Cause and circumstance of in-hospital mortality among patients undergoing contemporary percutaneous coronary intervention: a root-cause analysis.
Prior studies suggest that most deaths in patients undergoing percutaneous coronary intervention (PCI) are related to procedural complications. Mortality associated with PCI has steadily declined during the past decade, and the cause and circumstance of death among patients undergoing PCI in the contemporary era remain unknown. We evaluated all patients undergoing PCI at the University of Michigan from 2001 to 2009. There were 85 deaths among a total of 5520 patients undergoing PCI during this time period. By using a standardized data collection form, 3 cardiologists (2 interventional, H.S.G. and D.S.M.; 1 noninvasive, A.M.B.) determined the cause and circumstance of death, in addition to grading the preventability of death. Left ventricular failure was the most common cause of death (35.3%, n=30), followed by neurological compromise (16.5%, n=14) and arrhythmia (12.1%, n=12). The circumstance of death was mostly acute cardiac (52.9%, n=45), with a procedural complication composing a small fraction (7.1%, n=6). Reviewers determined 93% of deaths to be mostly or entirely unpreventable. Procedural complications are responsible for a small fraction of deaths among patients undergoing contemporary PCI. Measures to further enhance procedural safety are unlikely to translate into meaningful reductions in PCI mortality.


Mind-body practices for cancer-related symptoms management: an overview of systematic reviews including one hundred twenty-nine meta-analyses.
Mind-body practices such as qigong, tai chi, or yoga combine physical movements, deep breathing, and meditation techniques aiming to improve how people self-care. Our purpose was to develop an overview of systematic reviews to summarize the available evidence on the effectiveness of mind-body practices for cancer-related symptoms management. CINAHL, Embase, PsycINFO, PubMed, and the Cochrane Library were used to search systematic reviews with meta-analysis from inception until March 2022. Cancer-related symptoms such as fatigue, pain, psychological measures, and overall quality of life were chosen as outcomes of interest. The methodological quality of each systematic review was assessed using AMSTAR 2. Citation matrices were developed, and the corrected covered area was calculated to explore the potential primary study overlap. A total of 38 systematic reviews comprising 134 distinct primary studies and 129 separate meta-analyses were included. The items of AMSTAR 2 regarding the review protocol, the reasons to choose a specific research design, and the provision of a list of studies that justify their exclusion were scarcely performed. The primary study overlap was moderate for qigong trials and high for both tai chi and yoga trials. Mainly, we found that qigong showed promising effects to reduce fatigue. Tai chi produced positive effects in reducing anxiety. Yoga improved anxiety, depression, distress, stress, and overall quality of life. Finally, the effects of mind-body practices on pain were inconsistent. Qigong, tai chi, and yoga could be effective approaches to relief cancer-related symptoms in adults with different cancer diagnoses.


Glycosylated Chromogranin A: Potential Role in the Pathogenesis of Heart Failure.
Endocrine and paracrine factors influence the cardiovascular system and the heart by a number of different mechanisms. The chromogranin-secretogranin (granin) proteins seem to represent a new family of proteins that exerts both direct and indirect effects on cardiac and vascular functions. The granin proteins are produced in multiple tissues, including cardiac cells, and circulating granin protein concentrations provide incremental prognostic information to established risk indices in patients with myocardial dysfunction. In this review, we provide recent data for the granin proteins in relation with cardiovascular disease, and with a special focus on chromogranin A and heart failure. Chromogranin A is the most studied member of the granin protein family, and shorter, functionally active peptide fragments of chromogranin A exert protective effects on myocardial cell death, ischemia-reperfusion injury, and cardiomyocyte Ca2+ handling. Granin peptides have also been found to induce angiogenesis and vasculogenesis. Protein glycosylation is an important post-translational regulatory mechanism, and we recently found chromogranin A molecules to be hyperglycosylated in the failing myocardium. Chromogranin A hyperglycosylation impaired processing of full-length chromogranin A molecules into physiologically active chromogranin A peptides, and patients with acute heart failure and low rate of chromogranin A processing had increased mortality compared to other acute heart failure patients. Other studies have also demonstrated that circulating granin protein concentrations increase in parallel with heart failure disease stage. The granin protein family seems to influence heart failure pathophysiology, and chromogranin A hyperglycosylation could directly be implicated in heart failure disease progression.


The role of the ventrolateral nucleus of the thalamus in the switching of descending influences to motor activity in the rat.
Studies on rats showed that the facilitating influence of preliminary transection of the rubrospinal tract on recovery of motor activity and operant reflexes disrupted by lesioning of the red nucleus was more apparent when lesioning was chemical than when lesioning was electrolytic. This is due to the survival of cerebellothalamic fibers to the ventrolateral nucleus of the thalamus after chemical lesioning of the red nucleus with quinolinic acid. It was also shown that preliminary lesioning of the ventrolateral thalamic nucleus strongly hindered the switching of motor activity under the control of the corticospinal tract in rats subjected to section of the rubrospinal tract and lesioning of the red nucleus.


Elevated choline in dorsolateral prefrontal cortex of lithium responders with bipolar I disorder.
Response to lithium maintenance varies widely across patients with bipolar disorder (BD). The studies on neurochemical correlates of long-term lithium response in BD remain scant. To assess the neurochemical profile in DLPFC based on lithium response status among subjects with bipolar I disorder (BD-I) using in vivo MRS. This was an observational study of 40 right-handed, euthymic adult participants with DSM-5 BD-I on long-term lithium maintenance with no psychiatric comorbidities (MINI 7.0). Using Alda Lithium Response Scale (LRS), a cut-off ≥ 7 for excellent lithium response, the sample was grouped into study group I for responders and group II for non-responders. All participants were assessed using NIMH Life Chart Method and IGSLI typical/atypical features scale. 1H-MRS was carried out on a 3 T MR scanner (Achieva, Phillips) using a 32-channel head coil, with a voxel placed at the left DLPFC. LC model was used to measure absolute concentrations of neurochemicals and their ratios in relation to creatine. Group I (n = 20) was comparable to Group II (n = 20) with respect to demographic and illness profile. The GPC/Cr+PCr ratio was significantly higher (p = 0.028) among excellent lithium responders (0.32 ± 0.20 mmol/l) compared to sub-optimal responders (0.25 ± 0.05 mmol/l). Choline-containing compounds reflect alterations in cell membrane synthesis or myelin turnover, and are a marker of overall cell density. No significant alterations were detected in NAA, glutamate, glutamine, myo-inositol and creatine. The lithium responders exhibited elevated choline (GPC) in the left DLPFC compared to non-responders.


COX-2 inhibition attenuates endotoxin-induced downregulation of organic anion transporters in the rat renal cortex.
Renal excretion of organic anions such as para-aminohippurate is reduced during severe sepsis and following ischemia/reperfusion injury. In order to better define the pathophysiology of sepsis-associated renal tubular dysfunction we measured the effect of lipopolysaccharide on renocortical organic anion transporter (OAT) expression in the rat. Prostaglandin E2 (PGE2) downregulates OATs in vitro, therefore, we also evaluated the effect of the cyclooxygenase (COX)-2 inhibitor parecoxib on this process. Endotoxemia caused a time- and dose-dependent decrease of OAT1 and OAT3 expression that paralleled increased renocortical COX-2 expression and PGE2 formation. Pretreatment with parecoxib decreased endotoxin-stimulated PGE(2) formation. Parecoxib attenuated OAT1 and OAT3 gene repression in the rat kidney following endotoxin treatment and during ischemia/reperfusion-induced acute renal injury. COX-2 inhibition improved the creatinine clearance in lipopolysaccharide-treated rats but not after ischemia/reperfusion-induced acute renal injury. The decreased clearance of para-aminohippurate in rats following endotoxin- or ischemia/reperfusion-induced renal injury was improved by parecoxib. Our findings show that COX-2 derived prostanoids downregulate OATs during lipopolysaccharide-induced acute renal injury.


Somatic activating BRAF variants cause isolated lymphatic malformations.
Somatic activating variants in PIK3CA, the gene that encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been previously detected in ∼80% of lymphatic malformations (LMs).1 , 2 We report the presence of somatic activating variants in BRAF in individuals with LMs that do not possess pathogenic PIK3CA variants. The BRAF substitution p.Val600Glu (c.1799T>A), one of the most common driver mutations in cancer, was detected in multiple individuals with LMs. Histology revealed abnormal lymphatic channels with immunopositivity for BRAFV600E in endothelial cells that was otherwise indistinguishable from PIK3CA-positive LM. The finding that BRAF variants contribute to low-flow LMs increases the complexity of prior models associating low-flow vascular malformations (LM and venous malformations) with mutations in the PI3K-AKT-MTOR and high-flow vascular malformations (arteriovenous malformations) with mutations in the RAS-mitogen-activated protein kinase (MAPK) pathway.3 In addition, this work highlights the importance of genetic diagnosis prior to initiating medical therapy as more studies examine therapeutics for individuals with vascular malformations.


O-RADS US: A Systematic Review and Meta-Analysis of Category-specific Malignancy Rates.
Background Ovarian-Adnexal Reporting and Data System (O-RADS) US provides a standardized method with which to stratify lesions into risk of malignancy categories, which is crucial for proper management. Purpose To perform a systematic review and meta-analysis to estimate malignancy rates for each O-RADS US score and evaluate the diagnostic performance of combined O-RADS US scores 4 and 5 in the diagnosis of malignancy. Materials and Methods A systematic literature search from the inception of the MEDLINE, EMBASE, and Web of Science databases through January 27, 2023, was performed for articles that reported using the O-RADS US stratification system and included malignancy rates per each O-RADS score. Bivariate random-effects models were used to determine the pooled malignancy rates for each O-RADS US score and to obtain summary estimates of the diagnostic performance of combined O-RADS US scores 4 and 5 in the diagnosis of malignant lesions. Results The final analysis included 18 studies consisting of 11 605 patients and 11 818 ovarian-adnexal lesions, with 2996 malignant (25.4%) and 8822 benign (74.6%) lesions. No malignant lesions were reported in O-RADS 1 category. The pooled percentages of malignancy were 0.6% (95% CI: 0.3, 1.0) for O-RADS 2, 3.9% (95% CI: 2.5, 5.4) for O-RADS 3, 43.5% (95% CI: 33.8, 53.2) for O-RADS 4, and 87.3% (95% CI: 83.0, 91.7) for O-RADS 5. The pooled sensitivity and specificity of combined O-RADS scores 4 and 5 in the diagnosis of malignant lesions were 95.6% (95% CI: 94.0, 97.2) and 76.6% (95% CI: 70.4, 82.7), respectively. Conclusion Each O-RADS US score provided the intended probability of malignant lesions as outlined by the O-RADS risk stratification system. When O-RADS US scores 4 and 5 were combined as a predictor for malignancy, O-RADS US showed a high sensitivity and moderate specificity. Clinical trial registration no. CRD42022352166 © RSNA, 2023 Supplemental material is available for this article.


