etiology, especially obese patients with NASH, present lower prevalences of portal hypertension compared with other cACLD etiologies. LSM ≥25 kPa is sufficient to rule in CSPH in most etiologies, including nonobese patients with NASH, but not in obese patients with NASH.


Low self-control promotes the willingness to sacrifice in close relationships.
Although previous theories and research have suggested that human behavior is automatically driven by selfish impulses (e.g., vengeance rather than forgiveness), the present research tested the hypothesis that in close relationships, people's impulsive inclination is to be prosocial and to sacrifice for their partner-to pursue the interests of the partner or of the relationship at some costs for the self. Results from four studies demonstrated that people with low self-control, relative to those with high self-control, reported greater willingness to sacrifice for their close others. Furthermore, Study 4 demonstrated that communal orientation was more strongly associated with sacrifice among participants with low self-control than participants with high self-control. This moderational pattern supports the hypothesis that communal orientation functions as a default approach to sacrifice in the context of close relationships. Taken together, these findings suggest that under certain crucial conditions in close relationships, gut-level impulses are more likely than deliberative considerations to promote prorelationship behavior.


Alzheimer's disease and frontotemporal dementia are differentiated by discriminant analysis applied to (99m)Tc HmPAO SPECT data.
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the most frequent neurodegenerative cognitive disorders. However, FTD remains poorly recognised clinically. The use of (99m)HmPAO-single photon emission computed tomography (SPECT) has been demonstrated in the differentiation of AD and FTD. Nethertheless, there are very few comparative studies designed to assess its precise value in this differential diagnosis. The aim was to determine a simple decision rule, deduced from statistical analysis, which, if applied to regions of interest (ROIs) and mini mental state examination (MMSE), could improve the predictive value of SPECT in differential diagnosis between AD and FTD. Forty patients, 20 with probable AD and 20 with probable FTD were included. All patients underwent brain SPECT imaging, after an intravenous injection of (99m)Tc HmPAO-(555mBq). For each patient, 20 ROIs were determined on the Fleishig's slice and their activity was normalised to the mean cerebellar activity. Bivariate analysis (Wilcoxon rank tests) and multivariate analysis (stepwise discriminant analysis) were performed to determine the subgroup of variables able to give the highest predictive value for this differential diagnosis. A simple decision rule was built from a predictive score derived by factorial discriminant analysis. As previously described, the fixation defect was found in frontal regions of interest (ROIs) in FTD and in the left temporoparietal-occipital ROIs in AD. Among the 21 variables, five were finally selected: right median frontal, left lateral frontal, left tempoparietal, left temporoparietal-occipital areas, and MMSE. One hundred per cent of patients with FTD were correctly classified by the decision rule (20/20 patients) and 90% of patients with AD (18/20). AD and FTD are differentiated by SPECT. Automatic classification based on a decision rule deduced from factorial discriminant analysis could enhance its performance.


Chronic ethanol feeding increases activation of NADPH oxidase by lipopolysaccharide in rat Kupffer cells: role of increased reactive oxygen in LPS-stimulated ERK1/2 activation and TNF-alpha production.
Reactive oxygen species (ROS) contribute to the development of chronic ethanol-induced liver injury. Although ROS modulate the activity of many signal transduction pathways, the molecular targets of ROS during ethanol exposure are not well understood. Here, we investigated whether specific ROS-sensitive signal transduction pathways contribute to increased tumor necrosis factor alpha (TNF-alpha) production by Kupffer cells after chronic ethanol feeding to rats. Lipopolysaccharide (LPS) rapidly increased ROS production, measured by dihydrorhodamine fluorescence, in Kupffer cells from ethanol- and pair-fed rats, and ROS production was 2.5-fold greater in ethanol-fed compared with pair-fed. Pretreatment with diphenyleneiodonium (DPI), which inhibits reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, normalized ROS production in Kupffer cells from ethanol-fed rats. LPS rapidly increased Rac1-guanosinetriphosphatase (GTPase) activity and p67(phox) translocation to the plasma membrane in Kupffer cells from pair-fed rats. After ethanol feeding, Rac1-GTPase activity was already increased over pair-fed at baseline and remained elevated over pair-fed after LPS stimulation. Further, LPS-stimulated p67(phox) translocation to the plasma membrane was enhanced after chronic ethanol feeding. LPS-stimulated extracellular signal-regulated kinase (ERK)1/2 and p38 phosphorylation, two signaling pathways regulated by ROS, were increased twofold in Kupffer cells from ethanol-fed rats compared with pair-fed controls. However, only LPS-stimulated ERK1/2 phosphorylation was inhibited by DPI, which also reduced LPS-stimulated TNF-alpha production in Kupffer cells from pair- and ethanol-fed rats. These results demonstrate that chronic ethanol feeding increases LPS-stimulated NADPH oxidase-dependent production of ROS in Kupffer cells. Further, ERK1/2 is an important target of NADPH oxidase-derived ROS in Kupffer cells, contributing to enhanced LPS-stimulated TNF-alpha production by Kupffer cells after chronic ethanol feeding.


Diagnostic application of polymerase chain reaction for detection of Ehrlichia risticii in equine monocytic ehrlichiosis (Potomac horse fever).
Genomic amplification by the polymerase chain reaction (PCR) was used to identify a unique genomic sequence of Ehrlichia risticii directly in DNA isolated from peripheral-blood buffy coat cells of E. risticii-infected horses (Potomac horse fever) and from infected cell cultures. A specific primer pair, selected from a cloned, species-specific, 1-kb DNA fragment of the E. risticii genome as a template, was used for the amplification of the target DNA of 247 bp. The optimal number of 40 PCR cycles, determined by analyzing an amplification profile obtained with a constant Taq polymerase concentration, was used to achieve maximum amplification of the E. risticii DNA segment. Efficient amplification of target DNA was achieved with specimens processed by either the phenol extraction or rapid lysis method. The specificity of the amplified DNA product was confirmed by the proper size (247 bp) and appropriate restriction enzyme cleavage pattern of the amplified target DNA, as well as by the specific hybridization signal obtained by using a PCR-amplified 185-bp internal DNA probe. A 10(5)- to 10(6)-fold amplification of target DNA, which allowed detection of E. risticii from as few as two to three infected cells in culture and from a very small volume of buffy coat cells from infected horses, was achieved. This PCR amplification procedure was found to be highly specific and sensitive for the detection of E. risticii for the study of Potomac horse fever.


Isolation and partial characterization of the photoreceptive organelle for phototaxis of a flagellate green alga.
We report on the isolation and purification of structurally intact eyespot apparatuses from the naked, biflagellate green alga Spermatozopsis similis. Two eyespot-enriched fractions, separated by sucrose gradient centrifugation, retained the typical reflective properties of eyespots in situ as demonstrated by reflection confocal laser scanning microscopy. Ultrastructurally, both fractions contained eyespot plates consisting of a single layer of lipid globules. Structurally intact eyespot apparatuses, including patches of plasma membrane and chloroplast envelope overlying the eyespot plate and a single thylakoid subtending the eyespot plate, were particularly enriched in one of the two fractions (fraction 2a). Measurement of several marker enzymes and chlorophyll content (less than 0.001% of total) established the absence of most other cell organelles from the eyespot fractions. The absorption spectra of the two fractions were dominated by carotenoids with an additional shoulder at 540 nm. Following extraction with organic solvents and sodium dodecyl sulfate polyacrylamide gel electrophoresis, several proteins were found to be considerably enriched in the two fractions. In addition to several proteins in the high Mr range, at least 4 polypeptides of 35, 29, 23, and 20 kDa are selectively enriched in fraction 2a with the 29 and 20 kDa proteins being the most prominent. The presence of glycoproteins in fraction 2a was demonstrated by binding of the mannose-specific lectin Galanthus nivalis agglutinin to several high molecular weight polypeptides. In addition, a hydrophobic component with abnormal electrophoretic mobility that reacts strongly with periodic acid-Schiff and thymol/sulfuric acid was prominent in both fractions. Mass isolation and purification of the intact phototactic apparatus of a flagellate green alga now greatly facilitates the biochemical and molecular characterization of the signal transduction chain involved in green algal phototaxis.


Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes. A regulatory role for plasma LDL.
The subendothelial accumulation of macrophage-derived foam cells is one of the hallmarks of atherosclerosis. The recruitment of monocytes to the intima requires the interaction of locally produced chemokines with specific cell surface receptors, including the receptor (CCR2) for monocyte chemoattractant protein-1 (MCP-1). We have previously reported that monocyte CCR2 gene expression and function are effectively downregulated by proinflammatory cytokines. In this study we identified low density lipoprotein (LDL) as a positive regulator of CCR2 expression. Monocyte CCR2 expression was dramatically increased in hypercholesterolemic patients compared with normocholesterolemic controls. Similarly, incubation of human THP-1 monocytes with LDL induced a rapid increase in CCR2 mRNA and protein. By 24 hours the number of cell surface receptors was doubled, causing a 3-fold increase in the chemotactic response to MCP-1. The increase in CCR2 expression and chemotaxis was promoted by native LDL but not by oxidized LDL. Oxidized LDL rapidly downregulated CCR2 expression, whereas reductively methylated LDL, which does not bind to the LDL receptor, had only modest effects on CCR2 expression. A neutralizing anti-LDL receptor antibody prevented the effect of LDL, suggesting that binding and internalization of LDL were essential for CCR2 upregulation. The induction of CCR2 expression appeared to be mediated by LDL-derived cholesterol, because cells treated with free cholesterol also showed increased CCR2 expression. These data suggest that elevated plasma LDL levels in conditions such as hypercholesterolemia enhance monocyte CCR2 expression and chemotactic response and potentially contribute to increased monocyte recruitment to the vessel wall in chronic inflammation and atherogenesis.


