End-of-life communication: a nationwide study of bereaved parents' perceptions.
To investigate bereaved parents' perception of end-of-life communication with healthcare professionals after losing a child due to life-limiting diagnoses. A national register identified the causes of death of 951 children aged 0-18 years during the period 2012-2014. A previously described classification of life-limiting diagnoses identified 402 children. A modified version of the self-administered questionnaire 'To Lose a Child' was distributed to the parents of these 402 children, capturing their perceptions of communication with the healthcare professionals throughout the child's disease trajectory and imminent death. A total of 193 bereaved parents, representing 38% of the identified children, participated in the study. Overall, 98% of the parents expressed the view that physicians should immediately disclose when curatively intended treatment options were exhausted. Some 79% of parents reported that information about their child's incurable illness was given in an appropriate manner; however, 42% said that information about the child's imminent death was given too late. Finally, 31% felt deprived of the option to say goodbye to their child in their preferred manner, and 56% said that their child's death was "a shock". Parents request accurate and timely information. However, a substantial number of the parents surveyed reported that healthcare professionals communicated too late about palliative care and end-of-life issues. Even though healthcare professionals strive to communicate effectively with dying children and their parents, barriers were identified that may hinder even the best of intentions. National guidelines addressing communication issues and improved education of healthcare professionals should form part of any future agenda.


The family planning quotient and reproductive life index (FPQ/RepLI) tool: a solution for family planning, reproductive life planning and contraception counseling.
Access to comprehensive and culturally appropriate reproductive life planning is essential to women's health. Although many strategies and tools exist, few are designed for longitudinal use or provide visual aids. Our objective is to present the Family Planning Quotient (FPQ) and Reproductive Life Index (RepLI) (FPQ/RepLI) tool we created to facilitate the discussion of family planning and reproductive life goals between patients and providers and to provide a summary our evaluation of the tool. This tool was developed as a response to the Centers for Disease Control and Prevention's charge of developing a tool that could help facilitate reproductive life planning by giving the patient a better understanding of their reproductive goals and trajectory. This cross-sectional evaluation of our tool took place with patients and providers at an urban, public hospital in Chicago. Patients spoke with a health educator about their sexual, gynecological, and obstetric history to complete the FPQ/RepLI tool. Our primary objective was to measure the proportion of women who indicated the tool was helpful and that they would use it to track their reproductive goals. Patients and providers completed an evaluation survey rating their satisfaction with the tool. Survey responses were summarized using frequencies and percentages. During the study, 790 patients completed the evaluation.. Most patients (n = 725, 91.9%) agreed that the tool was helpful and that they would use it to track their reproductive goals. Fifty-five (83.5%) providers agreed that there is a need for reproductive health tools in clinical practice. Most agreed that the tool helped the patient communicate goals, aided in educating about contraception, and facilitated the discussion and decision-making process about available contraceptives. The tool gives patients a resource for family and reproductive goal planning. Broad dissemination amongst other medical specialties beyond obstetrics and gynecology may make reproductive life planning accessible to more women.


Regulatory enforcement and fiscal impact in local health agencies.
We used a cross-sectional, retrospective study design to analyze the association between local health agency regulatory activities and revenues from nonclinical fees and fines (NFF). We extracted data from the 2010 National Association of County and City Health Officials (NACCHO) Profile Survey, the most recent report including NFF information, and used 2-part multivariable regression models to identify relationships between regulatory activities and revenue. We also interviewed LHD directors on access to revenue from fines. NFFs generated substantial revenue for most LHDs, increasing in scope and amount with jurisdiction size for all but the largest municipalities. The greatest proportion of net revenue came from public pools, campgrounds and recreational vehicles, and solid waste disposal. For small and mid-sized LHDs, enforcement activities generated revenue in a dose-response pattern, with higher returns for increased activities. LHDs in decentralized governance states collected more NFF revenue than those in centralized states. States vary regarding LHD access to revenue from sanctions. The fiscal impact of changes in regulatory activity needs careful assessment to avoid unanticipated consequences of applicable law.


Anti-inflammatory effects of pancreatitis associated protein in inflammatory bowel disease.
Increased pancreatitis associated protein (PAP) mRNA has been reported in active inflammatory bowel disease (IBD). The aims of the current study were to characterise PAP production in IBD and the effects of PAP on inflammation. Serum PAP levels were determined in healthy controls (n = 29), inflammatory controls (n = 14), and IBD patients (n = 171). Ex vivo PAP secretion in intestinal tissue was measured in 56 IBD patients and 13 healthy controls. Cellular origin of PAP was determined by immunohistochemistry. The effects of exogenous PAP on nuclear factor kappaB (NFkappaB) activation, proinflammatory cytokine production, and endothelial adhesion molecule expression were also analysed ex vivo. Patients with active IBD had increased serum PAP levels compared with controls, and these levels correlated with clinical and endoscopic disease severity. Ex vivo intestinal PAP synthesis was increased in active IBD and correlated with endoscopic and histological severity of inflammatory lesions. PAP localised to colonic Paneth cells. Incubation of mucosa from active Crohn's disease with PAP dose dependently reduced proinflammatory cytokines secretion. PAP prevented TNF-alpha induced NFkappaB activation in monocytic, epithelial, and endothelial cells and reduced proinflammatory cytokine mRNA levels and adhesion molecule expression. PAP is synthesised by Paneth cells and is overexpressed in colonic tissue of active IBD. PAP inhibits NFkappaB activation and downregulates cytokine production and adhesion molecule expression in inflamed tissue. It may represent an anti-inflammatory mechanism and new therapeutic strategy in IBD.


Social Fitness and the Social Domain: A Holistic Approach Based on Total Force Fitness.
The Total Force Fitness (TFF) framework was envisioned as a holistic framework of interrelated domains, whereby impact in one domain could have cascading implications for the others. For this reason, definitional clarity surrounding how to achieve fitness in the various domains is crucial. Social fitness definitions tend to focus on individual efforts and overlook the powerful impact of the social group and the social environment on the individual. In this article, various definitions of social fitness are analyzed in an effort to broaden the current understanding of the social domain. Some of the knowledge gaps in understanding social fitness and the resulting challenges are addressed before reviewing a few existing social fitness interventions. Finally, this study offers recommendations for improvement, along with future directions for the increased integration of the social domain into the TFF framework.