Imaging Vascular Disorders of the Liver.
The liver's unique blood supply facilitates multiple important physiologic roles. Liver vascular disorders have distinct appearances on imaging examinations and may mimic other pathologies. This article reviews the imaging appearances of vascular disorders from a multimodality perspective. Liver vascular pathologies are categorized by how they affect liver inflow, liver outflow, and those with abnormal arterial-venous connections. By understanding the physiologic and pathologic underpinnings of the hepatic vasculature, the radiologist is well positioned to positively affect patient care.


Alterations in the brain monoaminergic neurotransmitters of rainbow trout related to naphthalene exposure at the beginning of vitellogenesis.
The contents of dopamine (DA), noradrenaline (NA), serotonin (5HT), and some related metabolites were studied in different brain regions of rainbow trout at two different stages of sexual maturation (at the beginning of vitellogenesis), after naphthalene (NAP) administration. The effects of NAP varied according to duration of exposure, brain region and vitellogenesis stage of the trout, and were more significant during previtellogenesis. The changes observed in DA metabolism were generally stimulatory after exposure for 3 h, and either stimulatory or inhibitory (depending on the brain regions) after exposure for 3 days to NAP. NA levels were altered by NAP in various brain regions, but only during previtellogenesis. With respect to 5HT, treatment with NAP reduced levels of the amine and/or its main metabolite in most of the brain regions studied, particularly 3 h after treatment. The results suggest that NAP might interfere with the processes regulating brain monoamine metabolism, either locally or indirectly by altering steroid feedback to brain centres, and thus disrupt endocrine control of reproductive development through the brain-pituitary axis.


Misclassification of colorectal cancer stage and area variation in survival.
We previously investigated the impact of health area of residence on colon and rectal cancer survival by estimating area-specific relative excess risk of death (RER), stratified by stage at diagnosis. The aims of this study were to quantify errors in colorectal cancer stage obtained from an Australian population-based cancer registry and assess the potential impact of errors in stage on these estimates. For a subset of cases, we compared the cancer registry stage with that from a survey of treating surgeons. We then randomly reallocated all cases to a simulated "corrected" stage according to the estimated misclassification probabilities and repeated the analysis of area variation stratified by simulated stage 1,000 times. We found 70% agreement between the Registry and Survey stage. This reallocation of the Registry cases by stage resulted in substantial variation in area-specific RERs across the simulated samples. Area variation in survival for localized colon and localized rectal cancer, which were previously statistically significant when classified using Registry stage, appeared no longer to be so. Misclassification of cancer registry stage can have an important impact on estimates of spatial variation in stage-specific colon and rectal cancer survival. If population-based cancer registry data are to be effectively used in evaluating and improving cancer care, the quality of the stage data may need to be improved.


Quantification of ovarian stromal Doppler signals in poor responders undergoing in vitro fertilization with three-dimensional power Doppler ultrasonography.
This was a prospective comparative clinical study to test the hypothesis that the decreased ovarian sensitivity to gonadotropins observed in women embarking on an in vitro fertilization (IVF) treatment may be due to changes in ovarian stromal blood flow. Three-dimensional (3D) power Doppler ultrasonographic indexes were used to quantify ovarian stromal blood flow and vascularization in poor responders. Forty patients undergoing an IVF cycle were collected and divided into two groups, a poor responder group (n=17) (estradiol <600 pg/mL or < or =3 oocytes retrieved) and normal responder group (n=23), based on their response to a standard down-regulation protocol for controlled ovarian stimulation. During ovarian stimulation, on the day of administration of human chorionic gonadotropin (HCG), patients underwent hormonal (serum E2), ultrasonographic (follicular number and diameter), and 3D power Doppler (ovarian stromal blood flow) evaluation. Compared with poor responders, the serum estradiol levels on the day of administration of HCG, the number of follicles more than 14 mm, the number of oocytes retrieved, the number of embryos transferred, and the pregnancy rate were significantly higher in normal responders. The Vascularization Index, Flow Index, and Vascularization Flow Index were significantly lower (P<.05) in the poor responder (0.13+/-0.11, 30.89+/-10.35, and 0.05+/-0.04, respectively) compared with the women with a normal response (1.20+/-1.10, 43.88+/-7.77, and 0.61+/-0.57, respectively). The 3D power Doppler indexes of ovarian stromal blood flow in poor responders was significantly lower than normoresponders. This may help to explain the poor response during HCG administration in controlled ovarian stimulation.


Comparing postoperative outcomes using electrocautery versus cold-knife de-epithelialization of dermal fat graft in parotidectomy reconstruction.
The present study was developed to evaluate the effectiveness of a simple rapid technique for de-epithelializing cutaneous flaps and grafts in parotidectomy reconstruction. 109 patients who underwent a parotidectomy with abdominal free dermal fat graft (FDFG) reconstruction between 2018 and 2021 were evaluated based on demographic factors, past medical/surgical history, type of parotidectomy performed, operative factors, and post-operative complications. These data were then stratified based on de-epithelialization technique as well as tumor malignancy status to determine any differences in complication rates or perioperative factors between electrocautery (EC) and cold knife (CK) techniques within both benign and malignant subgroups. 77 of the 109 participants underwent FDFG de-epithelialization using monopolar electrocautery (EC) and the remaining 32 participants underwent de-epithelialization using traditional cold knife (CK) technique. There was no statistical difference among the two groups in overall complication rate. The EC group had a significantly shorter operation time ("EC vs. CK": 144.2 min vs. 174.7 min; p = 0.031). Additionally, histopathologic samples showed that both techniques left the underlying dermis intact and without damage. This study demonstrated that there is no difference in complication rate or histology of FDFGs de-epithelialized using EC compared to CK. It was also shown that when controlling for confounders by looking solely at the benign subgroup of patients, EC de-epithelialization was a faster technique than CK. These findings suggest that EC is just as effective as CK, and may actually be a more efficient surgical technique to accomplish de-epithelialization of FDFG.


In situ expression of T-helper type 2 immunoregulatory response in myofibroblast of a pediatric bladder inflammatory pseudotumor.
Inflammatory pseudotumor (IP) is generally considered to be a non-neoplastic, inflammatory response despite its gross and microscopic features of spindle cell neoplasm. Reported herein is a case arising from the muscularis propria of the urinary bladder in a 14-year-old girl who presented with gross hematuria and impending hypovolemic shock. The tumor consisted of proliferating myofibroblastic cells and various types of inflammatory cells. The immunoregulatory responses and reactions were investigated with regard to infiltration of inflammatory mononuclear cells being a documented finding in IP. Immunhistochemical and in situ hybridization studies for cytokines showed that the myofibroblastic cells were positive for interleukin (IL)-4, IL-5 and negative for interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha expression. The patient has been free of disease since excision of the tumor 34 months ago. Thus, cytokine production in IP suggests that it is reactive in nature and myofibroblasts may be the source of cytokines in the pathogenic process.


A reusable AuNPS with increased stability applied for fast screening of trace heavy metals in edible and medicinal marine products.
Heavy metal pollution in marine environment poses a severe threat to the safety of marine products and is thus causing increasingly concerns in terms of their toxicity and potential health risks pose to human. Due to the complex matrix of marine products, a fast screening method for heavy metals at trace level with low price, reusability, high accuracy and long lifetime is of urgency and necessity for consumers and processing factories. This work described a simplified screening system through the preparation, characterization and particular application of Au nano particle sensor (AuNPS) in the complex marine matrix, the main aim is to significantly increase the stability, sensitivity and lifetime of detection system dedicated to Cu and Hg trace analysis in marine products. It is worth mentioning that, the proposed screening system was characterized through electrochemical experiments and theoretical calculations, which could be a new evidence for selecting the detection system in commercially complex samples. Importantly, the discipline of deposition and oxidative stripping process on AuNPS was explained based on the mechanism of Metal Ion Deficient Layer (MIDL), and illustrated with SEM changes during stripping process, as well as the dissolving-out rate of metals on AuNPS material. Moreover, to further improve the reusability and stability of AuNPS sensor, the complex marine matrix was purified by pre-plating interferences on indium tin oxide glass electrode. The screening system exhibited a liner response in the range of 0.02-0.10 μg mL-1 for Hg, 0.01-0.10 μg mL-1 and 0.001-0.01 μg mL-1 for Cu with the detection limits of 0.138 mg kg-1 and 1.51 mg kg-1 in marine matrix, respectively. The sensitivity and lifetime was at least two times better as compared to similar works even after 20-times use. Finally, this proposed analysis system combined with purification procedure was successfully applied for the edible and medicinal marine products analysis, meanwhile, the accuracy and stability were confirmed with standard analytical methods.


A novel strategy to investigate the factors regulating the Treg to Tfr transition during acute viral infection.
Follicular regulatory T cells (Tfrs), a specialized subset of regulatory T cells (Tregs), have a particular role in the control of follicular helper T cell-driven germinal center (GC) responses. Following differentiation signals similar to those received by follicular helper T cells (Tfhs), Tfrs gain expression of characteristic chemokine receptors and transcription factors, such as CXCR5 and Bcl-6, allowing them to migrate into the B-cell follicle and perform in situ suppression. Thus, together with Tfhs, Tfrs help maintaining an optimized GC-reaction. However, the mechanism underlying the Treg-to-Tfr transition remains obscure. Here, we established a highly reproducible protocol for investigating the differentiation of Tregs into Tfrs by constructing spleen-chimeric mice combined with retrovirus transduction. We demonstrated that using this strategy, over 4 folds of Tregs could differentiate into Tfrs in Bcl-6 overexpression group compared to control counterparts (Migr1), and Bcl-6 could efficiently promote Tfr differentiation during acute viral infection. Hence, this method provides us an easy access to investigate the factors that regulate the differentiation program that converts Tregs into Tfrs, which will enhance our understanding of the networks regulating GC-reaction and shed new light on the molecular basis of immune homeostasis.