Predictive Validity of Operationalized Criteria for the Assessment of Criminal Responsibility of Sexual Offenders With Paraphilic Disorders-A Randomized Control Trial With Mental Health and Legal Professionals.
The prevention of sexual violence is a major goal of sexual health. In cases of accused sexual offenders, the assessment of diminished criminal responsibility of the accused is one of the most important procedures undertaken by experts in the German legal system. This assessment follows a two-stage method assessing first the severity of a paraphilic disorder and then second criteria for or against diminished capacity. The present study examines the predictive validity of two different sets of criteria for the assessment of criminal responsibility in the context of paraphilic disorders combined with sexual offending. Two exemplary case vignettes of two suspected sexual offenders were developed to assess the criteria. For each participant, one of the two exemplary case vignettes was randomly presented. The presentation of the two different sets of criteria was also randomized, so that each participant was assigned only one of the two criteria sets to rate one of the presented cases. N = 349 participants from different professional backgrounds (mental health and legal professionals) completed their assessments and were included in the data analysis. The data were evaluated using logistic regression. Results show that the more recently published criteria set (Briken and Müller, 2014) predicts both the severity of the disorder as well as the diminished capacity twice as good as the older criteria set of Boetticher et al. (2005) currently used regularly for forensic court reports. In preliminary conclusion, the new criteria of Briken and Müller (2014) form an empirically based assessment of criminal responsibility. However, the proposed criteria cannot replace an extensive exploration of the accused person and a careful file analysis. Validity and reliability of the results are also limited due to the methodical choice of a vignette study.


Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents.
Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models. Graded noxious stimulus intensities were used in rats to establish the antinociceptive potency and efficacy of NKTR-181 relative to morphine, fentanyl, and oxycodone. Characteristics of MOR agonist actions, as measured by antinociceptive tolerance and cross-tolerance, as well as opioid-induced hyperalgesia (OIH) and naloxone-precipitated withdrawal in NKTR-181- and morphine-dependent in mice, were compared. NKTR-181 showed dose- and time-related antinociception with similar maximal effects to morphine in the rat and mouse hot-water tail-flick test. No sex or species differences were observed in NKTR-181 or morphine antinociception. Rats treated with NKTR-181 and morphine exhibited decreases in both potency and maximal efficacy as nociceptive stimulus intensity was increased from a water temperature of 50 °C to 54 °C. Evaluation of antinociception at a high stimulus intensity revealed that oxycodone and fentanyl exhibited greater efficacy than either NKTR-181 or morphine. The relative potency difference between NKTR-181 and morphine across all tail-flick studies was determined to be 7.6-fold (90% confidence interval, 2.6, 21.5). The peak antinociceptive effect of NKTR-181 was delayed compared to that of the other opioids and cumulative drug effects were not observed. Repeated treatment with escalating, approximately equi-analgesic doses of NKTR-181 or morphine, produced antinociceptive tolerance and cross-tolerance. Under these pharmacological conditions, OIH and naloxone-precipitated physical dependence were similar for NKTR-181 and morphine. NKTR-181 had a slower onset, but similar efficacy, to morphine in the models studied supporting reduced abuse potential while maintaining analgesic effect in comparison with current opioids.


[Analysis on the infection source of the first local cluster epidemic caused by the VOC/Gamma variant of SARS-CoV-2 in China].
Objective: To investigate a SARS-CoV-2 epidemic reported in Rongcheng City, Weihai, Shandong Province. Methods: The SARS-CoV-2 nucleic acid positive patients and their close contacts were investigated, and the whole genome sequencing and genetic evolution analysis of 9 variant viruses were carried out. An infection source investigation and analysis were carried out from two sources of home and abroad, and three aspects of human, material and environment. Results: A total of 15 asymptomatic infections were reported in this epidemic, including 13 cases as employees of workshop of aquatic products processing company, with an infection rate of 21.67% (13/60). Two cases were infected people's neighbors in the same village (conjugal relation). The first six positive persons were processing workers engaged in the first process of removing squid viscera in the workshop of the company. The nucleic acid Ct value of the first time were concentrated between 15 and 29, suggesting that the virus load was high, which was suspected to be caused by one-time homologous exposure. The whole genome sequence of 9 SARS-CoV-2 strains was highly homologous, belonging to VOC/Gamma (Lineage P.1.15). No highly homologous sequences were found from previous native and imported cases in China. It was highly homologous with the six virus sequences sampled from May 5 to 26, 2021 uploaded by Chile. The infection source investigation showed that the company had used the squid raw materials captured in the ocean near Chile and Argentina from May to June 2021 over the last 14 days. Many samples of raw materials, products and their outer packages in the inventory were tested positive for nucleic acid. Conclusion: This epidemic is the first local epidemic caused by the VOC/Gamma of SARS-CoV-2 in China. It is speculated that the VOC/Gamma, which was prevalent in South America from May to June 2021, could be imported into China through frozen squid.


A genome-wide screen reveals that Dyrk1A kinase promotes nucleotide excision repair by preventing aberrant overexpression of cyclin D1 and p21.
Nucleotide excision repair (NER) eliminates highly genotoxic solar UV-induced DNA photoproducts that otherwise stimulate malignant melanoma development. Here, a genome-wide loss-of-function screen, coupling CRISPR/Cas9 technology with a flow cytometry-based DNA repair assay, was used to identify novel genes required for efficient NER in primary human fibroblasts. Interestingly, the screen revealed multiple genes encoding proteins, with no previously known involvement in UV damage repair, that significantly modulate NER uniquely during S phase of the cell cycle. Among these, we further characterized Dyrk1A, a dual specificity kinase that phosphorylates the proto-oncoprotein cyclin D1 on threonine 286 (T286), thereby stimulating its timely cytoplasmic relocalization and proteasomal degradation, which is required for proper regulation of the G1-S phase transition and control of cellular proliferation. We demonstrate that in UV-irradiated HeLa cells, depletion of Dyrk1A leading to overexpression of cyclin D1 causes inhibition of NER uniquely during S phase and reduced cell survival. Consistently, expression/nuclear accumulation of nonphosphorylatable cyclin D1 (T286A) in melanoma cells strongly interferes with S phase NER and enhances cytotoxicity post-UV. Moreover, the negative impact of cyclin D1 (T286A) overexpression on repair is independent of cyclin-dependent kinase activity but requires cyclin D1-dependent upregulation of p21 expression. Our data indicate that inhibition of NER during S phase might represent a previously unappreciated noncanonical mechanism by which oncogenic cyclin D1 fosters melanomagenesis.


Overview on cranberry and urinary tract infections in females.
Cranberry (Vaccinium macrocarpon) has been used for decades to prevent urinary tract infections (UTIs) that are among the most common bacterial infections in women. As to the traditional use of cranberry and its A-type proanthocyanidins' ability to inhibit adherence of the bacterial P fimbriae in a dose-dependent manner, clinical trials have been conducted on different subpopulations. A Cochrane meta-analysis in 244 females with symptomatic UTI suggests that the effect was more pronounced in women with recurrent UTIs than elderly males and females or people requiring catheterization. A first head-to-head trial in older females has been published comparing effectiveness of a low-dose antibiotic versus cranberry in which investigators suggest that cranberry products may have a role in older females with recurrent UTI. Still with regard to antibiotic treatment in women, a recently published study investigated also the potential cranberry juice interaction with beta-lactam antibiotics supporting the hypothesis that cranberry juice in usual quantities as prophylaxis for UTI is not likely to alter the pharmacokinetics of these oral antibiotics. In addition, the effects of cranberry in pregnant female patients have been investigated. A first pilot trial has been published in which, while a possible protective effect was shown, more than one third of the females withdrew mainly for gastrointestinal upset.


Theta and gamma coordination of hippocampal networks during waking and rapid eye movement sleep.
Rapid eye movement (REM) sleep has been considered a paradoxical state because, despite the high behavioral threshold to arousing perturbations, gross physiological patterns in the forebrain resemble those of waking states. To understand how intrahippocampal networks interact during REM sleep, we used 96 site silicon probes to record from different hippocampal subregions and compared the patterns of activity during waking exploration and REM sleep. Dentate/CA3 theta and gamma synchrony was significantly higher during REM sleep compared with active waking. In contrast, gamma power in CA1 and CA3-CA1 gamma coherence showed significant decreases in REM sleep. Changes in unit firing rhythmicity and unit-field coherence specified the local generation of these patterns. Although these patterns of hippocampal network coordination characterized the more common tonic periods of REM sleep (approximately 95% of total REM), we also detected large phasic bursts of local field potential power in the dentate molecular layer that were accompanied by transient increases in the firing of dentate and CA1 neurons. In contrast to tonic REM periods, phasic REM epochs were characterized by higher theta and gamma synchrony among the dentate, CA3, and CA1 regions. These data suggest enhanced dentate processing, but limited CA3-CA1 coordination during tonic REM sleep. In contrast, phasic bursts of activity during REM sleep may provide windows of opportunity to synchronize the hippocampal trisynaptic loop and increase output to cortical targets. We hypothesize that tonic REM sleep may support off-line mnemonic processing, whereas phasic bursts of activity during REM may promote memory consolidation.