Antiviral susceptibility of variant influenza A(H3N2)v viruses isolated in the United States from 2011 to 2013.
Since 2011, outbreaks caused by influenza A(H3N2) variant [A(H3N2)v] viruses have become a public health concern in the United States. The A(H3N2)v viruses share the A(H1N1)pdm09 M gene containing the marker of M2 blocker resistance, S31N, but do not contain any known molecular markers associated with resistance to neuraminidase (NA) inhibitors (NAIs). Using a fluorescent NA inhibition (NI) assay, the susceptibilities of recovered A(H3N2)v viruses (n=168) to FDA-approved (oseltamivir and zanamivir) and other (peramivir, laninamivir, and A-315675) NAIs were assessed. All A(H3N2)v viruses tested, with the exception of a single virus strain, A/Ohio/88/2012, isolated from an untreated patient, were susceptible to the NAIs tested. The A/Ohio/88/2012 virus contained two rare substitutions, S245N and S247P, in the NA and demonstrated reduced inhibition by oseltamivir (31-fold) and zanamivir (66-fold) in the NI assay. Using recombinant NA (recNA) proteins, S247P was shown to be responsible for the observed altered NAI susceptibility, in addition to an approximately 60% reduction in NA enzymatic activity. The S247P substitution has not been previously reported as a molecular marker of reduced susceptibility to the NAIs. Using cell culture assays, the investigational antiviral drugs nitazoxanide, favipiravir, and fludase were shown to inhibit the replication of A(H3N2)v viruses, including the virus with the S247P substitution in the NA. This report demonstrates the importance of continuous monitoring of susceptibility of zoonotic influenza viruses to available and investigational antiviral drugs.


Effect of fork-lift truck driving on low-back trouble.
In a population of 240 male fork-lift truck drivers who drove at least 4 h daily, the occurrence of low-back trouble was studied in relation to that of two reference groups. The participation rate of the fork-lift truck drivers was 88%. The responses to a questionnaire concerning low-back trouble were reviewed. Among the fork-lift truck drivers, a statistically significant higher occurrence of low-back trouble was reported for the year preceding the study, in comparison, according to age, to that of a reference group of 399 working men (65 against 47%); however, there was no significantly increased frequency when compared to that of a reference group of 66 unskilled male workers (65 against 51%). The fork-lift truck drivers had a significantly higher rate of absence from work within the previous year due to low-back trouble than the two reference groups (22% compared to 7 and 9%). These findings were confirmed during the follow-up year. A correlation was found between length of employment as a fork-lift truck driver and the occurrence of low-back trouble within the preceding year. It was concluded that fork-lift truck driving may be a contributory cause for low-back trouble.


The calcium-sensing receptor as a regulator of cellular fate in normal and pathological conditions.
The calcium-sensing receptor (CaSR) belongs to the evolutionarily conserved family of plasma membrane G protein-coupled receptors (GPCRs). Early studies identified an essential role for the CaSR in systemic calcium homeostasis through its ability to sense small changes in circulating calcium concentration and to couple this information to intracellular signaling pathways that influence parathyroid hormone secretion. However, the presence of CaSR protein in tissues is not directly involved in regulating mineral ion homeostasis points to a role for the CaSR in other cellular functions including the control of cellular proliferation, differentiation and apoptosis. This position at the crossroads of cellular fate designates the CaSR as an interesting study subject is likely to be involved in a variety of previously unconsidered human pathologies, including cancer, atherosclerosis and Alzheimer's disease. Here, we will review the recent discoveries regarding the relevance of CaSR signaling in development and disease. Furthermore, we will discuss the rational for developing and using CaSR-based therapeutics.


[The enteral feeding during the treatment of appendicular peritonitis in children].
A total of 65 patients, aged 3 to 14, with different forms of appendicular peritonitis, in whom the intestinal insufficiency syndrome (IIS), stage 2, was diagnosed, were investigated. 35 patients were in the main group, and 30 patients were in the control group; the subjects of the latter group had a similar form of peritonitis, i.e. IIS, stage 2, it was confirmed clinically and by ultrasound examinations. The laparoscopic operations were carried out in all patients. The patients of both groups received postoperatively a similar therapy, i.e. the antibacterial, metabolic and infusive ones, as well as vitamins and parenteral feeding (daily caloric values--50-120 kcal/kg, protein--2-3 g/kg/day) according to a child's age and a clinical course of peritonitis. All children of the main group received postoperatively an early enteral therapy (EET), which involved 4 stages. Stage 1: introduction of the salt solution with added glutamine through the naso-gastric probe by increasing volumes and with respect to an individual tolerability of a patient; stage 2: introduction of semi-element mixtures; stage 3: introduction of 10% solutions of polymer balanced mixture; stage 4: introduction of 20% solutions of polymer mixtures. Ultrasound scanning and clinical methods were used to assess the efficiency of the recovery of intestinal peristalsis. The conducted investigations showed that the mean duration of the gastric-type EET amounted to 3-4 days, and the IIS was, on the average, arrested by days 6 or 7. The duration of infusive therapy and parenteral feeding went down, in the main group, by 2 days. A trend towards an increase of the erythrocyte level was noted in these patients. No differences were registered in the values of concentrations of total protein and albumin in the blood serum of patients in both groups from the 1st to 7th postoperative days, however, the infusions of plasma and albumin were made by 2 times more often in the main group as compared to the control one. The EET technique preserved the gastric mucous tunic intact, which cut the postoperative complications 2-fold, and consequently, it reduced the stay of patients in hospital on the average by 8 days. A conclusion was made, on the basis of the conducted study, that EET is a pathophysiologically substantiated treatment method for IIS, stage 2, in children with appendicular peritonitis; EET ensures a rapid recovery of gastric-tract functions, it reduces the frequency rate of postoperative complications and cuts the length of both the infusive therapy and of the patients' stay in hospital.


Mortality pattern of silicotic subjects in the Latium region, Italy.
A mortality study was carried out on 595 workers who were compensated for silicosis in the Latium region, Italy, during the period 1946-84 who died between 1 January 1969 and 31 December 1984. Respiratory disorders, tuberculosis, lung cancer, bone cancer, and cirrhosis of the liver showed significantly increased risk ratios (4.1, 3.7, 1.5, 4.1, and 1.9 respectively); excesses of brain cancer and leukaemia did not reach statistical significance. Lung cancer mortality was further analysed by age, period of compensation, final degree of disability, and occupational activity. The possible confounding role of smoking was assessed by comparing the lifetime smoking habits of a sample of silicotic subjects with those of the general male population as estimated by a national health survey; the prevalence of ever smokers among silicotic subjects (70.7%) was similar to that estimated for the general population (68.5%). The present study indicates that silicosis is associated with lung cancer even though it does not clarify the respective roles of exposure to silica and silicosis.