Pseudocyphellaria dissimilis: a desiccation-sensitive, highly shade-adapted lichen from New Zealand.
Pseudocyphellaria dissimilis, a foliose, cyanobacterial lichen, is shown not to fit into the normal ecological concept of lichens. This species is both extremely shade-tolerant and also more intolerant to drying than aquatic lichens previously thought to be the most desiccation-sensitive of lichens. Samples of P. dissimilis from a humid rain-forest site in New Zealand were transported in a moist state to Germany. Photosynthesis response curves were generated. The effect of desiccation was measured by comparing CO2 exchange before and after a standard 20-h drying routine. Lichen thalli could be equilibrated at 15° C to relative humidities (RH) from 5% to almost 100%. Photosynthesis was saturated at a photosynthetically active radiation (PAR) level of 20 μmol m-2 s-1 (350 μbar CO2) and PAR compensation was a very low 1 μmol m-2 s-1. Photosynthesis did not saturate until 1500 μbar CO2. Net photosynthesis was relatively unaffected by temperature between 10° C and 30° C with upper compensation at over 40° C. Temporary depression of photosynthesis occurred after a drying period of 20 h with equilibration at 45-65% relative humidity (RH). Sustained damage occurred at 15-25% RH and many samples died after equilibration at 5-16% RH. Microclimate studies of the lichen habitat below the evergreen, broadleaf forest canopy revealed consistently low PAR (normally below 10-20 μmol m-2 s-1) and high humidities (over 80% RH even during the day time). The species shows many features of an extremely deep shade-adapted plant including low PAR saturation and compensation, low photosynthetic and respiratory rates and low dry weight per unit area.


Enzyme induction in cultured human hair follicle cells.
The enzyme aryl hydrocarbon hydroxylase is present in murine and human cultures of keratinocytes. While the activity of aryl hydrocarbon hydroxylase in murine cultures was found to be inducible after exposure to benz(a)anthracene, human keratinocytes originating from the hair follicle did not respond to this treatment. Hence, cultured human keratinocytes are not suitable for studying the molecular events that mediate the process of aryl hydrocarbon hydroxylase induction.


Production of characteristic volatile markers and their relation to Staphylococcus aureus growth status in pork.
The 3-methyl-butanal and 3-methyl-butanoic acid are known as fingerprint compounds from Staphylococcus aureus. In this study, we investigated production of these two volatile biomarkers and their correlation to S. aureus growth in pork. Both 3-methyl-butanal and 3-methyl-butanoic acid presented high specificity for S. aureus in either media or pork. In sterile minced pork and pork broth, production of volatile biomarkers and the growth of S. aureus were significantly correlated for most single cultures. However, for mixed cultures, only 3-methyl-butanoic acid indicated correlations with growth of S. aureus. Similar trending was also discovered in raw pork, where production of 3-methyl-butanoic acid was significantly correlated with the growth of S. aureus, but not for 3-methyl-butanal. In summary, 3-methyl-butanoic acid was a more stable metabolic marker than 3-methyl-butanal which could be used as an indicator for the presence of S. aureus in pork. This rapid, convenient and cost-effective detection approach could be applied in meat industry to achieve specific detection of S. aureus.


The effects of maternal nutrient restriction and day of early pregnancy on the location and abundance of neutral amino acid transporters in beef heifer utero-placental tissues.
We hypothesized that maternal nutrition and day of gestation would influence the abundance of the neutral amino acid transporters SLC1A1, SLC1A5, SLC7A5, SLC38A2, and SLC38A7 in heifer utero-placental tissues. Angus-cross heifers (n = 43) were estrus synchronized and bred via AI. At breeding, heifers were assigned to one of two dietary intake groups (CON = 100% of requirements to achieve 0.45 kg/d gain or restricted heifers (RES) = 60% of CON intake) and ovariohysterectomized on day 16, 34, or 50 of gestation (n = 6 to 9/d). Thus, the experimental design was a completely randomized design with a 2 × 3 factorial arrangement of treatments. Uterine cross sections were taken from the horn ipsilateral to the CL, fixed in 10% NBF, sectioned at 5 µm, and stained for transporters. For each image, the areas of fetal membrane (FM; chorioallantois), endometrium (ENDO), superficial glands (SG), deep glands (DG), and myometrium (MYO) were analyzed separately for relative intensity of fluorescence as an indicator of transporter abundance. Analysis of FM was only conducted on days 34 and 50. In ENDO, SLC7A5 was greater (P < 0.01) in CON compared with RES heifers. In SG, SLC1A1 was greater (P = 0.02) in day 16 RES compared with day 16 CON and days 34 and 50 RES. In DG, SLC1A1 was greater (P = 0.02) on day 16 compared with 50 of gestation. In MYO, SLC1A1 was greater (P = 0.02) in day 50 CON compared with day 16 CON and day 50 RES. Additionally, in MYO SLC38A2 was greater (P = 0.02) in day 16 RES compared with day 16 CON and day 34 RES. In FM, SLC7A5 tended (P = 0.08) to be greater in CON vs RES. Analysis of all uterine tissues on day 16 determined that expression of SLC1A1, SLC1A5, SL38A2, and SL38A7 differed across uterine tissue type (P < 0.01); however, only SLC7A5 tended (P = 0.10) to differ and be greater in CON compared with RES heifers. Analysis of all utero-placental tissues on days 34 and 50 determined that SLC1A1, SLC7A5, SLC38A2, and SLC38A7 were greater (P ≤ 0.03) in CON compared with RES heifers. Furthermore, abundance of all transporters investigated on days 34 and 50 differed across utero-placental tissue types (P < 0.01). These data support our hypothesis that maternal nutrition and day of gestation influence the abundance of neutral amino acid transporters in utero-placental tissues from days 16 to 50 of gestation. Additionally, these data combined with previously published works help further elucidate nutrient supply and demands of the maternal and fetal system during early gestation in beef heifers.


Antidepressant effect of Yueju-Wan ethanol extract and its fractions in mice models of despair.
Yueju-Wan (YJ), a traditional Chinese medicinal formula, is commonly used for the treatment of depression-related syndromes in China. This study was conducted to evaluate the antidepressant activity of YJ ethanol extract (YJ-E) and its four different fractions, the petroleum ether fraction (YJ-EA), ethyl acetate fraction (YJ-EB), n-butanol fraction (YJ-EC) and final aqueous fraction (YJ-ED). Two experimental despair animal models: the mice tail suspension test (TST) and the mice forced swimming test (FST) were used to evaluate the antidepressant activity of YJ-E and its fractions. These extracts or fractions were administered orally for 7 days, while the parallel positive control was given at the same time using fluoxetine hydrochloride (FLU) in TST and imipramine hydrochloride (IMI) in FST respectively. YJ-E high dose (YJ-E2), YJ-EA, YJ-EC and the positive control groups could decrease the duration of immobility in the TST and FST and have no significant changes in locomotor activity. YJ-E low dose (YJ-E1), YJ-EB, YJ-ED and the vehicle solvent (VEH) control group have no obvious effect on these same tests. In these despair animal models, YJ ethanol extract, the petroleum ether fraction and n-butanol fraction show potent antidepressant effects. The petroleum ether fraction and n-butanol fraction appear to be the active fractions of YJ-E.


[Carrier-bound measurement of serum theophylline levels in children].
Long time treatment of asthma in children with theophylline requires therapeutic drug monitoring by determination of serum concentrations. Beside established assays a carrier-bound reagent test has recently been developed, which has been demonstrated to be accurate, precise and cheaper than other assays. It has the advantage to give rapid results within minutes, which makes it suitable for intensive care units as well as for outpatient care.


Phase 1 and preclinical profiling of ESM-HDAC391, a myeloid-targeted histone deacetylase inhibitor, shows enhanced pharmacology and monocytopaenia.
To improve the tolerability and therapeutic application of histone deacetylase inhibitors (HDACi), by application of an esterase-sensitive motif (ESM), to target pharmacological activity directly to mononuclear myeloid cells expressing the processing enzyme carboxylesterase-1 (CES1). This first-in-human study comprised single and multiple ascending dose cohorts to determine safety and tolerability. Pharmacodynamic parameters included acetylation, cytokine inhibition and intracellular concentrations of processed acid metabolite in isolated monocytes. Mechanistic work was conducted in vitro and in a CES1/Es1elo mouse strain. ESM-HDAC391 showed transient systemic exposure (plasma half-life of 21-30 min) but selective retention of processed acid for at least 12 hours, resulting in robust targeted mechanistic engagement (increased acetylation in monocytes plus inhibition of ex vivo stimulated cytokine production). ESM-HDAC391 was well tolerated and clinical toxicities common to non-targeted HDACi were not observed. ESM-HDAC391 treatment was accompanied by the novel finding of a dose-dependent monocyte depletion that was transient and reversible and which plateaued at 0.06 × 109 monocytes/L after repeat dosing with 20 or 40 mg. Characterisation of monocyte depletion in transgenic mice (CES1/Es1elo ) suggested that colony stimulating factor 1 receptor loss on circulating cells contributed to ESM-HDAC-mediated depletion. Further mechanistic investigations using human monocytes in vitro demonstrated HDACi-mediated change in myeloid fate through modulation of colony stimulating factor 1 receptor and downstream effects on cell differentiation. These findings demonstrate selective targeting of monocytes in humans using the ESM approach and identify monocytopaenia as a novel outcome of ESM-HDACi treatment, with implications for potential benefit of these molecules in myeloid-driven diseases.


Noradrenergic sympathetic innervation of the spleen: III. Development of innervation in the rat spleen.
The ontogeny of noradrenergic innervation and its compartmental development were studied in the rat spleen using glyoxylic acid histofluorescence and high-performance liquid chromatography (HPLC). Noradrenergic nerves were present at birth in bundles adjacent to the splenic artery and vein. On days 1-3, fluorescent profiles largely were associated with the vasculature and with the perivascular zone. By day 6, these fibers formed increasingly elaborate and tortuous plexuses around the central arteries and their branches. By day 10, fibers were present along the marginal sinus and extended into the developing marginal zone. Between day 10 and day 13 the largest increase in norepinephrine (NE) levels (per mg protein) were noted, and the periarteriolar lymphatic sheath (PALS) achieved its adult form, with increased innervation of the parenchyma. In contrast, the venous/trabecular system developed relatively late. The first trabecular fibers were evident at day 10, and the capsule was not innervated until day 13. From 13 days to adulthood, there was a gradual refinement and extension of existing patterns with no change in NE levels as measured by HPLC (per mg protein), suggesting that the innervation was keeping pace with rapid increases in spleen growth. The pattern of growth and development for noradrenergic nerves in the PALS remarkably parallels changes in T cell compartmentation during this period. We propose that norepinephrine is available for interaction with T cells at the earliest stages of development and could play a role in such processes as lymphocyte packing and the onset of immunocompetence.