Center-surround organization in bipolar cells: symmetry for opposing contrasts.
Intracellular recordings were obtained from 73 cone-driven bipolar cells in the light-adapted retina of the tiger salamander (Ambystoma tigrinum). Responses to flashes of negative and positive contrast for centered spots and concentric annuli of optimum spatial dimensions were analyzed as a function of contrast magnitude. For both depolarizing and hyperpolarizing bipolar cells, it was found that remarkably similar responses were observed for the center and surround when comparisons were made between responses of the same response polarity and thus, responses to opposite contrast polarity. Thus, spatial information and contrast polarity appear to be rather strongly confounded in many bipolar cells. As a rule, the form of the contrast/response curves for center and surround approximated mirror images of each other. Contrast gain and C50 (the contrast required for half-maximal response) were quantitatively similar for center and surround when comparisons were made for responses of the same response polarity. The average contrast gain of the bipolar cell surround was 3-5 times higher than that measured for horizontal cells. Contrast/latency measurements and interactions between flashed spots and annuli showed that the surround response is delayed by 20-80 ms with respect to that of the receptive-field center. Cones showed no evidence for center-surround antagonism while for bipolar cells, the average strength of the surround ranged from about 50% to 155% of the center, depending on the test and response polarity. The results of experiments on the effects of APB (100 microM) on depolarizing bipolar cells suggest that the relative contribution of the feedback pathway (horizontal cell to cones) and the feedforward pathway (horizontal cell to bipolar cell) to the bipolar surround varies in a distributed manner across the bipolar cell population.


Gene therapy of Cav1.2 channel with VIP and VIP receptor agonists and antagonists: a novel approach to designing promotility and antimotility agents.
Recent findings show that the enteric neurotransmitter VIP enhances gene transcription of the alpha1C subunit of Cav1.2 (L-type) Ca2+ channels in the primary cultures of human colonic circular smooth muscle cells and circular smooth muscle strips. In this study, we investigated whether systemic infusion of VIP in intact animals enhances the gene transcription and protein expression of these channels to accelerate colonic transit. We also investigated whether similar systemic infusions of VPAC1/2 receptor antagonist retards colonic transit by repressing the constitutive gene expression of the alpha1C subunit. We found that the systemic infusion of VIP for 7 days by a surgically implanted osmotic pump enhances the gene and protein expression of the alpha1C subunit and circular muscle contractility in the proximal and the middle rat colons, but not in the distal colon. A similar systemic infusion of VPAC1/2 receptor antagonist represses the expression of the alpha1C subunit and circular smooth muscle contractility in the proximal and the middle colons. The VIP infusion accelerates colonic transit and pellet defecation by rats, whereas the infusion of VPAC1/2 receptor antagonist retards colonic transit and pellet defecation. VPAC1 receptors, but not VPAC2 receptors, mediate the above gene transcription-induced promotility effects of VIP. We conclude that VIP and VPAC(1) receptor agonists may serve as potential promotility agents in constipation-like conditions, whereas VPAC receptor antagonists may serve as potential antimotility agents in diarrhea-like conditions produced by enhanced motility function.


Utilization of psychotropic medications in children with FASD: a retrospective review.
Fetal Alcohol Spectrum Disorder (FASD) is a neurodevelopmental condition resulting from pre-natal alcohol exposure. In Canada, an estimated 1.4-4% of newborns are affected by FASD. FASD is often associated with behavioural comorbidities and many individuals require psychotropic medication. However, to date there are no FASD specific guidelines for prescribing medication. Recently, Mela and colleagues described four behavioural symptom clusters commonly seen in FASD with suggested pharmacologic treatment for each cluster within an algorithm. The primary objective was to compare the proposed treatment algorithm retrospectively to actual treatment in a real-world FASD pediatric practice. The secondary objective was to refine the description of symptom clusters which will be targeted with treatment. We collected the diagnostic and medication history from all patient visits of a Regina Developmental Pediatrician who specializes in FASD diagnosis and medication treatment. Three hundred fifty-four FASD patients were identified between 2005 to 2020. The medications that would be predicted from the algorithm were compared to the real-world historical data. A positive case was defined as all algorithm-predicted medications matching the historical data; a negative case had one or more medications failing to match. Of the 354 patients, 36 were removed for insufficient information. Of the remaining 318 cases, 172 (54.1%) were positive compared to 146 (45.9%) negatives. In single prescription cases (n=147), the incidence of positives was 67.3%; in multi-prescriptions (n=72) it was 27.8%; and in cases where no prescription was needed (n=99), the positive incidence was 53.5%. The prescription algorithm is promising but requires further refinement to accommodate the range of presentations in children with FASD. With respect to unclassified symptoms, we propose the following: sleep onset difficulty as hyperarousal; gender dysphoria and obsessive compulsive disorder as cognitive inflexibility; grief as emotional regulation; and autism spectrum disorder as hyperactive/neurocognitive.


Association between apolipoprotein E e4 allele and arteriosclerosis, cerebral amyloid angiopathy, and cerebral white matter damage in Alzheimer's disease.
To investigate the association between white matter damage, as evidenced by myelin loss (ML), the extent of cerebral amyloid angiopathy (CAA), or arteriosclerosis (Art), and apolipoprotein E (ApoE) e4 allele in Alzheimer's disease (AD), in order to understand the causes of damage to white matter in AD and its contribution to the pathogenesis of the disorder. Brain tissues were obtained from 94 patients with AD confirmed by autopsy. ApoE genotyping was performed by PCR on DNA extracted from frontal cortex or cerebellum. CAA and Art were assessed on Weigert's haematoxylin and eosin stained sections in frontal, temporal, parietal, and occipital cortices; the extent of ML was scored on Luxol fast blue stained sections of these regions. The ApoE e4 allele frequency in the 61 patients with ML was not significantly different from that in the 33 patients without ML, nor did this differ in the 84 patients with Art from that in the 10 patients without Art. There were no significant differences in the proportions of patients with genotypes containing 0, 1, or 2 ApoE e4 alleles in the presence or absence of ML or Art. The mean ML, Art, or CAA scores within each region, and the total scores summed across all four brain regions, did not differ between patients with 0, 1, or 2 ApoE e4 alleles. However, the mean ML severity score in the occipital cortex was significantly greater than that in the frontal or temporal cortices in patients with 1 or 2 ApoE e4 alleles. The severity of CAA in the occipital cortex was significantly higher than that in other areas of cortex in patients with 0 or 2 ApoE e4 alleles. The mean Art score in the occipital cortex was greater than that in the temporal cortex in patients with two ApoE e4 alleles and was higher than that in the frontal cortex in patients with one ApoE e4 allele. The likelihood of patients with AD suffering from CAA, Art, or ML is not influenced by ApoE e4 allele, nor is the overall burden of these pathological changes in the brain. However, the distribution of ML, CAA, and Art within the brain is at least partly influenced by genotype and dosage of ApoE e4 allele, with the occipital cortex being more severely affected by all of these pathological changes in e4 allele bearers, particularly when two ApoE e4 alleles are present.


To eat or get heat: Behavioral trade-offs between thermoregulation and feeding in gregarious necrophagous larvae.
The thermoregulation behavior of Lucilia sericata larvae (Diptera: Calliphoridae), a necrophagous species that feeds on vertebrate cadavers, was investigated. These larvae require high heat incomes to develop, and can elevate temperatures by forming large aggregates. We hypothesized that L. sericata larvae should continue to feed at temperatures up to 38 °C, which can be reached inside larval masses. Thermal regulation behavior such as movement between a hot food spot and colder areas was also postulated. The hypotheses were tested by tracking for 1 h the activity of single, starved third instar larvae in a Petri dish containing 1 food spot (FS) that was heated to a constant temperature of 25 °C, 34 °C or 38 °C with an ambient temperature of 25 °C. The influence of previous conspecific activity in the food on larval behavior was also tested. The crops of larvae were dissected to monitor food content in the digestive systems. Based on relative crop measurements, larvae fed at all food temperatures, but temperature strongly affected larval behavior and kinematics. The total time spent by larvae in FS and the duration of each stay decreased at high FS temperature. Previous activity of conspecifics in the food slightly increased the time spent by larvae in FS and also decreased the average distance to FS. Therefore, necrophagous L. sericata larvae likely thermoregulate during normal feeding activities by adjusting to local fluctuations in temperature, particularly inside maggot masses. By maintaining a steady internal body temperature, larvae likely reduce their development time.