Appropriate Prescribing for Older People: A New Tool for the General Practitioner.
Appropriate prescribing for older people is a challenge. General practitioners (GPs) are aware of their key position in relation to prescribing practice in the elderly. However, they often feel powerless and report a need for simple GP friendly tools to assess and support their prescribing practice. In this study such a tool is developed: the Appropriate Medication for Older people-tool (AMO-tool). The purpose of the study is to investigate whether GPs consider the use of the AMO-tool to be practically feasible and resulting in more appropriate prescribing. This pilot study with an interventional design was conducted over a period of six months. The study was conducted in nursing homes visited by GPs. The studied population consisted of nine GPs and 67 nursing home residents. The intervention consisted of the use of the AMO-tool. The Short Form (SF)-12 questionnaire was administered to the patients. Patients' medication lists were recorded. The GPs completed a semi-quantitative questionnaire on their experiences with the AMO-tool. A descriptive qualitative and semi-quantitative analysis was carried out on the GP questionnaire. The results of the SF-12 questionnaires and medication lists were analysed quantitatively. A multivariate analysis was carried out. In the perception of GPs, applying the AMO-tool to medication lists of nursing home residents was feasible and resulted in more appropriate prescribing. A slight reduction was recorded in the number of medications prescribed. Self-reported well-being improved and rose in parallel with the number of medication changes. According to GPs, the AMO-tool offers GPs the support in their prescribing practice. Changes are made to medication lists and improvements occur in patients' self-reported well-being. Future research should objectify the appropriateness of prescriptions before and after using the tool. Furthermore, it should investigate the possible causal relationship between the use of the AMO-tool, an increase in appropriateness of medication lists and an improvement of general well-being.


Effects of insulin and epinephrine on Na+-K+ and glucose transport in soleus muscle.
To identify possible cause-effect relationships between changes in active Na+-K+ transport, resting membrane potential, and glucose transport, the effects of insulin and epinephrine were compared in rat soleus muscle. Epinephrine, which produced twice as large a hyperpolarization as insulin, induced only a modest increase in sugar transport. Ouabain, at a concentration (10(-3) M) sufficient to block active Na+-K+ transport and the hyperpolarization induced by the two hormones, did not interfere with sugar transport stimulation. After Na+ loading in K+-free buffer, the return to K+-containing standard buffer caused marked stimulation of active Na+-K+ transport, twice the hyperpolarization produced by insulin but no change in sugar transport. The insulin-induced activation of the Na+-K+ pump leads to decreased intracellular Na+ concentration and hyperpolarization, but none of these events can account for the concomitant activation of the glucose transport system. The stimulating effect of insulin on active Na+-K+ transport was not suppressed by amiloride, indicating that in intact skeletal muscle it is not elicited by a primary increase in Na+ influx via the Na+/H+-exchange system.


Patient and Caregiver Attitudes toward Disorders of Sex Development Nomenclature.
The medical terminology applied to differences/disorders of sex development has been viewed negatively by some affected individuals. A clinical population of patients with differences/disorders of sex development and their caregivers were surveyed regarding current nomenclature, hypothesizing that those unaffiliated with support groups would have more favorable attitudes. We recruited English and Spanish speaking patients 13 years old or older with differences/disorders of sex development and their caregivers at 5 national tertiary care clinics from July 2016 to December 2018. No diagnoses were excluded. Participants completed a survey rating terminology commonly applied to differences/disorders of sex development. Responses were compared between subgroups, including members vs nonmembers of a support group. Of 185 potential participants approached 133 completed the survey (72% response rate). Congenital adrenal hyperplasia (33%) was the most common diagnosis. "Variation of sex development" was the most liked term (37%) but was not liked more significantly than "disorders of sex development" (27%, p=0.16). No term was liked by a majority of respondents. "Disorders of sex development" (37%) and "intersex" (53%) were the only terms most frequently viewed unfavorably. Support group members were significantly more likely to dislike the term "intersex" (p=0.02) and to like "variation of sex development" (p=0.02). A clinical population of patients and their caregivers had generally neutral attitudes toward nomenclature applied to differences/disorders of sex development. Members of a support group had clearer terminology preferences. "Variation of sex development" was the most liked term, and "disorders of sex development" and "intersex" were the most disliked. No term was liked by most respondents, and no clear alternative to the present nomenclature was identified.


Escherichia coli "TatExpress" strains export several g/L human growth hormone to the periplasm by the Tat pathway.
Escherichia coli is a heavily used platform for the production of biotherapeutic and other high-value proteins, and a favored strategy is to export the protein of interest to the periplasm to simplify downstream processing and facilitate disulfide bond formation. The Sec pathway is the standard means of transporting the target protein but it is unable to transport complex or rapidly folding proteins because the Sec system can only transport proteins in an unfolded state. The Tat system also operates to transport proteins to the periplasm, and it has significant potential as an alternative means of recombinant protein production because it transports fully folded proteins. Here, we have tested the Tat system's full potential for the production of biotherapeutics for the first time using fed-batch fermentation. We expressed human growth hormone (hGH) with a Tat signal peptide in E. coli W3110 "TatExpress" strains that contain elevated levels of the Tat apparatus. This construct contained four amino acids from TorA at the hGH N-terminus as well as the initiation methionine from hGH, which is removed in vivo. We show that the protein is efficiently exported to the periplasm during extended fed-batch fermentation, to the extent that it is by far the most abundant protein in the periplasm. The protein was shown to be homogeneous, disulfide bonded, and active. The bioassay showed that the yields of purified periplasmic hGH are 5.4 g/L culture whereas an enzyme-linked immunosorbent assay gave a figure of 2.39 g/L. Separate analysis of a TorA signal peptide linked to hGH construct lacking any additional amino acids likewise showed efficient export to the periplasm, although yields were approximately two-fold lower.


Health Care Professionals' Perceptions about Sensory-Based Interventions in the NICU.
The main objective of this article is to define perceptions of health care professionals regarding current use of sensory-based interventions in the neonatal intensive care unit (NICU). A multidisciplinary group of NICU health care professionals (n = 108) defined the types of sensory-based interventions used in their NICU, the postmenstrual age (PMA) sensory-based interventions are administered, conditions under which sensory-based interventions are used, and personnel who administer sensory-based interventions. The most commonly reported tactile intervention was infant holding (88% of respondents), the most common auditory intervention was recorded music/singing (69% of respondents), the most common kinesthetic intervention was occupational and physical therapy (85% of respondents), and the most common vestibular intervention was infant swings (86% of respondents). Tactile interventions were initiated most often at 24 to 26 weeks PMA (74% of respondents), auditory interventions at 30 to 32 weeks (60% of respondents), kinesthetic interventions at 30 to 32 weeks (76% of respondents), vestibular interventions at 33 to 34 weeks (86% of respondents), and visual interventions at 32 to 36 weeks (72% of respondents). Conditions under which sensory-based interventions were administered, and personnel who provided them, varied across settings. Varied use of sensory-based interventions in the NICU were reported. While this study was limited by biased sampling and the identification of health care professionals' perceptions but not real-world practice, this information can be used to build a comprehensive approach to positive sensory exposures in the NICU.