Leukemia and lymphoma of natural killer lineage cells.
Natural killer (NK) cells are lymphocytes with a large granular lymphocyte morphology, a CD3- CD56+ phenotype, a non-major histocompatibility complex-restricted cytotoxicity, and germline configuration T-cell receptor genes. NK cell lineage tumors originate from either precursor NK cells or mature NK cells. Tumors originating conceivably from precursor NK cells include myeloid/NK cell precursor acute leukemia, precursor NK cell acute lymphoblastic leukemia, and blastic NK cell lymphoma. However, because the developmental pathway of normal NK cells and the characteristics of these NK precursors are not fully understood, the definition and characterization of the tumors are only provisional. Tumors of mature NK cell origin include aggressive NK cell leukemia/lymphoma, nasal-type NK cell lymphoma, and chronic NK lymphocytosis, but the last disorder seems to be reactive in most cases. Because NK cell tumors are rare and difficult to manage, vigorous studies are required for their understanding and management.


Acetaldehyde activates Jun/AP-1 expression and DNA binding activity in human oral keratinocytes.
Oral cancer is a significant health problem, particularly among individuals that ingest alcohol in combination with the use of tobacco products. The enhanced development of tobacco-initiated oral cancers by ethanol suggests that ethanol or one of its metabolites may act as a type of tumor promoter. Nevertheless, the mechanisms underlying the ability of ethanol to enhance oral carcinogenesis remain unclear. We hypothesize that acetaldehyde, the first metabolite of ethanol, may activate the expression and/or activity of Jun/AP-1 in oral keratinocytes analogous to the phorbol ester TPA and other tumor promoters in epidermal keratinocytes. To test this hypothesis, we treated HPV immortalized, non-tumorigenic human oral keratinocytes with acetaldehyde at various concentrations and for various times and measured several parameters of Jun/AP-1expression and function. Our results indicated that c-Jun mRNA and protein levels increased in the acetaldehyde treated cells compared to untreated control cells. Moreover, Jun/AP-1 DNA binding activity was rapidly activated by acetaldehyde in a dose-dependent fashion. The increases in Jun protein and AP-1 DNA binding activity were accompanied by increased transactivation of an AP-1 responsive reporter construct as well as increased transcript levels of a candidate AP-1 responsive gene, stromelysin 3. The levels of acetaldehyde employed were minimally toxic to the cells as determined by MTT assays. Thus, acetaldehyde was found to activate the expression and activity of an oncogenic transcription factor in HPV-initiated cells. Taken together, these results suggest that acetaldehyde may participate, at least in part, in the promotion stage of oral carcinogenesis.


Paget's disease of bone: the skeletal distribution, complications and quality of life as perceived by patients.
Paget's disease of bone (PDB) is a focal disorder of bone metabolism with overgrowth of affected bone resulting in the skeletal complications of this disease. This study examines what patients know about the skeletal distribution of their PDB, and correlates this with their reports of complications and quality of life. The New England Registry for PDB (NRPD) is a voluntary registry with a questionnaire linked to a radiographic database. Data were collected by mail beginning in 2001. Ambulatory population. Any patient with PDB living in New England was eligible to enroll; 285 elected to participate, mean age 73.2 years. Patients were asked what bones were affected by PDB, and whether they suffered complications from PDB. Radiographic studies were sought to corroborate their responses. An SF-12 was administered. Compared to the general population, they reported substantially lower levels of physical health (Physical Component Score (PCS) mean=40), and slightly better mental health (Mental Component Score (MCS) mean=52). There were more instances of agreement on disease presence and fewer instances on disagreement (p=0.001). Radiographic studies supported the presence of a complication from PDB when deformity, fracture and joint replacement had occurred, but were less correlative when headache or hearing loss was reported. Most patients with PDB are aware of the skeletal distribution of their disease; there is a reasonable correlate between complications ascribed to PDB and the presence of PDB on the radiograph except when headache or hearing loss is reported.


Spectral Photoluminescent Parameters of Barley Seeds (Hordéum vulgáre) Infected with Fusarium ssp.
We needed effective and sustainable technologies for better microbiological control of crops, including Fusarium. However, photoluminescent UV-Vis methods are potential for diagnosing plant diseases with Fusarium. It has not been sufficiently studied despite the application of these methods for other biological researches. The excitation spectrum of the seeds during infection shifts to the shorter wavelength and a new maximum appears in the region λ ≈ 232 nm. The photoluminescence of infected seeds increases with excitation by radiation of wavelengths λe,1 = 232 nm, λe,2 = 362 nm and λe,3 = 424 nm by 1.33-3.14 times, and λe,3 = 424 nm-decreases by 1.1 times. Statistical moments μ3 and μ4 , asymmetry and kurtosis change only with short-wave excitation. When analyzing the decomposition of the frequency spectrum into Gaussian curves, the most informative ratio is the ratio of right-handed and left-handed Gaussians under excitation λe,2 = 362 nm and λe,3 = 424 nm. The ratios of their maxima change during infection by 1.36-3.2 times, and for excitation by radiation λe,2 , the frequency boundaries of Gaussians change. The results of measurements and calculations provide a basis for the development of a method and device for photoluminescence diagnostics of fusarium seeds in UV-Vis ranges.


[Management of acute asthma].
All patients with asthma are at risk of exacerbations. Mortality is often associated with failure to identify patients at risk and/or to appreciate the severity of acute episode, resulting in inadequate initial treatment, delay in referring to emergency care and inappropriate hospitalization rates, including delayed transfer to intensive care units. This review focuses on the management of acute severe and near fatal asthma. Lung mechanics and cardiopulmonary interactions associated with airflow obstruction explain the physical presentation and severity criteria for exacerbations. The past and recent medical history, the initial evaluation of severity and the assessment of response to treatment direct the in-hospital management: emergency department visit, transfer to ward or intensive care unit. In any cases, the goals of therapy are summarized as oxygenation, repetitive inhalations of bronchodilators and early administration of systemic corticosteroids. Mechanical ventilation is required in a few patients with near fatal attacks resulting in asphyxia or progressive exhaustion despite maximal therapy. Controlled hypoventilation with permissive hypercapnia is the best strategy to avoid barotrauma. The role of adjunctive therapies, mainly halogenated agents and heliox, is discussed. During the last decade, asthma related mortality has decreased in France (<1000/year). The majority of deaths occur at home or during transport to the hospital but some deaths occur suddenly. Most deaths could be preventable if one adopts the approach that every exacerbation is potentially fatal. This practice should be more vigorously included in patient and general practitioner educational programs.


How measurements affected by medication use are reported and handled in observational research: A literature review.
In epidemiological research, measurements affected by medication, for example, blood pressure lowered by antihypertensives, are common. Different ways of handling medication are required depending on the research questions and whether the affected measurement is the exposure, the outcome, or a confounder. This study aimed to review handling of medication use in observational research. PubMed was searched for etiological studies published between 2015 and 2019 in 15 high-ranked journals from cardiology, diabetes, and epidemiology. We selected studies that analyzed blood pressure, glucose, or lipid measurements (whether exposure, outcome or confounder) by linear or logistic regression. Two reviewers independently recorded how medication use was handled and assessed whether the methods used were in accordance with the research aim. We reported the methods used per variable category (exposure, outcome, confounder). A total of 127 articles were included. Most studies did not perform any method to account for medication use (exposure 58%, outcome 53%, and confounder 45%). Restriction (exposure 22%, outcome 23%, and confounders 10%), or adjusting for medication use using a binary indicator were also used frequently (exposure: 18%, outcome: 19%, confounder: 45%). No advanced methods were applied. In 60% of studies, the methods' validity could not be judged due to ambiguous reporting of the research aim. Invalid approaches were used in 28% of the studies, mostly when the affected variable was the outcome (36%). Many studies ambiguously stated the research aim and used invalid methods to handle medication use. Researchers should consider a valid methodological approach based on their research question.


Varicella zoster virus meningoencephalitis accompanied by sporadic skin lesions in an older immunocompetent adult.
A previously healthy 75-year-old man complained of persistent fever, headache, nausea, mild gait disturbance, memory disorder, and sporadic vesicular skin lesions. Viral meningoencephalitis was diagnosed, based on cerebrospinal fluid (CSF) analysis. Intensive CSF analysis suggested that the patient's illness was caused by varicella zoster virus (VZV). The patient recovered completely after treatment with intravenous acyclovir. VZV infection should be considered as a possible cause of central nervous system disease, even in an immunocompetent patient. VZV reactivation was strongly suspected because of the results of anti-VZV antibody evaluations in serum and CSF, although the skin lesions were not similar to those of herpes zoster.


Contributions of endocrinology to the migration life history of birds.
Migration is a key life cycle stage in nearly 2000 species of birds and is a greatly appreciated phenomenon in both cultural and academic arenas. Despite a long research tradition concerning many aspects of migration, investigations of hormonal contributions to migratory physiology and behavior are more limited and represent a comparatively young research field. We review advances in our understanding of the hormonal mechanisms of migration with particular emphasis on the sub-stages of the migration life history: development, departure, flight and arrival. These sub-stages vary widely in their behavioral, ecological and physiological contexts and, as such, should be given appropriate individual consideration.


Growth and genetic stability of 4 temperature sensitive (ts) mutants of respiratory syncytial (RS) virus in newborn ferrets.
Four temperature sensitive (ts) mutants of respiratory syncytial (RS) virus were evaluated for growth and genetic stability in newborn ferrets. ts-1, the mutant previously tested in children as a possible live virus vaccine and found to be insufficiently attenuated for the upper respiratory tract, grew in the lungs of newborn ferrets to the same peak titer as wild type RS virus. In addition some genetic alteration of the ts-1 mutant occurred. Two more defective subclones of ts-1, ts-1 NG-1 and ts-1 NG-16, were greatly restricted in growth in the ferret's lungs. ts-1 NG-16 was also restricted in the nasal turbinates, but ts-1 NG-1 grew to high titer in the nasal turbinates. Growth of ts-1 NG-1, however, was delayed 2 weeks compared to the growth of wild type virus. Genetic alteration occurred during growth of either subclone; the virus isolated was intermediate between wild type and input virus in plaque forming ability at restrictive temperatures. In no instance was wild type virus isolated from the ferrets infected with either subclone. ts-2, a plaque morphology mutant that does not fuse cells to form syncytia even at the permissive temperature of 32 degrees C, was restricted in growth in both the lungs and nasal turbinates, and genetically altered virus was not recovered from these animals. Of the mutants tested, ts-2 was the most restricted mutant in the newborn ferret and should be evaluated further as a candidate vaccine virus.