Geldanamycin and its analogue 17-allylamino-17-demethoxygeldanamycin lowers Bcr-Abl levels and induces apoptosis and differentiation of Bcr-Abl-positive human leukemic blasts.
HL-60/Bcr-Abl cells, with ectopic expression of p185 Bcr-Abl tyrosine kinase (TK), and K562 cells, with endogenous expression of p210 Bcr-Abl TK, display a high degree of resistance against antileukemic drug-induced apoptosis (G. Fang et al., Blood, 96: 2246-2256, 2000). Present studies demonstrate that treatment with ansamycin antibiotic geldanamycin (GA), or its less toxic analogue 17-allylamino-17-demethoxygeldanamycin (17-AAG), induces cytosolic accumulation of cytochrome c and cleavage and activities of caspase-9 and caspase-3, triggering apoptosis of HL-60/Bcr-Abl and K562 cells. GA or 17-AAG down-regulated intracellular Bcr-Abl and c-Raf protein levels, as well as reduced Akt kinase activity. Similar to Raf-1, v-Src, and Her-2-neu, Bcr-Abl TK has chaperone association with heat shock protein 90 (Hsp90). By binding and inhibiting Hsp90, GA or 17-AAG treatment shifted the binding of Bcr-Abl from Hsp90 to Hsp70 and induced the proteasomal degradation of Bcr-Abl, because cotreatment with proteasome inhibitor PSC341 reduced both GA (or 17-AAG)-mediated down-regulation of Bcr-Abl levels and inhibited apoptosis of HL-60/Bcr-Abl and K562 cells. These data establish the in vitro activity of GA and 17-AAG against Bcr-Abl-positive leukemic cells and support the in vivo investigation of 17-AAG against Bcr-Abl-positive leukemias.


A comparison of the copper sensitivity of six invertebrate species in ambient salt water of varying dissolved organic matter concentrations.
The copper sensitivity of four saltwater invertebrates (the mussel Mytilus galloprovincialis, the oyster Crassostrea virginica, the sand dollar Dendraster excentricus, and the sea urchin Strongylocentrotus purpuratus) was determined experimentally using chronic-estimator embryo-larval test procedures. The effect of sample dissolved organic matter (DOM) content on Cu bioavailability was determined for these species using commonly prescribed test procedures. Comparisons were made among these test results and test results reported previously for two other invertebrate species: the mussel Mytilus edulis and the copepod Eurytemora affinis. All six species exhibited a direct and significant relationship between the sample dissolved organic carbon (DOC; a surrogate measure of DOM) and either the dissolved Cu median lethal concentration (LC50) values or median effect concentration (EC50) values. This relationship is significant even when the DOM has different quality as evidenced by molecular fluorescence spectroscopy. Once normalized for the effects of DOM, the Cu sensitivity of these species from least to most sensitive were E. affinis < D. excitricus < C. virginica approximately S. purpuratus approximately M. edulis approximately M. galloprovincialis. This ranking of species sensitivity differs from the saltwater species sensitivity distribution proposed in 2003 by the U.S. Environmental Protection Agency. These results support the need to account for factors that modify Cu bioavailability in future saltwater Cu criteria development efforts. More specifically, Cu saltwater species sensitivity distribution data will need to be normalized by factors affecting Cu bioavailability to assure that accurate and protective criteria are subsequently developed for saltwater species and their uses.


Salmonella persistence in soil depends on reciprocal interactions with indigenous microorganisms.
Fresh fruits and vegetables have numerous benefits to human health. Unfortunately, their consumption is increasingly associated with food-borne diseases, Salmonella enterica being their most frequent cause in Europe. Agricultural soils were postulated as reservoir of human pathogens, contributing to the contamination of crops during the growing period. Since the competition with the indigenous soil microbiota for colonization sites plays a major role in the success of invading species, we hypothesized that reduced diversity will enhance the chance of Salmonella to successfully establish in agricultural environments. We demonstrated that the abundance of Salmonella drastically decreased in soil with highly diverse indigenous prokaryotic community, while in soil with reduced prokaryotic diversity, Salmonella persisted for a long period. Furthermore, in communities with low diversity, Salmonella had an impact on the abundance of other taxa. The high physiological plasticity allows Salmonella to use agricultural soils as alternative habitat which might provide a route of animal/human infections. In addition, adjusted transcriptional profile with amino acid biosynthesis and the glyoxylate cycle most prominently regulated, suggests an adaptation to the soil environment. Our results underline the importance of the maintenance of diverse soil microbiome as a part of strategy aiming at reduced risk of food-borne salmonellosis outbreaks.


Single photon emission computed tomography and apolipoprotein E in Alzheimer's disease: impact of the epsilon4 allele on regional cerebral blood flow.
The aim of this study was to examine the impact of the apolipoprotein E (APOE) epsilon4 allele on semiquantitative regional cerebral blood flow (rCBF) in Alzheimer's disease. Single photon emission computed tomography technetium (SPECT) with (99m)Tc d,l-hexamethyl propylenamine oxine was used to determine rCBF in 41 consecutive patients (18 males/23 females) with probable Alzheimer's disease according to the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria (mean age 71.0 years; range 54-85). The mean Mini-Mental State Examination (MMSE) score was 20.4 (range 10-30). After normalization of CBF to mean blood flow in the cerebellum, values for rCBF in several cortical regions of interest, side-to-side asymmetry indices, and anterior-posterior ratios were calculated. Determination of the APOE genotype from blood samples was performed using restriction enzyme polymerase chain reaction technique. Multivariate regression analyses and the Wilcoxon rank-sum test for unpaired data (Mann-Whitney) were used for statistical analysis. The patients comprised 27APOE epsilon4-positive and 14APOE epsilon4-negative individuals. Five patients were APOE epsilon4 homozygotes. APOE epsilon4-positive patients had significantly reduced rCBF in the right frontal and left occipital lobes. On nonparametric analysis, the most prominent differences between epsilon4-negative and epsilon4-positive patients were demonstrated in subregions representing the frontal association cortex (Mann-Whitney, P < .01). Age-stratified analysis suggested that these findings could be demonstrated predominantly in the elderly patients. The results of this study suggest that the APOE genotype in itself may have an impact on the pattern of rCBF deficits in Alzheimer's disease. The more pronounced reduction of rCBF in frontal association cortex observed in elderly APOE epsilon4-positive patients might predict clinical progression.


Clinical features of sickle cell disease in eastern Saudi Arab children.
The clinical features of sickle cell disease (SCD) in Saudi Arab children of eastern origin are presented. One hundred and seventy-three children were diagnosed at birth and followed prospectively from 3 months to up to 4 years of age. There were 87 boys and 86 girls. Genotype distribution included 146 sickle cell anemia, 24 sickle beta +-thalassemia, two sickle beta 0-thalassemia, and one sickle hemoglobin C disease. Of our patients, 7% presented in the first 12 months of age and 27% remained asymptomatic at 4 years. Painful crises of bones and joints were the most common initial symptoms, followed by dactylitis, abdominal crises and acute splenic sequestration (ASS), occurring in 60%, 31.6%, 6.7%, and 1.7% of the patients, respectively. None of the patients presented with severe bacterial infections. During this study, 175 sickle cell crises were documented, but only 16 (9.1%) required hospital admissions. There were no deaths in this series. High hemoglobin F levels correlated with delayed clinical presentation and reduced number of crises. We conclude that SCD in children of eastern origin is clinically milder than earlier descriptions from the Eastern Province of Saudi Arabia.


Oocyte Retrieval in Asymptomatic Patients Positive for SARS-CoV-2.
To report two cases of oocyte retrieval performed in asymptomatic SARS-CoV-2-positive patients. Case report. Setting. Outpatient private practice infertility center. Patients. A 28-year-old woman at risk for OHSS who took her trigger injection prior to testing positive for SARS-CoV-2 and a 19-year-old oncofertility patient who tested positive prior to retrieval due to a family exposure. Both patients were asymptomatic. Main Outcome Measures. Cycle outcomes, patient safety, and staff safety. Both patients underwent successful oocyte retrieval procedures without developing symptoms or complications from COVID-19. No staff members that cared for these patients developed symptoms of COVID-19. Worsening fertility outcomes and potential for psychological and financial burdens to the patient must be balanced with risk of perioperative complications in patients testing positive for SARS-CoV-2. As we continue to provide fertility care in a world with COVID-19, appropriate risk mitigation strategies should be implemented to minimize exposure to SARS-CoV-2.


Lacto-N-fucopentaose-III (LNFPIII) ameliorates acute aberrations in hippocampal synaptic transmission in a Gulf War Illness animal model.
Approximately one-third of Persian Gulf War veterans are afflicted by Gulf War Illness (GWI), a chronic multisymptom condition that fundamentally presents with cognitive deficits (i.e., learning and memory impairments) and neuroimmune dysfunction (i.e., inflammation). Factors associated with GWI include overexposures to neurotoxic pesticides and nerve agent prophylactics such as permethrin (PM) and pyridostigmine bromide (PB), respectively. GWI-related neurological impairments associated with PB-PM overexposures have been recapitulated in animal models; however, there is a paucity of studies assessing PB-PM-related aberrations in hippocampal synaptic plasticity and transmission that may underlie behavioral impairments. Importantly, FDA-approved neuroactive treatments are currently unavailable for GWI. In the present study, we assessed the efficacy of an immunomodulatory therapeutic, lacto-N-fucopentaose-III (LNFPIII), on ameliorating acute effects of in vivo PB-PM exposure on synaptic plasticity and transmission as well as trophic factor/cytokine expression along the hippocampal dorsoventral axis. PB-PM exposure resulted in hippocampal synaptic transmission deficits 48 h post-exposure, a response that was ameliorated by LNFPIII coadministration, particularly in the dorsal hippocampus (dH). LNFPIII coadministration also enhanced synaptic transmission in the dH and the ventral hippocampus (vH). Notably, LNFPIII coadministration elevated long-term potentiation in the dH. Further, PB-PM exposure and LNFPIII coadministration uniquely altered key inflammatory cytokine and trophic factor production in the dH and the vH. Collectively, these findings demonstrate that PB-PM exposure impaired hippocampal synaptic responses 48 h post-exposure, impairments that differentially manifested along the dorsoventral axis. Importantly, LNFPIII ameliorated GWI-related electrophysiological deficits, a beneficial effect indicating the potential efficacy of LNFPIII for treating GWI.