Intimate partner violence and positive parenting across early childhood: Comparing self-reported and observed parenting behavior.
The current study examined self-reported and observed positive (i.e., nurturing, sensitive, and responsive) parenting behavior among women who experienced intimate partner violence (IPV) during pregnancy and through their early parenting years. Mother-child dyads were assessed during the third trimester of pregnancy and each year postpartum until age 4. Latent growth curve models of self-reported positive parenting suggested that IPV experienced during pregnancy was related to women reporting more gradual reductions in positive parenting between ages 1 and 4 and higher levels of positive parenting behavior at age 4. However, IPV experienced during pregnancy was associated with lower levels of observed positive parenting at age 4. These findings suggest that mothers who experience IPV during pregnancy may positively distort their perceptions of their positive parenting during early childhood, such that it is inconsistent with actual parenting behavior. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Nerve growth factor receptor immunoreactivity in the new world monkey (Cebus apella) and human cerebellum.
The present study used the NGFR-5 monoclonal antibody raised against human nerve growth factor receptor (NGFR) to determine the extent of NGFR immunoreactivity within the embryonic and young adult Cebus apella cerebellum as well as the human cerebellum. Immunohistochemically processed tissue revealed NGFR expressing Purkinje cell somata, axons, and dendrites, the latter being observed within the molecular layer of both adult species. Within all regions of the cerebellum we observed both darkly and lightly immunostained Purkinje cells. The proximal axons of these cells, which were visualized for short distances within the granular cell layer, appeared to contain bulbous aggregates of reaction product. In sagittal sections, the full extent of the Purkinje cell dendritic tree was observed in the more lightly stained portions of the cerebellum. In situ hybridization experiments revealed NGFR mRNA within Purkinje cells in a pattern similar to that seen with immunohistochemistry. The distribution of NGFR immunoreactivity within the cerebellum exhibits a general topographic organization with the heaviest and most consistent staining occurring within the archi- and neocerebellum and weaker staining within the paleocerebellum. In fetal Cebus monkey cerebellum obtained at gestational day 50 and 70, NGFR immunoreactivity was observed as a band composed of developing Purkinje cell neurites. These profiles were seen in the paleo- and neocerebellum, but not the archicerebellum. The present investigation is the first demonstration of NGFR immunoreactive profiles in the adult monkey and human cerebellum. These findings suggest that nerve growth factor may influence locomotor and vestibular behaviors that are mediated by cerebellar circuity. The precise mode of action for the NGF/NGFR system within the cerebellum remains to be determined.


Insulin resistance and LVH progression in patients with calcific aortic stenosis: a substudy of the ASTRONOMER trial.
The objective of this substudy of the ASTRONOMER (Aortic Stenosis Progression Observation: Measuring Effects of Rosuvastatin) trial was to examine the association between insulin resistance and progression of left ventricular hypertrophy (LVH) in patients with aortic stenosis (AS). In a recent cross-sectional study, the authors reported that the metabolic syndrome was associated with an increased prevalence of concentric LVH in patients with AS. As a central feature of the metabolic syndrome, insulin resistance could be an important mediator of this association. This substudy included 250 of 269 patients enrolled in ASTRONOMER. Follow-up was 3.4 ± 1.3 years. Insulin resistance was evaluated using the homeostatic assessment model (HOMA) index, and patients were dichotomized using the median HOMA index value (1.24). The rate of LVH progression was estimated by calculating the annualized change in LV mass index (LVMi), measured on echocardiography. The presence of LVH was defined as an LVMi >47 g/m(2.7) in women and >49 g/m(2.7) in men. There was a significant progression of LVH among the patients without LVH at baseline (n = 134; p < 0.0001) but not in those with it (n = 116; p = NS). In those without LVH at baseline, the annualized progression rate of LVMi was significantly faster in the subset with HOMA >1.24 compared to that in the subset with HOMA <1.24 (2.49 ± 4.38 g/m(2.7)/year vs. -0.03 ± 3.90 g/m(2.7)/year; p = 0.001). During follow-up, LVH developed in 46% of patients with HOMA >1.24 compared to 11% of those with HOMA <1.24 (p = 0.0005). Independent predictors of faster LVH progression identified on multivariate analysis were history of hypertension (p = 0.048), degree of aortic valve calcification (p = 0.035), and HOMA index (p = 0.02). In this ASTRONOMER substudy, insulin resistance was a powerful independent predictor of progression to LVH in patients with AS. Visceral obesity and ensuing insulin resistance may thus present novel therapeutic targets in AS patients.


Identifying the Growth Factors for Improving Neointestinal Regeneration in Rats through Transcriptome Analysis Using RNA-Seq Data.
Using our novel surgical model of simultaneous intestinal adaptation "A" and neointestinal regeneration "N" conditions in individual rats to determine feasibility for research and clinical application, we further utilized next generation RNA sequencing (RNA-Seq) here in normal control tissue and both conditions ("A" and "N") across time to decipher transcriptome changes in neoregeneration and adaptation of intestinal tissue at weeks 1, 4, and 12. We also performed bioinformatics analyses to identify key growth factors for improving intestinal adaptation and neointestinal regeneration. Our analyses indicate several interesting phenomena. First, Gene Ontology and pathway analyses indicate that cell cycle and DNA replication processes are enhanced in week 1 "A"; however, in week 1 "N", many immune-related processes are involved. Second, we found some growth factors upregulated or downregulated especially in week 1 "N" versus "A". Third, based on each condition and time point versus normal control tissue, we found in week 1 "N" BMP2, BMP3, and NTF3 are significantly and specifically downregulated, indicating that the regenerative process may be inhibited in the absence of these growth factors. This study reveals complex growth factor regulation in small neointestinal regeneration and intestinal adaptation and provides potential applications in tissue engineering by introducing key growth factors identified here into the injury site.


Identifying predictors of Day 5 blastocyst utilization rate using an artificial neural network.
Can artificial intelligence identify predictors of an increased Day 5 blastocyst utilization rate (D5BUR), which is one of the most informative key performance indicators in an IVF laboratory? This retrospective, multicentre study evaluated six variables for predicting D5BUR using an artificial neural network (ANN): number of metaphase II (MII) oocytes injected (intracytoplasmic sperm injection); use of autologous/donated gametes; maternal age at oocyte retrieval; sperm concentration; progressive sperm motility rate; and fertilization rate. Cycles were divided into training and testing sets through stratified random sampling. D5BUR on Day 5 was grouped into <60% and ≥60% as per the Vienna consensus benchmark values. The area under the receiver operating characteristic curve (AUC) to predict the D5BUR groups was 80.2%. From the ANN model, all six independent variables were found to be of significant value for the prediction of D5BUR (P<0.0001), with the most important variable being the number of MII oocytes injected. Investigation of the effect of MII oocytes injected on D5BUR indicated an inverse correlation, with injection of an increasing number of MII oocytes resulting in a decreasing D5BUR (r=-0.344, P<0.001) and injection of up to six oocytes resulting in D5BUR ≥60%. The number of MII oocytes injected is the most important predictor of D5BUR. Exploration of additional variables and further validation of models that can predict D5BUR can guide the way towards personalized treatment and increased safety.