Abnormal brain-stem function (brain-stem auditory evoked response) correlates with acoustic cry features in term infants with hyperbilirubinemia.
We hypothesized that changes in brain-stem auditory evoked responses related to bilirubin would be associated with changes in cry because of the anatomic proximity in the brain stem of cranial nerves 8 (auditory) and 9 to 12 (vagal complex, which controls cry). Brain-stem auditory evoked responses and computerized cry analysis were used to study the concurrent effects of moderate hyperbilirubinemia on auditory function and cry. Fifty term infants were divided equally into two groups on the basis of serum bilirubin concentrations: low (less than 8 mg/dl; 136) mumol/L and moderate (10 to 20 mg/dl, 170 to 342 mumol/L). Forty-three infants had successful tracings of brain-stem auditory evoked responses recorded with a Cadwell model 5200A evoked response unit during two successive trials, and a cry recording of each infant was analyzed by computer. The moderate serum bilirubin group had an increase in percent cry phonation (p less than 0.02) and an increase in the variability of the first formant (p less than 0.04) in comparison with the low serum bilirubin group. Serum bilirubin values correlated positively with brain-stem conduction time (r = 0.36, p less than 0.01), percent phonation (r = 0.42, p less than 0.004), and variability of the first formant (r = 0.39, p less than 0.02). Percent phonation, the voiced component produced by increased neural control, correlated with the interpeak of waves latencies I to III (r = 0.32, p less than 0.03) and brain-stem conduction time (wave I to V) (r = 0.35, p less than 0.01). We conclude that hyperbilirubinemia affects adjoining areas of the brain stem that control hearing and cry production.


Therapeutic effects of captopril on ischemia and dysfunction of the left ventricle after Q-wave and non-Q-wave myocardial infarction.
Treatment with angiotensin-converting enzyme inhibitors has a beneficial effect on myocardial ischemia and left ventricular dysfunction after myocardial infarction. The effect of captopril on myocardial ischemia was evaluated in 58 patients with left ventricular dysfunction (ejection fraction < 45%) after Q-wave or non-Q-wave myocardial infarction in a placebo-controlled, parallel, double-blind study. Patients were randomized on day 7 to either placebo or captopril (50 mg daily) and monitoring for a period of 180 days by serial echocardiography and ambulatory ST-segment monitoring. There was a significant effect of captopril on the duration of ambulatory ST depression during the 180 days: The values per day were reduced from 28 +/- 5 min at baseline to 2 +/- 1 min on day 180 in the Q-wave group (p < 0.01) and from 39 +/- 10 min at baseline to 6 +/- 1 min on day 180 in the non-Q-wave group (p < 0.05). In the placebo group the duration of ST depression on day 180 were 21 +/- 8 min in the Q-wave group and 22 +/- 7 min in the non-Q-wave group, thus being significantly higher as compared with the corresponding captopril groups (p < 0.01 and p < 0.05, respectively). In the placebo Q-wave group there was a significant increase in left ventricular end-diastolic volume index from 74 +/- 3.5 to 89 +/- 4.5 ml/m2 (p < 0.01) during the study period, which was in contrast to unchanged values of 75.5 +/- 3.0 and 75.0 +/- 3.5 ml/m2 (not significant [NS]) in the captopril Q-wave group.(ABSTRACT TRUNCATED AT 250 WORDS)


The first latent green fluorophores for the detection of azoreductase activity in bacterial cultures.
An efficient synthesis of original bio-reductive probes suitable for the detection of azoreductases from the fluorescent rhodamine 110 dye is presented. A "turn-on" green fluorescence response upon reduction of the two diazo bonds of these latent fluorophores was observed both in vitro and in the context of bacterial cultures.


Genetic polymorphisms and risk of recurrent deep venous thrombosis in young people: prospective cohort study.
To determine the incidence of deep venous thrombosis (DVT) recurrence in young people, and its association with some genetic polymorphisms (FV G1691A, FII G20210A, MTHFR C677T, PAI-1 4G/5G). Prospective cohort study. A database was established prospectively to follow-up a cohort of unselected patients who had had a first episode of objectively proven DVT under the age of 40 years. All patients had DNA analysis for heritable thrombophilia. We excluded patients with deficiency of antithrombin, protein C or protein S, malignant disease, antiphospholipid syndrome, or a requirement for long-term antithrombotic treatment. The end-point was objective evidence of symptomatic DVT recurrence. Eighty-seven patients were enrolled in the study. Mean duration of follow-up was 4.07 years. At 2 years, the cumulative recurrence rate was 19.3%. The risk of risk was not related to presence or absence of laboratory evidence of genetic polymorphisms: FV G1619A (HR 1.26 [95%CI: 0.64-2.46]; p = 0.51), FII G20210A (HR 0.81 [95%CI: 0.35-1.89]; p = 0.62), MTHFR C677T (HR 1.26 [95%CI: 0.56-2.81]; p = 0.58), PAI-1 4G/5G (0.84 [95%CI: 0.35-2.05]; p = 0.71). In this study, the risk of recurrent deep venous thrombosis in young people was not related with the presence of FV G1691A, FII G20210A, MTHFR C677T or PAI-1 4G/5G polymorphisms.


Disrupted sex differentiation and feminization of man and domestic animals.
Genital malformations constitute the most common birth defects in man and domestic animals and occur frequently in males since the participation of many genes is required for sex differentiation to proceed in the male direction. The precise dose, timing, and coordination needed for their expression add to the proneness of various stages in male sex differentiation to external influences. The emerging insight, through the identification of genes involved in the sex differentiation cascade, is that over 85% of sex anomalies in human and domestic animal populations are not attributable to chromosome aberrations or to mutations in a known gene. Since a majority of severely malformed individuals are incapable of reproduction, the high rates of these defects have to be results either of new mutations or of collaboration of environmental factors with genes. Increase in specific malformations in domestic animals often indicates increased concentration of liability genes brought together in the conceptus by inbreeding. However, in human populations where inbreeding is not the norm such increases may reflect environment-induced new mutations or interaction of environmental agents with hormone-sensitive genes. This review summarizes the information currently available on the genetics of major events in male sex differentiation and briefly discusses the collaborative role that environment may play in disrupting different components of this process.


Breast cancer incidence and month of birth: evidence against an etiologic association.
To investigate the potential relationship between month of birth and breast cancer risk, the authors examined the month of birth of 14,289 women with breast cancer and 38,151 women with cancer of sites other than the breast. All cases were newly diagnosed between 1974 and 1984, and were identified through the Cancer Surveillance System, one of 10 population-based cancer registries comprising the Surveillance, Epidemiology and End Results Program of the National Cancer Institute in the United States. Although breast cancer cases exhibited spring and fall peaks in their month of birth (confirming a previous report), the month of birth of non-breast cancer cases followed a similar distribution. Such patterns have also been reported from populations in other parts of the United States, western Europe, Japan and Australia. These findings suggest that the seasonal variation observed in month of birth of women who develop breast cancer is a reflection of the pattern of births in the underlying population, rather than a new variant in breast cancer epidemiology.


The Impact of Family History on the Clinical Features of Huntington's Disease.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. In most cases the disease is inherited from a parent, although a considerable number of affected persons have no reported family history of the disease. While CAG repeat length is negatively correlated with age of symptom onset, variability exists suggesting that other variables may influence symptom onset. The objective of this study is to determine whether awareness of a family history of HD has an impact on symptom onset and disease manifestations. Data were obtained from Enroll-HD to compare subjects with a family history of HD to subjects without on various key clinical outcomes. In addition, multiple regressions were performed to investigate the impact of family history on the age at onset of depression and motor symptoms. 4,285 mutation positive subjects were included in the analysis, of which 4.81% had a negative family history. Controlling for CAG repeat length, a positive family history predicted an onset of depression 11.438 years earlier and an onset of motor symptoms 6.681 years earlier when compared to having a negative family history. Subjects with a positive family history were more likely to report behavioral manifestations as the initial major symptom of HD (38.6% vs. 29.6%, p = 0.023), and were more likely to report previous suicidal ideation/attempts (26.2% vs. 20.3%, p = 0.046). A positive family history of HD appears to be associated with an earlier onset of depression and overall disease manifestations. Implications regarding the role of genetic versus environmental contributions to symptom onset in HD are discussed.


[Usefulness of hepatic biopsy in an internal medicine service].
Study the percentage of clinical successes which have been confirmed by percutaneous hepatic biopsy guided by echography (PHBE) in those diseases which can affect the liver in an Internal Medicine service. 78 patients were chosen for this study. All of them were admitted to hospital during the last eight years. Each patient had had a PHBE made regarding clinical, analytical and echographic criteria that were necessary to conclude their diagnostic studies. They were distributed into different groups. Patients could be distributed into five different groups. There was a higher percentage of clinical successes on those who suffered from chronic hepatopathy derived from alcohol-addiction and on those with carcinomatous hepatopathies. When corroborating the diagnosis of clinical suspect, the diagnostic profitability of the biopsy proved to get down in the others groups, depending on it was the group of miscellaneous, dissociate cholestasis and, in the last place, unknownly originated fever. The diversity of diseases which can affect the liver in an Internal Medicine service gives PHBE a particular diagnostic character. The diagnosis of clinical suspect was confirmed in 78.2% of the total of cases that made up the different groups. Therefore, PHBE plays a main role in a large amount of hepatic repercussive diseases that are treated in Internal Medicine services where, despite the clinical suspect, a diagnostic corroboration is often required for a right treatment.


A comparison of several modulated radiotherapy techniques for head and neck cancer and dosimetric validation of VMAT.
Volumetric modulated arc therapy (VMAT) has the potential to shorten treatment times for fluence modulated radiotherapy. We compared dose distributions of VMAT, step-and-shoot IMRT and serial tomotherapy for typical head and neck (H&N) planning target volumes (PTV) with sparing of one parotid, a complex paradigm and a situation often encountered in H&N radiotherapy. Finally, we validated the dosimetric accuracy of VMAT delivery. Based on CT datasets of 10 patients treated for H&N cancer (PTV1:60 Gy/PTV2:56 Gy) with IMRT (7/9 fields), serial tomotherapy (MIMiC) and VMAT were compared with regard to plan quality and treatment efficiency. Plan quality was assessed by calculating homogeneity/conformity index (HI/CI), mean dose to parotid and brain stem and the maximum dose to the spinal cord. For plan efficiency evaluation, total treatment time (TTT) and number of monitor units (MU) were considered. A dosimetric evaluation of VMAT was performed using radiosensitive film, ion chamber and 2D-array. For MIMiC/IMRT(7F)/IMRT(9F)/VMAT, mean CI was 1.98/2.23/2.23/1.82, HI(PTV1) was 1.12/1.20/1.20/1.11 and HI(PTV2) was 1.11/1.15/1.13/1.12. Mean doses to the shielded parotid were 19.5 Gy/14.1 Gy/13.9 Gy/14.9 Gy and the spinal cord received maximum doses of 43.6 Gy/40.8 Gy/41.6 Gy/42.6 Gy. The mean MU's were 2551/945/925/521 and the mean TTT was 12.8 min/7.6 min/8.5 min/4.32 min. The ion chamber measurements showed an absolute deviation of 0.08 ± 1.10% and 98.45 ± 3.25% pixels passed γ-analyses for 3%/3mm and 99.95 ± 0.09% for 5%/5mm for films. 2D-array measurements reported an agreement for 3%/3mm of 95.65 ± 2.47%-98.33 ± 0.65% and for 5%/5mm 99.79 ± 0.24%-99.92 ± 0.09% depending on the measurement protocol. All treatment paradigms produced plans of excellent quality and dosimetric accuracy with IMRT providing best OAR sparing and VMAT being the most efficient treatment option in our comparison of treatment plans with high complexity.