Rapid engineering of versatile molecular logic gates using heterologous genetic transcriptional modules.
We designed and constructed versatile modular genetic logic gates in bacterial cells. These function as digital logic 1-input Buffer gate, 2-input and 3-input AND gates with one inverted input and integrate multiple chemical input signals in customised logic manners. Such rapidly engineered devices serve to achieve increased sensing signal selectivity.


Relationship between the tuberculin-type and Jones-Mote-type hypersensitivities: suppression of basophil infiltration by mycobacterial adjuvant.
Guinea-pigs immunized with bovine gammaglobulin (BGG) in incomplete Freund's adjuvant (IFA) showed the typical Jones-Mote-type hypersensitivity (JMH) reaction when tested 5 days later. This is characterized by prominent basophil infiltration. After pretreatment with complete Freund's adjuvant (CFA) 16 days before immunization with BGG in IFA, the lesions resembled the JMH reaction macroscopically in their evolution over time and in the absence of a positive macrophage migration inhibition (MIT) test. However, histologically, the lesions resembled classical tuberculin-type hypersensitivity with prominent mononuclear cell infiltration without any basophils. The pretreated animals, which failed to show basophil infiltration, were able to transfer JMH reactions with basophil infiltration into normal animals. In contrast, pretreatment of recipients with CFA or Corynebacterium parvum prevented the passive transfer of the characteristic effect on the JMH reaction when given shortly before skin testing. We postulate that macrophages activated by CFA may play an important role in regulating basophil infiltration in the effector phase of the delayed hypersensitivity reaction.


Applying Machine Learning to Workers' Compensation Data to Identify Industry-Specific Ergonomic and Safety Prevention Priorities: Ohio, 2001 to 2011.
This study leveraged a state workers' compensation claims database and machine learning techniques to target prevention efforts by injury causation and industry. Injury causation auto-coding methods were developed to code more than 1.2 million Ohio Bureau of Workers' Compensation claims for this study. Industry groups were ranked for soft-tissue musculoskeletal claims that may have been preventable with biomechanical ergonomic (ERGO) or slip/trip/fall (STF) interventions. On the basis of the average of claim count and rate ranks for more than 200 industry groups, Skilled Nursing Facilities (ERGO) and General Freight Trucking (STF) were the highest risk for lost-time claims (>7 days). This study created a third, major causation-specific U.S. occupational injury surveillance system. These findings are being used to focus prevention resources on specific occupational injury types in specific industry groups, especially in Ohio. Other state bureaus or insurers may use similar methods.


MIMICKING COUNTERFACTUAL OUTCOMES TO ESTIMATE CAUSAL EFFECTS.
In observational studies, treatment may be adapted to covariates at several times without a fixed protocol, in continuous time. Treatment influences covariates, which influence treatment, which influences covariates, and so on. Then even time-dependent Cox-models cannot be used to estimate the net treatment effect. Structural nested models have been applied in this setting. Structural nested models are based on counterfactuals: the outcome a person would have had had treatment been withheld after a certain time. Previous work on continuous-time structural nested models assumes that counterfactuals depend deterministically on observed data, while conjecturing that this assumption can be relaxed. This article proves that one can mimic counterfactuals by constructing random variables, solutions to a differential equation, that have the same distribution as the counterfactuals, even given past observed data. These "mimicking" variables can be used to estimate the parameters of structural nested models without assuming the treatment effect to be deterministic.


Affective startle modulation in clinical depression: preliminary findings.
Modulation of the startle reflex by affective foreground stimuli was investigated in a group receiving inpatient treatment for major depressive episodes (n = 14) and an age and gender matched nondepressed group (n = 14). Participants viewed 27 pleasant, neutral, and unpleasant pictures chosen from the International Affective Picture System. Acoustic startle probes were presented during picture viewing, and participants also rated the affective qualities of the pictures. While ratings of the pictures were largely similar between the depressed and nondepressed groups, they displayed dissimilar patterns of startle modulation. In the nondepressed group, blinks elicited during unpleasant pictures were significantly larger than during pleasant pictures, whereas the depressed group failed to show this effect. Analyses, which separated the depressed participants into moderate and severe groups based on Beck Depression Inventory scores, revealed that while the moderately depressed group also showed a normal pattern of startle modulation, the severely depressed showed potentiated startles during the pleasant pictures. These preliminary results suggest that severely depressed patients may respond to some pleasant stimuli as if they are aversive, possibly because such stimuli are seen as signals of frustrative nonreward.


Reinforcement learning models and their neural correlates: An activation likelihood estimation meta-analysis.
Reinforcement learning describes motivated behavior in terms of two abstract signals. The representation of discrepancies between expected and actual rewards/punishments-prediction error-is thought to update the expected value of actions and predictive stimuli. Electrophysiological and lesion studies have suggested that mesostriatal prediction error signals control behavior through synaptic modification of cortico-striato-thalamic networks. Signals in the ventromedial prefrontal and orbitofrontal cortex are implicated in representing expected value. To obtain unbiased maps of these representations in the human brain, we performed a meta-analysis of functional magnetic resonance imaging studies that had employed algorithmic reinforcement learning models across a variety of experimental paradigms. We found that the ventral striatum (medial and lateral) and midbrain/thalamus represented reward prediction errors, consistent with animal studies. Prediction error signals were also seen in the frontal operculum/insula, particularly for social rewards. In Pavlovian studies, striatal prediction error signals extended into the amygdala, whereas instrumental tasks engaged the caudate. Prediction error maps were sensitive to the model-fitting procedure (fixed or individually estimated) and to the extent of spatial smoothing. A correlate of expected value was found in a posterior region of the ventromedial prefrontal cortex, caudal and medial to the orbitofrontal regions identified in animal studies. These findings highlight a reproducible motif of reinforcement learning in the cortico-striatal loops and identify methodological dimensions that may influence the reproducibility of activation patterns across studies.


Review: Young people's recovery processes from mental health problems - a scoping review.
Recovery from mental illness and mental health problems is relatively well-researched among adults, but evidence that focuses on the recovery experiences of young people and what characterizes it is scarce. With this in mind, this article aims to map out the existing research in order to identify prevailing knowledge about the recovery of young people between the ages of 12 and 25. Drawing on scoping review methodology, this article is based on an analysis of 33 articles conducted in the USA, Australia, and Europe. Our findings reveal that young people express both similar and divergent lines of reasoning about recovery compared with adults. Our findings also indicate that young people often fluctuate in the way they view recovery, and that they thus tend to be ambivalent about what recovery means. Parents usually highlight the importance of professionals facilitating recovery, while care staff problematize the organizational frameworks available as aggravating circumstances for implementing personal recovery. Young people, parents, and care staff consistently describe recovery as a way to, despite lingering problems, enable a satisfying life. Through this review, we outline the need for a more distinct focus on agency and participation in young people's recovery processes, at the same time as family involvement needs to be further investigated and operationalized.


Admission after mild head injury: benefits and costs.
Large numbers of patients are admitted to hospital in Britain after mild head injury in the hope of anticipating complications. Investigation of 1442 consecutive admissions with head injury to the Edinburgh Royal Infirmary yielded 56 intracranial haematomas. Of 865 patients who were alert and orientated in the accident and emergency department after having been briefly knocked out but who had no skull fracture, no focal neurological signs, and no history of headache or vomiting, only one developed an intracranial haematoma. In deciding which patients should be admitted a skull fracture is a much more important risk factor than is a history of brief unconsciousness. If criteria for admission took account of this fewer patients would be admitted and the saving would be considerable.


Relatively stable population of c-myc RNA that lacks long poly(A).
We examined the turnover of c-myc RNA in the human promyelocytic cell line HL-60. In whole-cell RNA from rapidly growing cells we observed two major size classes of c-myc RNA, 2.4 and 2.2 kilobases (kb). When HL-60 cells were treated with actinomycin D for 30 min to inhibit transcription, the 2.4-kb c-myc RNA population was rapidly degraded, while the 2.2-kb c-myc RNA was degraded much more slowly. S1 nuclease transcript mapping and promoter-specific probes were utilized to show that both the stable 2.2-kb and the labile 2.4-kb c-myc RNA populations have 5' ends at the second promoter site (P2) and 3' ends at the second poly(A) addition site. To examine further possible structural differences between these two RNA populations, we fractionated RNA on an oligo(dT)-cellulose column to separate RNAs that contained long poly(A) tails from those which did not. We found that the labile 2.4-kb c-myc RNA population bound to oligo(dT)-cellulose, while the more stable 2.2-kb c-myc RNA population did not. Preliminary estimates of their half-lives (t1/2) showed that the poly(A)+ c-myc RNA had a t1/2 of 12 min, while the c-myc RNA that did not bind to oligo(dT)-cellulose had a t1/2 of greater than 1 h. Several other cell types contain both poly(A)+ and nonpoly(A)+ c-myc RNAs including HeLa cells, normal human bone marrow cells, and normal mouse fetal liver cells. In agreement with the results in HL-60 cell, HeLa cell poly(A)+ c-myc RNA was more labile than c-myc RNA that lacked poly(A). The stable, nonpoly(A)+ c-myc RNA population may be important in the posttranscriptional regulation of c-myc expression.


Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study.
Information on the psychosexual outcome of individuals with disorders of sex development (DSDs) and intersex conditions is of great importance for sex assignment at birth of newborns with DSD. To assess gender change and gender dysphoria in a large sample of individuals with different DSDs. A cross-sectional study was conducted in 14 European centers with 1,040 participants (717 female-identifying and 311 male-identifying persons and 12 persons identifying with another gender) with different forms of DSD. The cohort (mean age = 32.36 years, SD = 13.57) was divided into 6 major subgroups: women with 45,X DSD and variants (Turner syndrome; n = 325), men with 47,XXY DSD and variants (Klinefelter syndrome; n = 219), women with XY DSD without androgen effects (n = 107) and with androgen effects (n = 63), men with XY DSD (n = 87), and women with 46,XX congenital adrenal hyperplasia (n = 221). Data on psychosexual outcome were gathered by medical interviews and questionnaires. Gender change and gender dysphoria. Although gender changes were reported by 5% of participants, only in 1% (3% if those with Klinefelter and Turner syndromes-conditions in which gender issues are not prominent-are excluded) did the gender change take place after puberty and was likely initiated by the patient. 39 participants (4%) reported gender variance: between male and female, a gender other than male or female, or gender queer, alternating gender roles, or a gender expression that differed from the reported gender. This group had lower self-esteem and more anxiety and depression than the other participants. Clinicians should be aware of and sensitive to the possibility that their patients with DSD not only might have transgender feelings and a desire to change gender, but also identify as different from male or female. The complexity of their feelings might require counseling for some patients. The study is unique in the large number of participants from many different clinics, with sizable numbers in most subgroups, and in the large number of aspects that were measured. However, the very broadness of the study made it impossible to focus in detail on gender issues. Also, there is a need for instruments specifically measuring gender dysphoria in individuals with DSD that take non-binary genders into account. To make appropriate gender care possible for people with DSD, the gender-normative and gender-variant development of children with DSD should be studied in longitudinal studies. Kreukels BPC, Köhler B, Nordenström A, et al. Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study. J Sex Med 2018;15:777-785.


The Association Between Obstructive Sleep Apnea Characterized by a Minimum 3 Percent Oxygen Desaturation or Arousal Hypopnea Definition and Hypertension.
The association between obstructive sleep apnea (OSA) and hypertension in prior studies has been determined using a definition of hypopnea requiring a 4% O₂ desaturation. However, the American Academy of Sleep Medicine (AASM) recommends using a 3% O₂ desaturation or an arousal. This analysis assesses the relationship between OSA and hypertension utilizing the AASM recommended definition and the 2018 American College of Cardiology/American Heart Association hypertension guidelines. Data from 6113 participants from the Sleep Heart Health Study were analyzed. The AASM recommended apnea-hypopnea index (AHI) was classified into 4 categories of OSA severity: < 5, 5 to < 15, 15 to < 30 and ≥ 30 events/h. Three definitions of hypertension were used: elevated (> 120/< 80 or use of hypertension medications [meds]), stage 1/stage 2 (> 130/80 or meds), stage 2 (> 140/90 or meds). Data were analyzed using logistic regression controlling for demographics, smoking and body mass index. Multiple linear regression analysis assessed the relationship between natural log AHI, and systolic and diastolic blood pressure controlling for the same covariates. For all definitions of blood pressure elevation, increasing OSA severity was associated with greater likelihood of an elevated or hypertensive status in fully adjusted models (odds ratio [95% confidence interval]): elevated 1.30 (1.09-1.54), 1.39 (1.13-1.70) 1.69 (1.29-2.13); stage 1/2: 1.25 (1.06-1.47), 1.32 (1.10-1.59), 1.53 (1.23-1.91); stage 2: 1.07 (0.91-1.25), 1.21 (1.01-1.44), 1.37 (1.11-1.69) for AHI 5 to < 15, 15 to < 30 and > 30 events/h (< 5 events/h reference). Linear regression found that AHI was associated with both systolic and diastolic blood pressure in fully adjusted models. Use of the AASM recommended definition of hypopnea as a component of the AHI is associated with the presence of hypertension. Budhiraja R, Javaheri S, Parthasarathy S, Berry RB, Quan SF. The association between obstructive sleep apnea characterized by a minimum 3 percent oxygen desaturation or arousal hypopnea definition and hypertension. J Clin Sleep Med. 2019;15(9):1261-1270.


Forearm arterial venous shunt for hemodialysis.
A new technique for creation of an arterial venous shunt for hemodialysis is described. The proximal radial artery is used for the arterial inflow anastomosis site instead of the brachial artery. The technique provides an adequate arterial inflow but avoids all the complications of utilization of the brachial artery in the forearm arterial venous shunt for hemodialysis.


[Theory and practice in medical specialization. I. An instrument for measuring learning strategies].
We present the development and validation of a measurement instrument intended to estimate the degree of vinculation between the theoretical and practical learning activities of medical residents in their usual working conditions in hospitals. The main reason for residents to read medical literature is to find support to their decisions when treating patients. Based on this perspective we designed a self-applied questionnaire that explores diverse circumstances in which the vinculation between theory and practice may be expressed. This instrument was validated through rounds of experts in terms of its construction and content. Its external validity was explored with two groups of internal medicine residents with a different degree of vinculation between theory and practice: one high and the other with a low vinculation. In addition, we designed a guide for the direct observation of the theoretical and practical clinical learning activities in order to estimate its concordance with the results of the questionnaire. The questionnaire was able to discriminate the group differences and showed a satisfactory concordance with the information provided by direct observation. A copy of the questionnaire is available by request to the authors. We conclude that in its present stage of development, the instrument has shown internal and external validity and may be used to explore the process training of medical residents.


Dysregulation of Angiopoietin-like-4 Associated with Hyperlipidemia-induced Renal Injury by AMPK/ACC Pathway.
Angiopoietin-like protein 4 (Angptl4) is a glycoprotein that is involved in regulating lipid metabolism, which has been indicated as a link between hypertriglyceridemia and albuminuria in glomerulonephropathy. Deregulated lipid metabolism is increasingly recognized as an important risk factor of glomerulonephropathy. This study aimed to investigate the Angptl4 expression in renal tissue and podocyte under hyperlipidemia conditions and explore the potential molecular mechanisms. The role of Angptl4 in hyperlipidemia-induced glomerular disease and the detailed underlying mechanisms are unclear. This study sought new insights into this issue. We measured Angptl4 levels in the plasma and urine from patients with hyperlipidemia and healthy people. Rats were fed a high fat diet (HFD) to induce dyslipidemia model and the human podocytes were stimulated by palmitic acid as in vivo and in vitro experiments. The podocytes injury and the Angptl4 level in renal tissues were evaluated. Furthermore, the mechanism of Angptl4 on podocytes injury was investigated. The urinary Angptl4 level was gradually upregulated in both patients with hyperlipidaemia and high fat-diet-induced rats. HFD rats showed increased 24 h urinary protein and glomerular tuft area at week 12. The levels of nephrin and WT-1 were down-regulated, but the Angptl4 levels were markedly upregulated on the glomerular of rats on HFD. In the human podocytes, lipid accumulation accompanied by increases of Angptl4, but the expression of nephrin, WT-1, p-AMPKα and p-ACC was decreased after palmitic acid treatment. However, this injury effect was mediated by the aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR), activator of the low energy sensor AMPK/ACC signaling. This study was the first of its kind to show that podocyte damage induced by dyslipidemia could be associated with upregulated Angptl4 and that patients with hyperlipidemia might have relatively high urinary Angptl4 expression. The dysregulation of Angptl4 in the podocytes under hyperlipidemia is possibly carried out through AMPK/ACC signaling pathway.


Moroccan National Immunization Technical Advisory Group: a valuable asset for the national immunization program and the immunization agenda in the EMRO region.
The main mission of a National Immunization Technical Advisory Group (NITAG) is to provide impartial, evidence-based recommendations on immunization to the Ministry of Health. We report on the findings from an evaluation of the Moroccan NITAG with emphasis on its functionality, quality of work processes and outputs, and its integration into the immunization policy process. We conducted a cross-sectional study from October to December 2019. We used the standardized, US-CDC/WHO-developed "simplified assessment tool for national immunization technical advisory groups". The evaluation included eight participants. The evaluation has shown that it fully complies with the WHO recommendations. Among its strengths, the Moroccan NITAG has a solid legal basis, diverse expertise and many years of combined experience. This composition contributed to the credibility and strength of its recommendations and facilitated their implementation. The NITAG could, however, benefit from implementing written declarations of interests and standardized operating procedures in addition to establishing a standardized methodology to guide and document the decision-making process. The Moroccan NITAG could also gain from inviting members with public health/epidemiology research experience and from exchanging with other NITAGs in the region and globally. Finally, ensuring sustainable funding for the NITAG's activities will be crucial, so that it can continue its valuable support to the national immunization program.