BACE1 activity is modulated by cell-associated sphingosine-1-phosphate.
Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-β peptide (Aβ) production, is modulated by S1P in mouse neurons. Treatment by SphK inhibitor, RNA interference knockdown of SphK, or overexpression of S1P degrading enzymes decreased BACE1 activity, which reduced Aβ production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer's disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer's disease.


The acquisition of transferable extrachromosomal fec operon is associated with a cefiderocol MIC increase in Enterobacterales.
Cefiderocol is a novel siderophore cephalosporin active against MDR Gram-negative bacilli, including MBL-harbouring Enterobacterales. The detection of multiple cefiderocol-resistant blaVIM-carrying Enterobacterales isolates (MIC = 4 mg/L) from a single patient suggested an additional, potentially transferable, resistance determinant as blaVIM typically does not elevate cefiderocol MIC above the resistance threshold. Transfer of a mobile genetic element was performed in liquid mating experiments. All donor isolates and transconjugants were characterized by short-read WGS to identify potential resistance determinants. mRNA expression of siderophore receptors was determined by quantitative RT-PCR. Validation was performed by transformation. Antibiotic susceptibility was determined by broth microdilution. Liquid mating experiments indicated the presence of transferable resistance determinants. Comparative genomic analysis of the clinical isolates and their respective transconjugants revealed the transfer of an accessory fec operon (fecABCDEIR). Transformation of the fec operon-containing vector into a TOP10 Escherichia coli led to an elevation of the cefiderocol MIC by at least 16-fold. Higher expression of fecA as a proxy for the fec operon mRNA expression was associated with phenotypic cefiderocol resistance. Both VIM and the accessory fec operon contribute to the elevation of cefiderocol MIC beyond the resistance threshold. The acquisition of an accessory fec operon via liquid mating confers phenotypic cefiderocol resistance in both E. coli J53 and Pseudomonas aeruginosa PAO1, indicating a broad-host-range nature of this mobile resistance determinant. The emergence of a transferable cefiderocol resistance determinant without prior exposure to the substance is worrisome and should be monitored closely.


Peri-Implant Fractures Distal to an Antegrade Femoral Nail: A Case Series.
Peri-implant fractures distal to an antegrade femoral nail are uncommon injuries, with no current consensus on the best treatment modality. We are presenting three cases of periimplant fractures distal to an antegrade femoral nail. All patients sustained an initial traumatic injury, which was managed with an antegrade femoral nail fixation. They subsequently suffer a second injury which causes periimplant fracture. Our first two patients were managed with removing the intramedullary nail followed by Less Invasive Stabilization System (LISS) plate fixation. In our third case, the intramedullary nail was left in-situ, and the fracture was fixed with a polyaxial locking plate We discuss their injury pattern, investigations and surgical management. Polyaxial locking plates show great promise in this setting as they allow fixation of the fracture whilst maintaining the existing nail to protect the entire femur from further injury.


Biomechanical and histomorphological analysis of the mandible in rats with chronic kidney disease.
The present study aimed to investigate the biomechanical and histomorphological features of mandibles in an adenine-induced chronic kidney disease-mineral and bone disorder (CKD-MBD) rat model of CKD. A total of 14 Sprague-Dawley rats were randomized into the following two groups: control group and CKD group. At the end of the sixth week, all rats were euthanized, and serum was collected for biochemical marker tests. Macroscopic bone growth and biomechanical parameters were measured in the right hemimandible, while the left hemimandible was used for bone histomorphometric analysis. Compared to the control group, the CKD group showed a significant increase in serum creatinine, blood urea nitrogen, and serum parathyroid hormone at the end of the sixth week. The biomechanical structural properties significantly decreased in the CKD group compared to the control group. Bone histomorphometric analysis indicated that the trabecular bone volume of rats in the CKD group was significantly lower than that of the control group. In the CKD groups, the bone formation parameters of the trabecular bone were significantly increased, while the bone mineralization apposition rates of both the trabecular bone and periosteal cortical bone were significantly increased. The rat CKD model showed deteriorated structural mechanics, low trabecular bone volume, high trabecular bone formation, increased trabecular bone mineralization apposition rate, and increased cortical bone mineralization apposition rate, which met the characteristics of osteitis fibrosa, indicating that this model is a useful tool for the study of mandible diseases in CKD patients.


Long-term protection against tobacco mosaic virus induced by the marine alga oligo-sulphated-galactan Poly-Ga in tobacco plants.
In order to study the antiviral effect of the oligo-sulphated galactan Poly-Ga, the leaves of tobacco plants Xhanti(NN) were sprayed with water (control), with increasing concentrations of Poly-Ga, for increasing numbers of treatments or cultivated for increasing times after treatment. Control and treated plants were infected with tobacco mosaic virus (TMV) and the numbers of necrotic lesions were measured in infected leaves. The number of necrotic lesions decreased with increasing concentrations of Poly-Ga, with increasing numbers of treatments and with increasing time after treatment, indicating a long-term protection against TMV that mimicks vaccination. In addition, control Xhanti(nn) plants and plants treated with Poly-Ga and cultivated for increasing times after treatment were infected with TMV in the middle part of the plant, and the levels of TMV-capsid protein (CP) transcripts were measured in apical leaves. TMV-CP transcripts decreased in distant leaves, indicating that Poly-Ga induces systemic protection against TMV. The activities of the defence enzymes phenylalanine ammonia lyase (PAL) and lipoxygenase (LOX) and the amounts of several phenylpropanoid compounds (PPCs) were measured in control and treated plants without infection. A progressive increase in PAL activity was observed with increasing time after treatment, together with the accumulation of free and conjugated PPCs. In contrast, LOX activity remained unchanged. Interestingly, the increase in PAL activity showed a linear correlation with the decrease in necrotic lesions and the decrease in TMV-CP transcript level. Thus, Poly-Ga induced systemic and long-term protection against TMV in tobacco plants that is determined, at least in part, by a sustained activation of PAL and the accumulation of PPCs with potential antiviral activity.