Structure and function of desmosomes.
Desmosomes are prominent adhesion sites that are tightly associated with the cytoplasmic intermediate filament cytoskeleton providing mechanical stability in epithelia and also in several nonepithelial tissues such as cardiac muscle and meninges. They are unique in terms of ultrastructural appearance and molecular composition with cell type-specific variations. The dynamic assembly properties of desmosomes are important prerequisites for the acquisition and maintenance of tissue homeostasis. Disturbance of this equilibrium therefore not only compromises mechanical resilience but also affects many other tissue functions as becomes evident in various experimental scenarios and multiple diseases.


A crossover, randomized, controlled trial of dornase alfa before versus after physiotherapy in cystic fibrosis.
Although dornase alfa is a widely used, aerosolized, mucolytic agent in patients with cystic fibrosis (CF), its efficacy in relation to the timing of physiotherapy has not been tested. We sought to determine whether dornase alfa is more efficacious when it is administered 30 minutes before versus 30 minutes after physiotherapy/positive expiratory pressure (PEP) therapy in clinically stable children. Using a crossover, randomized, double-blind, and placebo-controlled trial, we undertook a 6-week study of the efficacy of dornase alfa in relation to the timing of physiotherapy at home. There were 2 treatment orders. Dornase alfa before + placebo after physiotherapy/PEP for 2 weeks was followed by a 2-week washout and then the reverse order placebo before and dornase alfa after physiotherapy/PEP for the final 2 weeks. The second treatment order reversed the placebo and dornase alfa therapy for the first and last 2-week blocks. The main outcome measures used included the change in predicted percentage of forced expiratory volume in 1 second (FEV1), a composite quality of well-being score (QWB), and a measure of aerobic fitness (maximal oxygen consumption, [VO2max]), determined using shuttle testing. Fifty-two patients who had CF (27 female) with mild to moderate suppurative lung disease, were a mean +/- SD age of 10.7 +/- 3.2 years, had Shwachman scores of 86 +/- 11.8, had predicted FEV1 of 83% +/- 18%, had quality of well-being score of 0.76 +/- 0.08, and had VO2max of 42.6 +/- 6.3 ml/kg per min were enrolled. Fifty patients completed the study. Intention-to-treat analysis was used. Nonsignificant mean (95% confidence interval) differences in FEV1 (0.02 L [-0.05 to 0.10]), VO2max (-0.75 ml/kg per min [-1.85 to 0.35]), and QWB (0.005 [-0.94 to 0.0028]) for dornase alfa after physiotherapy/PEP were detected. A post hoc analysis showed that patients who were colonized persistently with Pseudomonas aeruginosa had a significantly greater improvement in FEV1 (0.12 L [0.23 to 0.01] vs -0.04 L [0.05 to -0.13]) when dornase alfa was administered after physiotherapy/PEP. Dornase alfa is equally efficacious when delivered before or after physiotherapy/PEP in patients with CF. Patients who are colonized persistently with P aeruginosa may derive more improvement in FEV1 when dornase alfa is delivered after physiotherapy/PEP.


Illustration of Different Disease Transmission Routes in a Pig Trade Network by Monopartite and Bipartite Representation.
Besides the direct transport of animals, also indirect transmission routes, e.g., contact via contaminated vehicles, have to be considered. In this study, the transmission routes of a German pig trade network were illustrated as a monopartite animal movements network and two bipartite networks including information of the transport company and the feed producer which were projected on farm level (n = 866) to enable a comparison. The networks were investigated with the help of network analysis and formed the basis for epidemiological models to evaluate the impact of different transmission routes on network structure as well as on potential epidemic sizes. The number of edges increased immensely from the monopartite animal movements network to both projected networks. The median centrality parameters revealed clear differences between the three representations. Furthermore, moderate correlation coefficients ranging from 0.55 to 0.68 between the centrality values of the animal movements network and the projected transportation network were obtained. The epidemiological models revealed significantly more infected farms for both projected networks (70% to 100%) compared to the animal movements network (1%). The inclusion of indirect transmission routes had an immense impact on the outcome of centrality parameters as well as on the results of the epidemiological models.


Effects of dietary fish oil on learning function and apoptosis of hippocampal pyramidal neurons in streptozotocin-diabetic rats.
Previous research has demonstrated that diabetes induces learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown to enhance learning and memory and prevent memory deficits in various experimental conditions. The present study investigated the effects of fish oil supplementation on the neuron apoptosis in the hippocampus of streptozotocin (STZ)-induced diabetes rats. The effects of diabetes and fish oil treatment on the spatial learning and memory were also evaluated using the Morris Water Maze. Diabetes impaired spatial learning and memory of rats. Diabetes increased the expression of Bax and caspase-3, which led the apoptosis of the CA1 pyramidal neurons, and further contributed to the deficits in learning and memory processing. Fish oil dietary supplementation in diabetic rats conducts neuron-protective function through an anti-apoptotic pathway and significantly improves the ability of learning and memory. These results partially explain the mechanism of the effect of diabetes and fish oil treatment on learning and memory, supporting a potential role for fish oil as an adjuvant therapy for the prevention and treatment of diabetic complications.


Can FDG-PET reduce the need for mediastinoscopy in potentially resectable nonsmall cell lung cancer?
Few fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) nonsmall cell lung cancer (NSCLC) trials have had sufficient patients to adequately evaluate PET for mediastinal staging. We question whether once PET is performed, is mediastinoscopy necessary? We performed a 5-year retrospective analysis of operable patients with known or suspicious NSCLC. Standard PET techniques were used. Inclusion criteria were (1) surgical mediastinal nodal sampling by mediastinoscopy within 31 days of the PET and (2) definitive diagnosis. There were 237 patients who met the evaluation criteria; ninety-nine patients with NSCLC and 138 with suspicious lesions (137 men and 100 women; aged 20 to 88 years). The PETs were performed from 0 to 29 days before mediastinoscopy (median, 7 days). The standardized uptake value for the primary lesion was 0 to 24.6 (7.9+/-5.0). Nine primary lesions had no FDG uptake (1 benign, 8 NSCLCs). Seventy-one patients (31%) had mediastinal PET positive disease, and 44 patients (19%) had histologic positive mediastinal disease; N2 41 patients (17%) and N3 9 patients (4%). In 6 patients (3%), the initial frozen sections were negative, but PET positivity encouraged further biopsies that were positive for cancer. The PET sensitivity was 82%, specificity 82%, accuracy 82%, negative predictive value 95%, and positive predictive value was 51%. All primary lesions with a standardized uptake value less than 2.5 and a negative mediastinal PET were negative histologically (n = 29). Logistic regression analysis resulted in 100% specificity for PET in this group. In NSCLC PET may reduce the necessity for mediastinoscopy when the primary lesion standardized uptake value is less than 2.5 and the mediastinum is PET negative. Accepting this approach in our patient population, the need for mediastinoscopy would have been reduced by 12%.


A Case Report and Review of the Literature: Infectious Aneurysm Formation in the Pulmonary Arteries-A Rare but Perilous Sequela of Persisting Infection With Klebsiella pneumoniae.
Septic aneurysms of the pulmonary artery are rare conditions, with few cases having been reported worldwide. They are assumed to result from septic emboli that cause a local inflammatory reaction of the arterial wall, ultimately leading to degenerative changes. We report the case of a 63-year-old female patient presenting with Klebsiella pneumoniae urosepsis and first diagnosis of diabetes mellitus, who developed a life-threatening infectious pulmonary artery aneurysm secondary to bacteremia with Klebsiella pneumoniae. The patient required a lobectomy due to pulmonary hemorrhage. We review the clinical hallmarks of Klebsiella pneumoniae related septic pulmonary embolic disease and summarize currently known risk factors for the development of infectious aneurysmatic disease including diabetes mellitus and other states of immunosuppression. The featured case aims to increase the awareness for this seldom but life-threatening complication of infectious diseases such as Klebsiella pneumoniae urosepsis.


Nonpharmacological pain management interventions in medical and surgical abortion: A scoping review.
The study aimed to present a broad overview of the research conducted and to synthesize evidence of the utility of nonpharmacological interventions for pain management in medical and surgical abortions. High-quality care for medical and surgical abortion requires pain to be managed effectively. However, women reported low satisfaction with pain management in abortion care. A scoping review design was employed. No date limit was set. PubMed, Cochrane Library, EMBASE, Web of Science, CINAHL, PsycINFO, ProQuest and Scopus were searched in April 2021. Arksey and O'Malley's framework was used. The Preferred Reporting Items for Systematic reviews and Meta-analysis extension-Scoping Reviews was followed. Fifteen studies were included. The results revealed that support interventions, music therapy, acupoint stimulation and hypnotic analgesia were nonpharmacological interventions used to decrease abortion pain. Clinical nurses, nurse managers and policymakers should attach full importance to the pain management in abortion and may use the study findings to guide the pain management practice.


BCL-2, a novel regulator of apoptosis.
The bcl-2 gene has a unique function among mammalian oncogenes as a negative regulator of apoptosis. Its expression pattern in embryonic and adult tissues is consistent with a role in maintaining in vivo survival of specific cell types. The biochemical function of bcl-2 is unknown, but its localization to mitochondrial and microsomal membranes suggests several possibilities. bcl-2 is protective against oxidative stress in mammalian cells and can be replaced by antioxidants in a factor-deprivation model of apoptosis. These results are consistent with a model of apoptotic death involving oxidative stress in a central pathway. The recent discovery of several bcl-2-related genes, some of which also inhibit apoptosis and others that unexpectedly promote apoptosis, has shed new light on several aspects of bcl-2 action.