Perceived support needs of family caregivers and implications for a telephone support service.
The purposes of this study were: to identify the perceived support needs of family caregivers of persons living with chronic illness (physical or cognitive) and receiving home-care services, and to describe the types of telephone services that would meet the expressed needs of caregivers. The qualitative design used semi-structured interviews. A total of 34 caregivers (mean age 62 years) participated in the study. The care recipients (mean age 78 years) were primarily the husband/wife or parent of the caregiver. The most commonly expressed caregiver needs were: a social life, instrumental support (e.g., respite, assistance with physical care, financial compensation), informational support, and emotional support. Most caregivers said they would use a telephone support service provided by a professional (71%) or a fellow caregiver (59%) if available. The results of this study support a pilot study and evaluation of a telephone support service for family caregivers.


Implementing a dietary intervention in primary care practice: a process evaluation.
Physicians acknowledge the need to advise their patients about dietary habits, but they may not have the training or tools to do this efficiently. In the context of a randomized trial, we investigated the feasibility of enlisting physicians to implement a dietary intervention in the primary care setting. Physicians from 14 primary care practices were assigned via randomization to introduce a self-help booklet to promote dietary change at routine appointments. Delivery of the booklet was recorded by these intervention physicians at the clinic appointment; intervention participants were asked 3 months later in a telephone interview about whether they received and used the booklet. According to physician documentation, 95% of intervention participants who kept an appointment (n = 935) received the booklet; among participants completing a 3-month interview (n = 890), 96% reported the same. However, only about 50% of participants reported receiving the booklet from their physician; the remainder received the booklet from other clinic staff. Overall, 93% reported reading at least part of the booklet. Use of the booklet varied little whether it was delivered by a physician or staff person, but it was more likely to be read as time spent discussing the booklet increased. Physician cooperation and evidence of intervention effectiveness support the use of primary care for the delivery of interventions to change diet; training the entire health team and repeating dietary advice at subsequent visits may improve the success of such interventions.


Gastric ulcer controlled trial using a licorice derivative rucedal.
A controlled trial of a licorice derivative, Rucedal, used in the management of gastric ulcer did not hasten the healing of the ulcer over eight weeks.


A randomized study on the effect of an extended voluntary waiting period in primiparous dairy cows on fertility, health and culling during first and second lactation.
When the voluntary waiting period (VWP), defined as the days between calving and when the cow is eligible to receive the first insemination, is extended, high-yielding dairy cows may have better opportunities to regain energy balance before first insemination. This study investigated the effect of an extended (145-215 DIM, n = 280) or conventional (25-95 DIM, n = 251) VWP treatment on fertility, disease incidence, and culling rate in cows during their first lactation. The cows were also followed through a second lactation without intervention regarding VWP, during which the farmers could decide when they wished to start the inseminations. This was done in a randomized-controlled study on 16 high-yielding commercial herds in southern Sweden containing a total of 531 primiparous cows of the Holstein (HOL) and Red Dairy Cattle (RDC) breeds. Data from the Swedish national dairy herd recording scheme (SNDRS) collected between August 2018 and September 2021 were used in the analysis, including records on breed, calvings, estrus intensity, inseminations, disease, somatic cell count (SCC), culling date, and culling reason. During first lactation, more cows receiving the extended VWP treatment showed strong estrus intensity (score 4-5, 55% vs. 48%), and fewer showed moderate estrus intensity (score 3, 35% vs. 43%), at first insemination, compared with cows receiving the conventional VWP treatment. First service conception rate (FSCR) was higher (67% vs. 51%) and number of inseminations per conception (NINS) was lower (1.6 vs. 2.0), during the first lactation, for cows receiving the extended compared with the conventional VWP treatment. For disease incidence rate or culling rate expressed as number of events per cow-time in the study, there were no differences between the cows receiving the 2 VWP treatments in any lactation. Calving to first service interval (CFI) during second lactation was longer (86 vs. 74 d) for cows with extended compared with conventional VWP. In conclusion, primiparous cows with extended VWP showed improved reproductive functions, in the form of higher estrus intensity, higher FSCR, and lower NINS, during the first lactation. However, there was no apparent effect on these fertility measures during the following lactation (without VWP intervention), and no differences in disease prevalence or culling between cows receiving the 2 VWP treatments in either lactation. Compliance with the planned VWP treatment was lower for cows with planned extended compared with planned conventional VWP treatment. We studied the "intention-to-treat" effect, i.e the results for all cows randomized to each treatment regardless of whether the planned VWP was achieved or not, to identify any bias arising due to degree of compliance. However, we found no difference in culling rate between cows randomized to an extended VWP compared with those randomized to a conventional VWP. These findings can be used to support management decisions on VWP length in high-yielding dairy herds.


Prox1 expression is negatively regulated by miR-181 in endothelial cells.
The specification of arterial, venous, and lymphatic endothelial cell fate is critical during vascular development. Although the homeobox transcription factor, Prox1, is crucial for the specification and maintenance of lymphatic endothelial cell identity, little is known regarding the mechanisms that regulate Prox1 expression. Here we demonstrate that miR-181a binds the 3' untranslated region of Prox1, resulting in translational inhibition and transcript degradation. Increased miR-181a activity in primary embryonic lymphatic endothelial cells resulted in substantially reduced levels of Prox1 mRNA and protein and reprogramming of lymphatic endothelial cells toward a blood vascular phenotype. Conversely, treatment of primary embryonic blood vascular endothelial cells with miR-181a antagomir resulted in increased Prox1 mRNA levels. miR-181a expression is significantly higher in embryonic blood vascular endothelial cells compared with lymphatic endothelial cells, suggesting that miR-181 activity could be an important mechanism by which Prox1 expression is silenced in the blood vasculature during development. Our work is the first example of a microRNA that targets Prox1 and has implications for the control of Prox1 expression during vascular development and neo-lymphangiogenesis.


[Structure, amount and composition of sulfuric, sulfonic and phosphoric esters of glycosyldiglycerides of three fucacea].
The mono and polyester glycosyl sulfates or phosphate diglycerides account for a group of polar lipids which is found in large amounts in the three fucacae that are studied: Pelvetia canaliculata (L) Deen and Thur, Fucus vesiculosus (L), Fucus serratus (L). These polar lipids have been shown to have complex structures, most of them are unknown in the present nomenclature. Both quantity and composition of these polar lipids are species characteristics, forming the equipment of polar lipids for every species of algae. Glycosyl ester sulfate and phosphate diglycerides are very unstable substances when pure, moreover photolabile and thremodegradable. This extreme fragility caused many difficulties in the determination of molecular structures which require a very high purity of isolated substances, The determination of the structures, studies of quantities and composition cytological localization of these polar lipids should allow to define clearly their physiological function and importance from the biochemical and ecological point of view.


Efficiency of DNA transfection of rat heart myoblast cells H9c2(2-1) by either polyethyleneimine or electroporation.
Expression of exogenous DNA in vitro is significantly affected by the particular transfection method utilized. In this study, we evaluated the efficiency of two transfection methods, chemically mediated polyethyleneimine (PEI) treatment and physically mediated electroporation, on a rat heart myoblast cell line, H9c2(2-1). After PEI transfection of pPgk-1/EGFP into H9c2(2-1) cells, EGFP expression could be easily detected by fluorospectrometer after 48 h (210 ± 12 RFU) and continued to increase after 72 h (243 ± 14 RFU). However, when H9c2(2-1) cells were transfected by electroporation (200 V, 500 μF, and one pulse), low level EGFP expression was observed after 48 h (49 ± 4 RFU) or 72 h (21 ± 14 RFU). In contrast, the easily transfectable control CHO-K1 cell line displayed a stronger EGFP expression than the H9c2(2-1) cells either by PEI or electroporation transfection. When transfection efficiencies were assayed by flow cytometry after 72 h, 13.6 ± 2.2% of PEI and 10.1 ± 1.5% of electroporation (250 V, 500 μF, and two pulses) transfected cells of H9c2(2-1) expressed EGFP, and PEI-transfected cells appeared to be less damaged (viability 93.6%) as compared to electroporation-transfected cells (39.5%). However, both PEI and electroporation (580 V, 50 Ω, and 50 μF) were effective for transfection of CHO-K1 with a higher efficiency, cell viability, and EGFP expression than H9c2(2-1). Our results indicate that the transfection efficiency of different methods varies among cell lines and that PEI is more efficient than electropolation for transfection of H9c2(2-1) whereas both PEI and electroporation are suitable for CHO-K1 transfection.


[Characteristics of various nerve tissue proteins using group-specific sorbents].
The use of micro-scale column chromatography and affinity immunoelectrophoresis with group-specific sorbents allows studying some physical and chemical properties of protein molecules. A comparison of properties of soluble and membrane brain amino-peptidases carried out by means of micro-scale phenyl-sepharose and ConA-sepharose column chromatography shows that the membrane-bound aminopeptidase is a glycoprotein which possesses a high capacity to hydrophobic interactions. Soluble forms of aminopeptidase do not interact with ConA or phenyl residues. The crossed affinity immunoelectrophoresis in the presence of phenyl-sepharose also shows the presence of hydrophobic domains on the surface of glial fibrillary acidic protein molecules. The both approaches may be useful to predict conditions for large-scale affinity chromatography methods of protein and enzyme purification.