Preclinical Evidence That 5-HT1B Receptor Agonists Show Promise as Medications for Psychostimulant Use Disorders.
5-HT1B receptor agonists enhance cocaine intake during daily self-administration sessions but decrease cocaine intake when tested after prolonged abstinence. We examined if 5-HT1B receptor agonists produce similar abstinence-dependent effects on methamphetamine intake. Male rats were trained to self-administer methamphetamine (0.1 mg/kg, i.v.) on low (fixed ratio 5 and variable ratio 5) and high (progressive ratio) effort schedules of reinforcement until intake was stable. Rats were then tested for the effects of the selective 5-HT1B receptor agonist, CP 94,253 (5.6 or 10 mg/kg), or the less selective but clinically available 5-HT1B/1D receptor agonist, zolmitriptan (10 mg/kg), on methamphetamine self-administration both before and after a 21-day forced abstinence period during which the rats remained in their home cages. The inverted U-shaped, methamphetamine dose-response function for intake on the fixed ratio 5 schedule was shifted downward by CP 94,253 both before and after abstinence. The CP 94,253-induced decrease in methamphetamine intake was replicated in rats tested on a variable ratio 5 schedule, and the 5-HT1B receptor antagonist SB 224,289 (10 mg/kg) reversed this effect. CP 94,253 also attenuated methamphetamine intake on a progressive ratio schedule both pre- and postabstinence. Similarly, zolmitriptan attenuated methamphetamine intake on a variable ratio 5 schedule both pre- and postabstinence, and the latter effect was sustained after each of 2 more treatments given every 2 to 3 days prior to daily sessions. Unlike the abstinence-dependent effect of 5-HT1B receptor agonists on cocaine intake reported previously, both CP 94,253 and zolmitriptan decreased methamphetamine intake regardless of abstinence. These findings suggest that 5-HT1B receptor agonists may have clinical efficacy for psychostimulant use disorders.


Prognostic value of MRI in arthroscopic treatment of chronic patellar tendinopathy: a prospective cohort study.
To date, prognostic outcome factors for patients undergoing arthroscopic treatment due to chronic patellar tendinopathy (PT) are lacking. The purpose of this study was to investigate whether preoperatively assessed MRI parameters might be of prognostic value for prediction of functional outcome and return to sports in arthroscopic treatment of chronic PT. A prospective cohort study was conducted including 30 cases (4 female and 24 male competitive athletes) undergoing arthroscopic patellar release (APR) due to chronic PT. The mean age was 28.2 years (range, 18-49 years) at the time of surgery, and the mean follow-up period was 4.2 years (range, 2.2-10.4 years). Preoperatively assessed MRI parameters included bone marrow edema (BME) of the inferior patellar pole, patellar tendon thickening, infrapatellar fat pad (IFP) edema, and infrapatellar bursitis. Prevalences of preoperative MRI findings were correlated to functional outcome scores in order to determine statistically significant predictors. All athletes regained their preinjury sports levels. Athletes featuring preoperative IFP edema showed significantly inferior modified Blazina score (0.6 ± 0.7 vs. 0.2 ± 0.5), single assessment numeric evaluation (SANE; 86.0 ± 8.8 vs. 94.3 ± 7.5), and Visual Analogue Scale (VAS; 1.0 ± 1.2 vs. 0.3 ± 0.8) compared to subjects without IFP edema (p < 0.05). Return to sports required a mean of 4 ± 3.2 months. On average, patients with IFP edema needed significantly more time to return to sports than subjects without IFP edema (6.5 vs 2.8 months; p < 0.05). The simultaneous presence of BME and IFP edema was associated with significantly inferior outcomes by means of the Victorian Institute of Sport Assessment questionnaire for patients with patellar tendinopathy (VISA-P; 88.1 ± 11.9 vs. 98.6 ± 4.2), SANE (84.3 ± 10.2 vs. 93.1 ± 8.3), and VAS (1.3 ± 1.4 vs. 0.3 ± 0.9) compared to an isolated BME or isolated IFP edema. This is the first study identifying prognostic outcome factors in arthroscopic treatment of chronic PT. Preoperative IFP edema alone or simultaneous BME and IFP edema on preoperative MRI were associated with inferior functional outcome and delayed return to sports. Knowledge of these predictive factors might improve risk stratification, individualize treatment and postoperative rehabilitation, and contribute to improve clinical outcome. Moreover, current findings offer the potential for novel therapeutic approaches.


Tobacco mosaic virus movement protein complements a Potato spindle tuber viroid RNA mutant impaired for mesophyll entry but not mutants unable to enter the phloem.
Tobacco mosaic virus movement protein (TMV MP) is essential for virus spread between cells. To accomplish its task, TMV MP binds viral RNA, interacts with components of the cytoskeleton, and increases the size exclusion limit (SEL) of plasmodesmata. Plasmodesmata are gated intercellular channels that allow passage of small molecules and macromolecules, including RNA and protein, between plant cells. Moreover, plasmodesmata are diverse and those connecting different cell types appear to have unique mechanisms to regulate macromolecular trafficking, which likely contributes to the establishment of distinct cell boundaries. Consequently, TMV MP might be competent to mediate RNA transport through some but not all plasmodesmal gates. Due to a lack of viral mutants defective for movement between specific cell types, the ability of TMV MP in this regard is incompletely understood. In contrast, a number of trafficking impaired Potato spindle tuber viroid (PSTVd) mutants have been identified. PSTVd is a systemically infectious non-coding RNA that nevertheless can perform all functions required for replication as well as cell-to-cell and systemic spread. Previous studies have shown that PSTVd employs different structure and sequence elements to move between diverse cell types in host plants, and mutants defective for transport between specific cell types have been identified. Therefore, PSTVd may serve as a tool to analyze the functions of MPs of viral and cellular origin. To probe the RNA transport activity of TMV MP, transgenic plants expressing the protein were inoculated with PSTVd mutants. Remarkably, TMV MP complemented a PSTVd mutant defective for mesophyll entry but could not support two mutants impaired for phloem entry, suggesting it fails to productively interface with plasmodesmata at the phloem boundary and that additional viral and host factors may be required. Consistent with this idea, TMV co-infection, but not the combination of MP and coat protein (CP) expression, was able to complement one of the phloem entry mutants. These observations suggest that phloem loading is a critical impediment to establishing systemic infection that could involve the entire ensemble of TMV proteins. They also demonstrate a novel strategy for analysis of MPs.