Prevalence and associated factors of anemia among pregnant women and the impact of clinical pharmacist counseling on their awareness level: A cross sectional study.
Anemia during pregnancy is a worldwide problem that affects females worldwide. There is not enough data on the magnitude of this health problem in Al-Madinah city in Saudi Arabia. This study aimed to assess the prevalence and associated factors related to anemia during pregnancy in Al-Madinah city. In addition, assessed the impact of counseling by clinical pharmacist on anemic pregnant females. 300 pregnant females were assessed for anemia based on their hemoglobin level in a descriptive cross-sectional study. Those females were further interviewed to identify associating factors related to presence of anemia during pregnancy. Anemic females were randomized to receive either counseling by the clinical pharmacist in addition to the standard of care (interventional group) or standard of care without counseling (control group). Our result showed that 44% of pregnant women were anemic upon recruitment. Pregnant females of low socioeconomic status, those during the first trimester, multipara females, and those who did not receive nutritional education during pregnancy showed significantly higher odds of developing anemia. Clinical pharmacist-led counseling program significantly improved adherence with iron regimen (p-value < 0.01) and significantly increased patients' hemoglobin level 30-days after the intervention (p-value < 0.001).


GSK3 and lamellipodin balance lamellipodial protrusions and focal adhesion maturation in mouse neural crest migration.
Neural crest cells are multipotent cells that delaminate from the neuroepithelium, migrating throughout the embryo. Aberrant migration causes developmental defects. Animal models are improving our understanding of neural crest anomalies, but in vivo migration behaviors are poorly understood. Here, we demonstrate that murine neural crest cells display actin-based lamellipodia and filopodia in vivo. Using neural crest-specific knockouts or inhibitors, we show that the serine-threonine kinase glycogen synthase kinase-3 (GSK3) and the cytoskeletal regulator lamellipodin (Lpd) are required for lamellipodia formation while preventing focal adhesion maturation. Lpd is a substrate of GSK3, and phosphorylation of Lpd favors interactions with the Scar/WAVE complex (lamellipodia formation) at the expense of VASP and Mena interactions (adhesion maturation and filopodia formation). This improved understanding of cytoskeletal regulation in mammalian neural crest migration has general implications for neural crest anomalies and cancer.


[Indication and problems of radiotherapy of primary bone and cartilage tumours of the thoracic wall (author's transl)].
The authors discuss the management in radiotherapy of bony tumours of the thoracic wall: necessity of accepting the risk due to the volume of healthy tissue which is inevitably irradiated, the technics of irradiation which limit these risks. Limited hope of improvement of the still modest results with new technics of radiotherapy. They emphasize the difference which exists between the idea of radiosensitivity and radiocurability.


Colonization of maritime glacier ice by bdelloid Rotifera.
Very few animal taxa are known to reside permanently in glacier ice/snow. Here we report the widespread colonization of Icelandic glaciers and ice fields by species of bdelloid Rotifera. Specimens were collected within the accumulation zones of Langjökull and Vatnajökull ice caps, among the largest European ice masses. Rotifers reached densities up to ∼100 individuals per liter-equivalent of glacier ice/snow, and were freeze-tolerant. Phylogenetic analyses indicate that glacier rotifers are polyphyletic, with independent ancestries occurring within the Pleistocene. Collectively, these data identify a previously undescribed environmental niche for bdelloid rotifers and suggest their presence in comparable habitats worldwide.


Design and conformation of non-Aib synthetic peptides enjoying alamethicin-like ionophore activity.
Analogues of alamethicin, a 20-mer amphipathic helical peptide with ionophore activity, in the sequence of which all Aib residues were substituted by Ala (A1) or Leu (L1), were synthesized by the solid phase method, purified by high performance liquid chromatography and characterized by fast atomic bombardment mass spectrometry. Infrared and CD studies showed that A1 easily underwent a transconformation to beta-structure whereas L1 displayed a predominant alpha-helical character, thus being a potential ionophore model. Its voltage-dependent multistate activity in model membranes showed that Aib is not a requisite residue to observe an alamethicin-like behavior. However, as the lifetime of the single channels was much shorter than for alamethicin, the peptide chain was lengthened by a Leu (LL1) or a Ser (SL1) residue. The last peptide gave an increased channel lifetime, but the design of other non-Aib peptides, taking into account the hydroxyl C-terminus and side-chain interactions between helices in a barrel-stave bundle, is desirable to approach more closely the alamethicin activity.


Mechanical viscoelastic behavior of dental adhesives.
The purpose of the study was to evaluate the mechanical properties of dental adhesive materials at different testing temperatures after dry and wet storage. Specimens (d=1 mm, l=18 mm) from six materials were tested: Silorane Adhesive System (SL), Heliobond (HE), One-Step Plus (OS), Optibond Solo Plus (OP), cmf Adhesive System (CF) and Protobond (PR). Static and creep testing was performed by applying a constant torque below the proportional limit of the materials, while dynamic testing consisted of dynamic torsional loading. Experiments were performed after 24h of dry and wet storage under temperatures from 21°C to 50°C and various viscoelastic parameters were calculated. Shear modulus ranged from 0.19 to 1.99 GPa, while flexural modulus from 0.67 to 5.69 GPa. Most of the materials were affected by the presence of water and increase of temperature. OP showed the highest recovery after creep, while SL exhibited the highest permanent deformation. Contact with water after polymerization and increase of temperature resulted in a decline of the mechanical properties, especially for the HEMA-containing adhesives.


Myogenic and agonist induced responses of coronary venules after cold hyperkalaemic cardioplegia.
The aim was to examine agonist induced and myogenic venular responses after crystalloid cardioplegia in conditions simulating cardiopulmonary bypass. Hearts of pigs were arrested with cold hyperkalaemic ([K+] = 25 mM) crystalloid cardioplegic solution for 1 h under conditions of cardiopulmonary bypass. In another group, hearts were arrested and then reperfused with warm blood for 1 h while being separated from cardiopulmonary bypass. In a third group, animals were supported on cardiopulmonary bypass for 75 min without diversion of coronary blood flow. Hearts from non-instrumented animals served as controls. Coronary venules (91-197 microns in internal diameter) were studied in vitro in a pressurised no flow state using video microscopy. Agonist induced responses were assessed in vessels precontracted with the thromboxane A2 analogue U46619. Endothelium dependent relaxations to adenosine diphosphate (ADP, P = 0.11 v control), or serotonin (P = 0.67), and endothelium independent relaxations to the beta adrenergic cyclic AMP mediated agonist isoprenaline (P = 0.20), adenosine (P = 0.98), or the KATP channel opener pinacidil (P = 0.40) were not significantly altered after cold cardioplegia alone. After cardioplegia followed by 1 h of warm blood reperfusion, venular responses to ADP (P = 0.003 v control), isoprenaline (P = 0.013), adenosine (P = < 0.001), and pinacidil (P = 0.005) were reduced compared to the respective control responses, while the response to serotonin (P = 0.97) remained unchanged. Endothelium independent cyclic GMP mediated relaxation to sodium nitroprusside was similar in all groups (P > 0.90). Myogenic reactivity was assessed after incremental increases in the intraluminal pressure from 2-40 mm Hg. As intraluminal pressure was increased, the diameter of control venules increased and reached a plateau. Following cardioplegia, the pressure-diameter relationship of venules was shifted upward (P = 0.04 v control) suggesting impaired myogenic tone. After reperfusion, myogenic tone partially recovered. Extracorporeal circulation without diversion of coronary perfusion did not significantly affect venular responses. Ischaemic cardioplegia using a cold hyperkalaemic solution under conditions of cardiopulmonary bypass does not significantly alter agonist induced venular responses, whereas myogenic contraction is slightly reduced. After 1 h of reperfusion, agonist induced relaxations of coronary venules are significantly impaired, whereas myogenic contraction recovers. These findings may have implications for the control of myocardial perfusion and diastolic properties of the heart after ischaemic cardioplegia under conditions of extracorporeal circulation.


Systemic Inflammatory Markers Predict Detrimental Outcome of Urosepsis in Kidney Transplant Recipients.
Urosepsis is a frequent cause of hospitalization among kidney transplant recipients (KTxR). Systemic inflammatory markers may reflect disease severity; nevertheless, their predictive value has not been evaluated in KTxRs. We sought to investigate the diagnostic and prognostic value of blood-derived systemic inflammatory markers during urosepsis in KTxR. We retrospectively enrolled 80 transplant recipients who were hospitalized between 2014 and 2017 due to urosepsis and followed for at least 1 year. Multiple parameters were calculated from medical records. The study endpoint was defined as death, graft loss, or a more than double serum creatinine level compared with baseline. Seventeen patients reached an endpoint and presented at admission significantly lower total serum protein [g/dL] (5.0 ± 0.6 vs 6.0 ± 0.7) and higher urea [mg/dL] (161, 118-218 vs 80, 56-125), neutrophil-to-lymphocyte ratio (NLR) (20.0, 12.5-48.3 vs 12.9, 7.0-20.1), platelet-to-lymphocyte ratio (PLR) (447, 203-706 vs 231, 160-357), derived neutrophil-to-lymphocyte ratio (dNLR) (8.5, 5.6-10.4 vs 5.3, 2.9-8.5), and maximal Sequential Organ Failure Assessment (SOFA) score (6, 4-7 vs 3, 3-5). Among blood markers, NLR showed the strongest correlation with C-reactive protein, procalcitonin, creatinine, urea, and maximal SOFA score. The NLR cut-off value >15 predicted endpoint occurrence with 59% specificity and 75% sensitivity (area under the curve [AUC] 0.67, P = .038). The combined impact of NLR, urea, and total serum protein increased the prognostic precision (sensitivity 85% and specificity 84%, AUC = 0.88, P < .001). The combined impact of NLR, urea, and total serum protein identifies KTxR who are at risk of a bad outcome after urosepsis and require more meticulous care.


Corrigendum: Real-World Lenvatinib Versus Sorafenib in Patients With Advanced Hepatocellular Carcinoma: A Propensity Score Matching Analysis.
[This corrects the article DOI: 10.3389/fonc.2021.737767.].


The tarballs on Texas beaches following the 2014 Texas City "Y" Spill: Modeling, chemical, and microbiological studies.
We modeled the transport of oil, source-fingerprinted 44 tarball samples from Galveston Island (GV) and Mustang Island (MT), and determined the hydrocarbon and bacterial community composition of these tarballs following the 2014 Texas City "Y" Oil Spill (TCY). Transport modeling indicated that the tarballs arrived in MT before the samples were collected. Source-fingerprinting confirmed that the tarballs collected from GV and MT, 6d and 11d after the TCY, respectively, originated from the spill. Tarballs from GV showed 21% depletion of alkanes, mainly C9-C17, and 55% depletion of PAHs mainly naphthalenes, and dominated by alkane-degrading Alcanivorax and Psychrobacter. Samples from MT were depleted of 24% alkanes and 63% PAHs, and contained mainly of PAH-degrading Pseudoalteromonas. To the best of our knowledge, this is the first study to relate oil transport, tarball source-fingerprinting, chemistry, and microbiology, which provides insights on the fate of oil in the northern Gulf of Mexico.