Overexpression of neuronal RNA-binding protein HuD increases reward induced reinstatement of an instrumental response.
The neuronal RNA-binding protein HuD is involved in synaptic plasticity and the molecular mechanisms of learning and memory. Previously, we have shown that HuD is upregulated after both spatial and addiction-associated forms of learning, such as conditioned place preference. However, what role HuD plays in non-drug dependent learning and memory is not fully understood. In order to elucidate the role that HuD plays in non-drug appetitive behavior, we assessed mice over-expressing HuD (HuDOE) throughout the forebrain on the acquisition of an instrumental response for a non-sucrose food reward utilizing a touch-screen paradigm. Next, we examined whether HuD level would alter the extinction or reward-induced reinstatement of responding. We found that HuDOE acquired and extinguished the instrumental response at rates similar to control littermates with no significant alterations in secondary measures of motor behavior or motivation. However, HuDOE reinstated their responding for food reward at rates significantly higher than control animals after a brief presentation of reward. These results suggest that HuD positively regulates the reinstatement of natural reward seeking and supports the role of HuD in forms of learning and memory associated with seeking of appetitive rewards.


Risk of recurrent venous thromboembolism in COPD patients: results from a prospective cohort study.
We aimed to assess the risk of recurrent venous thromboembolism (VTE) in patients with chronic obstructive pulmonary disease (COPD) following cessation of anticoagulation therapy.In a prospective cohort of 1468 patients with a documented episode of VTE, followed for up to 5 years after cessation of anticoagulation therapy, the diagnosis of COPD was confirmed in 136. The main outcome was recurrent VTE. The secondary outcome was overall mortality. Univariate and multivariate analyses were performed to identify the risk factors of recurrence.Of the 1468 patients included, recurrent VTE was observed in 306 (34 with COPD and 272 without) during a median follow-up period of 36.5 months. The incidence rate of recurrent VTE was 9.1% (95% CI 6.5-12.8) for COPD patients and 7.0% (95% CI 6.2-7.9) for non-COPD patients. COPD was not associated with an increased risk of VTE recurrence on univariate or multivariate analyses (hazard ratio: 1.0 (95% CI 0.7-1.4)). The risk of death, adjusted for demographic and clinical characteristics, showed no increase in COPD patients, as compared to non-COPD patients.In patients with COPD who had an acute episode of VTE, the risk of recurrent VTE was not any higher than that in non-COPD patients.


Multiscale research on spatial supply-demand mismatches and synergic strategies of multifunctional cultivated land.
Multifunctional cultivated land has both sides of supply and demand, and their matches are very important to boost the high-quality development of agriculture and rural areas. The supply-demand match index and GIS spatial analysis were employed to explore the supply-demand mismatches and synergic strategies of multifunctional cultivated land. Taking the Wuhan Metropolitan Area (WMA), China as an example, we obtained the following results: (1) There were obvious supply-demand mismatches of multifunctional cultivated land in the production function, ecological function, and landscape culture function. The spatial distribution of supply-demand mismatches of the three different functions of cultivated land is different. The supply of cultivated land production function is less than the demand, while the supply of landscape culture function is greater than the demand. The supply matches the demand of cultivated land in the ecological function. (2) The supply-demand mismatches of multifunctional cultivated land have scale effects. From the 1 km × 1 km grid scale to the township, county (district), and prefecture-level city scales, the proportion of deficit regions of production function and ecological function decreases with increasing scale. In contrast, the deficit regions of landscape culture function are always concentrated in the center of the WMA. It is considered that we should improve the supply of cultivated land in the production function, protect ecological function and enhance the demand of landscape culture function. Moreover, the management of multifunctional cultivated land needs to strengthen the multiscale spatial linkage and differential strategies of the supply side and demand side.


Risk assessment for pyrrolizidine alkaloids detected in (herbal) teas and plant food supplements.
Pyrrolizidine alkaloids (PAs) are plant metabolites present in some botanical preparations, with especially 1,2-unsaturated PAs being of concern because they are genotoxic carcinogens. This study presents an overview of tumour data on PAs and points of departure (PODs) derived from them, corroborating that the BMDL10 for lasiocarpine represents a conservative POD for risk assessment. A risk assessment using this BMDL10 and mean levels of PAs reported in literature for (herbal) teas, indicates that consumption of one cup of tea a day would result in MOE values lower than 10 000 for several types of (herbal) teas, indicating a priority for risk management for these products A refined risk assessment using interim relative potency (REP) factors showed that based on the mean PA levels, 7(54%) of 13 types of (herbal) teas and 1 (14%) of 7 types of plant food supplements (PFS) resulted in MOE values lower than 10 000, indicating a priority for risk management also for these products in particular. This includes both preparations containing PA-producing and non-PA-producing plants. Our study provides insight in the current state-of-the art and limitations in the risk assessment of PA-containing food products, especially (herbal) teas and PFS, indicating that PAs in food presents a field of interest for current and future risk management.


A randomised controlled trial to evaluate and optimize the use of antiplatelet agents in the perioperative management in patients undergoing general and abdominal surgery--the APAP trial (ISRCTN45810007).
Due to the increase of cardiovascular diseases acetylsalicylic acid (ASA) has become one of the most frequently prescribed drugs these days. Despite the rising number of patients with ASA medication presenting for elective general and abdominal surgery and the potentially increased risk of hemorrhage in these patients, there are no clear, evidence-based guidelines for the perioperative use of antiplatelet agents. The present randomised controlled trial was designed to evaluate the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. This is a two-arm, monocenter randomised controlled trial. Patients scheduled for elective surgical treatment (i.e. inguinal hernia repair, cholecystectomy and colorectal resections) with ASA as a permanent medication are randomised equally to perioperative continuation or discontinuation of ASA. Patients who are randomised in the discontinuation group stop the administration of ASA five days prior to surgical treatment and start intake of ASA on postoperative day 5. Fifty-two patients will be enrolled in this trial. The primary outcome is the incidence of postoperative bleeding and cardiovascular events at 30 days after surgery. In addition a set of general as well as surgical variables are analysed. This is a randomised controlled two-group parallel trial designed to assess the safety and optimize the use of ASA in the perioperative management of patients undergoing general and abdominal surgery. The results of this pilot study build the basis for a confirmative randomised controlled trial that may help to clarify the use and potential risk/benefits of perioperative ASA medication in patients undergoing elective surgery. The trial is registered with Current Controlled Trials ISRCTN45810007.


Primary Transitional Cell Carcinoma of the Conjunctiva.
A 77-year-old male presented with a large papillomatous conjunctival lesion on his lower eyelid. Biopsy and extensive systemic investigation revealed this to be a primary conjunctival transitional cell carcinoma. Patient preference and coexisting medical problems dictated conservative management with surgical debulking, topical mitomicin, and radiotherapy. Local control has been maintained for 4 years to date.


Induction of c-Jun immunoreactivity in spinal cord and brainstem neurons in a transgenic mouse model for amyotrophic lateral sclerosis.
Transgenic mice carrying amyotrophic lateral sclerosis (ALS)-linked superoxide dismutase 1 (SOD1) mutations develop a motoneuron disease resembling human ALS. c-Jun is a transcription factor frequently induced in injured neurons. In this study we have examined the distribution of c-Jun-immunoreactivity in the brainstem and spinal cord of transgenic SOD1 mice with a glycine 93 alanine (G93A) mutation. In non-transgenic littermates c-Jun immunostaining was predominantly situated in motoneurons. The number of c-Jun immunoreactive motoneuron was reduced in SOD1(G93A) mice due to pronounced loss of motoneurons. In SOD1(G93A) mice, however, c-Jun-immunoreactivity was strongly induced in neurons in the intermediate zone (Rexed's laminae V-VIII and X) of the spinal cord and throughout the brainstem reticular formation. These findings are of interest since increased levels of c-jun also have been found in the intermediate zone of the spinal cord of ALS patients. This c-Jun may be involved in the neurodegenerative processes both in ALS and in motoneuron disease in SOD1(G93A) mice.


SCHOOL-RELATED OUTCOMES FROM A RANDOMIZED CONTROLLED TRIAL OF ADOLESCENT DEPRESSION PREVENTION PROGRAMS.
Previous research has demonstrated the effectiveness of school-based depression prevention programs in reducing depressive symptoms and improving functioning. This study examined whether these programs have positive effects on school-related outcomes. Students at 10 middle and high schools in New Jersey were randomized to weekly sessions of Interpersonal Psychotherapy - Adolescent Skills Training (IPT-AST) or group counseling (GC). Analyses examined whether there were intervention effects on participants' grades, attendance rates, and disciplinary outcomes over approximately one year post-intervention. Although there were no significant main effects of intervention condition, moderation analyses indicated more favorable effects of IPT-AST among certain higher-risk subgroups (e.g., those from low-income families). Participants who experienced meaningful improvement in their depressive symptoms had significantly more positive outcomes on overall grades than those who did not experience meaningful improvement, regardless of intervention condition. Further research is needed to clarify the effects of depression prevention programs on these school-related outcomes.