Role of adrenal steroids on electroacupuncture analgesia and on antagonising potency of naloxone.
Electroacupuncture (EA), a form of transcutaneous electrical stimulation, produces opiate-like antinociception and catalepsy in rats. This effect of EA cannot be produced in hypophysectomised rats, whereas adrenalectomised rats show increased sensitivity. In intact rats, adrenocorticotrophic hormone and dexamethasone have been found to be effective to sensitise the animals to the analgesic effect of EA. Deoxycorticosterone, on the contrary, attenuates this effect. Spironolactone is also effective to potentiate EA response, which is accompanied with severe respiratory depression. Drugs that are known to affect adrenal aldosterone secretion also modulate the effect of EA. Naloxone administration, 15 min prior to the initiation of EA stimulation, potentiates the effect of EA, whereas it counteracts the effect of EA if administered after initiation of EA stimulation. Moreover, this counteracting ability of naloxone increases with the increase in time interval between initiation of stimulation and naloxone challenge. Pretreatment with drugs that impair adrenal mineralocorticoid response to physiological stimuli inhibits the counteracting effect of naloxone. On the contrary, mineralocorticoid supplemented rats show greater sensitivity to naloxone counteraction.


Angiotensin II AT1 receptors and Na+/K+ ATPase in human umbilical vein endothelial cells.
Cultured human umbilical vein endothelial cells (HUVECs) at passage 4 specifically bound 70 +/- 12 fmol [3,5-3H]Tyr4-Ile5-angiotensin (Ang) II/mg protein, with a Kd of 0.9 +/- 0.36 nM. Binding was eliminated in cells preincubated with a monoclonal antibody (6313/G2) raised against the subtype AT1 of the Ang II receptor. Freshly seeded HUVECs were positive for 6313/G2 antibody by immunocytochemistry, and such immunoreactivity was still retained at passage 4. Incubation of HUVECs for 20 min with different concentrations of Ang II provoked a significant increment in Na+/K+ ATPase activity compared with controls, in a dose- and time-dependent manner. Maximal response was obtained with 1000 pM Ang II after 20 min stimulation and resulted in a 2.2-fold increment in Na+/K+ ATPase activity. This stimulation was abolished when cells were incubated with 1000 pM Ang II in the presence of 1 microM of the specific AT1 subtype inhibitor, DuP753. Moreover, preincubation of HUVECs with 6313/G2 or with 1 mM dithiothreitol also inhibited the stimulatory effect of Ang II. These results suggest that the AT1 receptor subtype mediates the Na+/K+ ATPase response to Ang II in these cells.


Neuronal TRP channels: thermometers, pathfinders and life-savers.
Cation channels of the TRP superfamily are widely expressed in the nervous system, and important progress has been made in elucidating the gating properties and physiological roles of neuronal TRPs. Recent studies have firmly established the role of temperature-sensitive TRPs (thermoTRPs) as the principal molecular thermometers in the peripheral sensory system, and provided the first molecular insight into the mechanisms underlying the exquisite thermo- and chemosensitivity of these channels. Moreover, accumulating evidence implicates TRP channels in the development of the central nervous system. In particular, Ca(2+) influx via TRPC channels appears to be a critical component of the signalling cascade that mediates the guidance of growth cones and survival of neurons in response to chemical cues such as neurotrophins or Netrin-1.


Unusual cryptosporidium species recovered from human faeces: first description of Cryptosporidium felis and Cryptosporidium 'dog type' from patients in England.
DNA was extracted from faecal samples collected from 1680 patients in which Cryptosporidium oocysts were recognised by light microscopy. DNA from faeces from five of these patients failed to amplify by PCR three gene fragments--the Cryptosporidium oocyst wall protein (COWP) gene, the thrombospondin-related adhesive protein of Cryptosporidium-1 (TRAP-C1) gene and the thrombospondin-related adhesive protein of Cryptosporidium-2 (TRAP-C2) gene--with primers designed from C. parvum sequences. However, DNA from these five patients did amplify cryptosporidial 18S rDNA gene fragments and a heat-shock protein (HSP70) gene fragment was also amplified from four of them. The purpose of this study was to characterise further the Cryptosporidium associated with infection in these patients. DNA sequence analysis of 18S rDNA genes showed that four of these patients were infected by C. felis, and the remaining one by an as yet un-named Cryptosporidium species designated the 'dog type' (C. dt). Infection by C. felis was further confirmed in all four patients by DNA sequence analysis of the HSP70 gene. Oocysts present in all five samples reacted strongly with two anti-cryptosporidial oocyst monoclonal antibodies, except for the C. dt, which was tested with only one of the antibodies. Two of the patients infected by C. felis had underlying illness; one 8-year-old male had an undefined severe inherited underlying condition, and the second patient, a 32-year-old male, was HIV positive. Two of the remaining three patients (two females aged 1 and 2 years, respectively) were apparently immunocompetent (one infected with C. felis and one with the C. dt). No information was obtained for the fifth patient. The patient infected by C. dt had a recent history of travel to Africa. This is the first report of infection with these two Cryptosporidium species in immunocompetent patients, and in any patient in the UK.


[The endoscopic treatment of bronchial fistulas by submucosal injections].
A total of 21 patients (aged 30-72) with bronchial stump fistulas (307 mm) were treated by a newly developed method of treatment of purulent-destructive pulmonary diseases. This technique represents a gradual narrowing of the bronchial fistula lumen due to infiltrate formation in the submucosal bronchial layer. The volume formation substance biopolymer "DAM+", hydrogenous biopolymer with ions of silver "Argiform" for endoprosthesis of the soft tissues, is injected into the submucosal bronchial layer. It is necessary to make 5-20 fibrobronchoscopies for bronchial fistula healing. No complications occurred as a result of this treatment. The healing of bronchial fistula and bronchial stump epithelization were found in 18 patients.


A method for identifying allele-specific hydroxymethylation.
We previously identified sequence-dependent allele-specific methylation (sd-ASM) in adult human peripheral blood leukocytes, in which ASM occurs in cis depending on adjacent polymorphic sequences. A number of groups have identified sd-ASM sites in the human and mouse genomes, illustrating the prevalence of sd-ASM in mammalian genomes. In addition, sd-ASM can lead to sequence-dependent allele-specific expression of neighbouring genes. Imprinted genes also often exhibit parent-of-origin-dependent allele-specific methylation (pd-ASM), which causes parent-of-origin-dependent allele-specific expression. However, whether most of the already known sd-ASM and pd-ASM sites are methylated or hydroxymethylated remains unclear due to technical restrictions. Accordingly, a novel method that enables examination of allelic methylation and hydroxymethylation status and also overcomes the drawbacks of conventional methods is needed. Such a method could also be used to elucidate the mechanisms underlying polymorphism-associated inter-individual differences in disease susceptibility and the mechanism of genomic imprinting. Here, we developed a simple method to determine allelic hydroxymethylation status and identified novel sequence- and parent-of-origin-dependent allele-specific hydroxymethylation sites. Correlation analyses of TF binding sequences and methylation or hydroxymethylation between three mouse strains revealed the involvement of Pax5 in strain-specific methylation and hydroxymethylation in exon 7 of Pdgfrb.