Rapid assessment of knowledge, attitudes, practices, and risk perception related to the prevention and control of Ebola virus disease in three communities of Sierra Leone.
The recent outbreak of the Ebola virus disease (EVD) in Sierra Leone has been characterized by the World Health Organization as one of the most challenging EVD outbreaks to date. The first confirmed case in Sierra Leone was a young woman who was admitted to a government hospital in Kenema following a miscarriage on 24 May 2014. On 5 January 2015, intensified training for an EVD response project was initiated at the medical university of Sierra Leone in Jui. To understand the knowledge, attitudes, practices, and perceived risk of EVD among the public, especially after this training, a rapid assessment was conducted from 10 to 16 March 2015. Interviews were conducted with 466 participants based on questionnaires that were distributed from 10 to 16 March 2015 by cluster sampling in three adjacent communities, namely Jui, Grafton, and Kossoh Town, in the Western Area Rural District of Sierra Leone. It was found that knowledge about EVD was comprehensive and high. Positive attitude towards prevention was found to be satisfactory. Nearly all participants knew the reporting phone number 117 and had reported some change in behavior since learning about Ebola. More than half (62 %) of the participants had a history of travelling to urban areas, which increases the risk of infection. The multivariable logistic regression analysis showed that community and occupation were variables associated with perceived risk of EVD. Our study showed that community level social mobilization and community engagement were an effective strategy in the special context.


Intimate Partner Violence, HIV Pre-Exposure Prophylaxis (PrEP) Acceptability, and Attitudes About Use: Perspectives of Women Seeking Care at a Family Planning Clinic.
Pre-exposure prophylaxis (PrEP) presents an opportunity to expand prevention options for women at risk for HIV infection. Yet, women's PrEP use remains low and relatively little is known about PrEP acceptability and attitudes among a sub-population of women at risk for HIV-those experiencing intimate partner violence (IPV). A cross-sectional survey included closed and open-ended questions to assess IPV, PrEP acceptability, and attitudes about PrEP use among women seeking care at an urban family planning clinic in Pittsburgh, Pennsylvania (N = 145). Approximately 70% of women reported being willing to use PrEP with the key reasons for potential use including previous STI diagnosis, inconsistent condom use, and lack of or dishonest conversations with partners. Among women reporting recent IPV (41%), potential barriers to PrEP included concerns around drug effects, access/affordability, and adherence. Over half of women reporting recent IPV reported concerns around partner reaction impacting potential PrEP use. Results from this mixed-methods study highlight the need for a woman-centered PrEP intervention that uniquely includes awareness raising and understanding of PrEP for women, as well as reflects the context of IPV in decision-making and care.


ARB and cardioprotection.
A growing body of evidence has suggested that the use of angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs) leads to a significant decrease in mortality and morbidity in patients with congestive heart failure. The AT1 receptor is a seven-transmembrane G protein-coupled receptor, and is involved in regulating the physiological and pathological process of the cardiovascular system. Systemically and locally generated Ang II has agonistic action on AT1 receptor. However, recent in vitro studies have demonstrated that AT1 receptor is structurally flexible and instable, and has significant and varying levels of spontaneous activity in an Ang II-independent manner. Furthermore, mechanical stress activates AT1 receptor by inducing conformational switch without the involvement of Ang II. Experimental studies have demonstrated that Ang II-independent activation of AT1 receptor is profoundly relevant to the pathogenesis of cardiac remodeling in vivo, and that these agonist-independent activities of AT1 receptor can be inhibited by inverse agonists, but not by neutral antagonists. Therefore, inverse agonist activity emerges as an important pharmacological parameter that contributes to cardioprotective effects of ARBs through inhibiting both Ang II-dependent and -independent activation of AT1 receptor.


NAD-linked, GSH- and factor-independent aldehyde dehydrogenase of the methylotrophic bacterium, Hyphomicrobium X.
Cell-free extracts of Hyphomicrobium X showed NAD-dependent aldehyde dehydrogenase activity, provided that NAD addition preceded that of aldehyde. Activity was lost rather rapidly, especially during purification attempts, but this could be partially masked by including a time-dependent restoration step with thiol compounds in the protocol. The nature of the assay buffer appeared to be critical and stimulation occurred on incorporation of K+ ions in the mixture. An even higher specific activity could be achieved by 1,4-dithiothreitol (DTT) treatment of the preparation, followed by removal of DTT, and assaying in the absence of thiol compounds under anaerobic conditions. Exposure of such a preparation to O2 led to a significant decrease in activity within a couple of hours. Immediate inactivation occurred on addition of H2O2, but this could be prevented completely by prior addition of NAD. Since GSH does not participate in the reaction and no stimulating factor was detected, the role of thiol compounds is most probably confined to restoration or prevention of damage to an O2-sensitive, necessary thiol group. Since the same features were found for cell-free extract as for the partially purified enzyme, only one enzyme type seems to be present. Although the enzyme is a general aldehyde dehydrogenase, the kinetic parameters and the specific activity of the cell-free extract for formaldehyde indicate that it may play a role in formaldehyde dissimilation by Hyphomicrobium X. The NAD-linked, GSH- and factor-independent aldehyde dehydrogenase described here appears to be different in several respects from the formaldehyde dehydrogenase of Pseudomonas putida (EC 220.127.116.11) (despite showing similar behavior toward coenzymes and factors) but resembles the aldehyde dehydrogenase from baker's yeast (EC 220.127.116.11).


NFAT and Osterix cooperatively regulate bone formation.
Immunosuppressants are crucial in the prevention of detrimental immune reactions associated with allogenic organ transplantation, but they often cause adverse effects in a number of biological systems, including the skeletal system. Calcineurin inhibitors FK506 and cyclosporin A inhibit nuclear factor of activated T cells (NFAT) activity and induce strong immunosuppression. Among NFAT proteins, NFATc1 is crucial for the differentiation of bone-resorbing osteoclasts. Here we show FK506 administration induces the reduction of bone mass despite a blockade of osteoclast differentiation. This reduction is caused by severe impairment of bone formation, suggesting that NFAT transcription factors also have an important role in the transcriptional program of osteoblasts. In fact, bone formation is inhibited in Nfatc1- and Nfatc2-deficient cells as well as in FK506-treated osteoblasts. Overexpression of NFATc1 stimulates Osterix-dependent activation of the Col1a1 (encoding type I collagen) promoter, but not Runx2-dependent activation of the Bglap1 (encoding osteocalcin) promoter. NFAT and Osterix form a complex that binds to DNA, and this interaction is important for the transcriptional activity of Osterix. Thus, NFAT and Osterix cooperatively control osteoblastic bone formation. These results may provide important insight into the management of post-transplantation osteoporosis as well as a new strategy for promoting bone regeneration in osteopenic disease.


In vivo and in vitro toxicity of a stainless-steel aerosol generated during thermal spray coating.
Thermal spray coating is an industrial process in which molten metal is sprayed at high velocity onto a surface as a protective coating. An automated electric arc wire thermal spray coating aerosol generator and inhalation exposure system was developed to simulate an occupational exposure and, using this system, male Sprague-Dawley rats were exposed to stainless steel PMET720 aerosols at 25 mg/m3 × 4 h/day × 9 day. Lung injury, inflammation, and cytokine alteration were determined. Resolution was assessed by evaluating these parameters at 1, 7, 14 and 28 d after exposure. The aerosols generated were also collected and characterized. Macrophages were exposed in vitro over a wide dose range (0-200 µg/ml) to determine cytotoxicity and to screen for known mechanisms of toxicity. Welding fumes were used as comparative particulate controls. In vivo lung damage, inflammation and alteration in cytokines were observed 1 day post exposure and this response resolved by day 7. Alveolar macrophages retained the particulates even after 28 day post-exposure. In line with the pulmonary toxicity findings, in vitro cytotoxicity and membrane damage in macrophages were observed only at the higher doses. Electron paramagnetic resonance showed in an acellular environment the particulate generated free radicals and a dose-dependent increase in intracellular oxidative stress and NF-kB/AP-1 activity was observed. PMET720 particles were internalized via clathrin and caveolar mediated endocytosis as well as actin-dependent pinocytosis/phagocytosis. The results suggest that compared to stainless steel welding fumes, the PMET 720 aerosols were not as overtly toxic, and the animals recovered from the acute pulmonary injury by 7 days.


Design, synthesis, antitrypanosomal activity, DNA/RNA binding and in vitro ADME profiling of novel imidazoline-substituted 2-arylbenzimidazoles.
Novel imidazoline benzimidazole derivatives containing diversely substituted phenoxy moieties were synthesized with the aim of evaluating their antitrypanosomal activity, DNA/RNA binding affinity and in vitro ADME properties. The presence of the diethylaminoethyl subunit in 18a-18c led to enhanced antitrypanosomal potency, particularly for 18a and 18c, which contain unsubstituted and methoxy-substituted phenoxy moieties. They were found to be > 2-fold more potent against African trypanosomes than nifurtimox. Fluorescence and CD spectroscopy, thermal denaturation assays and computational analysis indicated a preference of 18a-18c toward AT-rich DNA and their minor groove binding mode. Replacement of the amidine group with less basic and ionisable nitrogen-containing moieties failed to improve membrane permeability of the investigated compounds. Due to structural diversification, the compounds displayed a range of physico-chemical features resulting in variable in vitro ADME properties, leaving space for further optimization of the biological profiles.


Computational modelling of energy balance in individuals with Metabolic Syndrome.
A positive energy balance is considered to be the primary cause of the development of obesity-related diseases. Treatment often consists of a combination of reducing energy intake and increasing energy expenditure. Here we use an existing computational modelling framework describing the long-term development of Metabolic Syndrome (MetS) in APOE3L.CETP mice fed a high-fat diet containing cholesterol with a human-like metabolic system. This model was used to analyze energy expenditure and energy balance in a large set of individual model realizations. We developed and applied a strategy to select specific individual models for a detailed analysis of heterogeneity in energy metabolism. Models were stratified based on energy expenditure. A substantial surplus of energy was found to be present during MetS development, which explains the weight gain during MetS development. In the majority of the models, energy was mainly expended in the peripheral tissues, but also distinctly different subgroups were identified. In silico perturbation of the system to induce increased peripheral energy expenditure implied changes in lipid metabolism, but not in carbohydrate metabolism. In silico analysis provided predictions for which individual models increase of peripheral energy expenditure would be an effective treatment. The computational analysis confirmed that the energy imbalance plays an important role in the development of obesity. Furthermore, the model is capable to predict whether an increase in peripheral energy expenditure - for instance by cold exposure to activate brown adipose tissue (BAT) - could resolve MetS symptoms.