Ionic currents in slow twitch skeletal muscle in the rat.
1. The ionic currents in slow fibres isolated from rat soleus muscle have been studied under voltage-clamp conditions with a double sucrose-gap method and the results are compared to those obtained from fast fibres isolated from the iliacus muscle. 2. The mean value of the resting potential in slow fibres is -70 mV. a value 8 mV more positive that the mean resting potential of fast fibres (-78 mV). 3. In slow muscle, a fast inward current which is blocked by tetrodotoxin and which depends on external sodium concentration is presumed to be carried by sodium ions. The characteristics of this current, which are time- and voltage-dependent, are similar to those of the iliacus fibres. From a holding potential at -86 mV, this inward current is maximal (2.6 mA/cm2 +/- 0.3) at +49.1 mV +/- 1.5 (mean +/- S.E. of mean), reverses at +127.3 mV +/- 2.2 (mean +/- S.E. of mean), and its half inactivation occurs at +23.2 mV +/- 0.8 (mean +/- S.E. of mean). 4. The delayed outward current in slow fibres is unchanged by exposure to chloride free solution and has a time course very different from that found in fast fibres. This current reaches an initial peak in 5-10 msec and a second peak or steady level after 40-150 msec. The decay of the outward current is also very different, being ten times slower than that in fast fibres (1500-3000 msec). 5. Analysis of the tail currents reveals the existence of two components of delayed current in slow fibres. The faster component reverses at a potential of 11.3 mV +/- 0.9 (mean +/- S.E. of mean) positive to the holding potential (equivalent to a membrane potential of about -75 mV), in contrast to a reversal potential of 35.4 mV +/- 2.5 (mean +/- S.E. of mean) positive to the holding potential for the slower component (equivalent to a membrane potential of about -51 mV. 6. In L-glutamate solution the characteristics of the inward-going rectification are the same in the two types of muscle.


[Optimization of diagnosis of postoperative peritonitis].
The syndrome approach to diagnosis of the postoperative intraabdominal complications was used. Analysed were 170 case records and 15 observations of the patients with postoperative peritonitis. The data were registered in a specially compiled for every patient formalized card. Materials were computer-processed. The integral criterion for diagnosis of postoperative peritonitis has been obtained.


Atypical in vitro and in vivo binding of [3H]S-14506 to brain 5-HT1A receptors.
The tritiated derivative of the potent 5-HT1A receptor agonist S-14506 ¿1[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)pipera zine¿ was tested for its capacity to selectively label the serotonin 5-HT1A receptors both in vitro in the rat and the mouse brain, and in vivo in the mouse. In vitro studies showed that the pharmacological profile and the distribution of [3H]S-14506 specific binding sites (Kd = 0.15 nM) in different brain regions matched perfectly those of the prototypical 5-HT1A receptor ligand [3H]8-OH-DPAT. However, in the three regions examined (hippocampus, septum, cerebral cortex), the density of [3H]S-14506 specific binding sites was significantly higher (+66-90%) than that found with [3H]8-OH-DPAT. Whereas the specific binding of [3H]8-OH-DPAT was markedly reduced by GTP and Gpp(NH)p and increased by Mn2+, that of [3H]S-14506 was essentially unaffected by these compounds. In addition, the alkylating agent N-ethylmaleimide was much less potent to inhibit the specific binding of [3H]S-14506 than that of [3H]8-OH-DPAT. Measurement of in vivo accumulation of tritium one hour after i.v. injection of [3H]S-14506 to mice revealed marked regional differences, with about 2.5 times more radioactivity in the hippocampus than in the cerebellum. Pretreatment with 5-HT1A receptor ligands prevented tritium accumulation in the hippocampus but not in the cerebellum. Autoradiograms from brain sections of injected mice confirmed the specific in vivo labeling of 5-HT1A receptors by [3H]S-14506, therefore suggesting further developments with derivatives of this molecule for positron emission tomography in vivo in man.


Targeting Autophagy by MPT0L145, a Highly Potent PIK3C3 Inhibitor, Provides Synergistic Interaction to Targeted or Chemotherapeutic Agents in Cancer Cells.
Anticancer therapies reportedly promote pro-survival autophagy in cancer cells that confers drug resistance, rationalizing the concept to combine autophagy inhibitors to increase their therapeutic potential. We previously identified that MPT0L145 is a PIK3C3/FGFR inhibitor that not only increases autophagosome formation due to fibroblast growth factor receptor (FGFR) inhibition but also perturbs autophagic flux via PIK3C3 inhibition in bladder cancer cells harboring FGFR activation. In this study, we hypothesized that combined-use of MPT0L145 with agents that induce pro-survival autophagy may provide synthetic lethality in cancer cells without FGFR activation. The results showed that MPT0L145 synergistically sensitizes anticancer effects of gefitinib and gemcitabine in non-small cell lung cancer A549 cells and pancreatic cancer PANC-1 cells, respectively. Mechanistically, drug combination increased incomplete autophagy due to impaired PIK3C3 function by MPT0L145 as evidenced by p62 accumulation and no additional apoptotic cell death was observed. Meanwhile, drug combination perturbed survival pathways and increased vacuolization and ROS production in cancer cells. In conclusion, the data suggest that halting pro-survival autophagy by targeting PIK3C3 with MPT0L145 significantly sensitizes cancer cells to targeted or chemotherapeutic agents, fostering rational combination strategies for cancer therapy in the future.


GP preferences for information systems: conjoint analysis of speed, reliability, access and users.
To elicit the preferences and trade-offs of UK general practitioners about key features of health information systems, to help inform the design of such systems in future. A stated choice study to uncover implicit preferences based on a binary choice between scenarios presented in random order. were all 303 general practice members of the UK Internet service provider, Medix who were approached by email to participate. The main outcome measure was the number of seconds delay in system response that general practitioners were willing to trade off for each key system feature: the reliability of the system, the sites from which the system could be accessed and which staff are able to view patient data. Doctors valued speed of response most in information systems but would be prepared to wait 28 seconds to access a system in exchange for improved reliability from 95% to 99%, a further 2 seconds for an improvement to 99.9% and 27 seconds for access to data from anywhere including their own home compared with one place in a single health care premises. However, they would require a system that was 14 seconds faster to compensate for allowing social care as well as National Health Service staff to read patient data. These results provide important new evidence about which system characteristics doctors value highly, and hence which characteristics designers need to focus on when large scale health information systems are planned.


Abundance and biomass of copepods and cladocerans in Atlantic and Arctic domains of the Barents Sea ecosystem.
Zooplankton in the Barents Sea have been monitored annually with a standard procedure with determination of size-fractioned biomass since the mid-1980s. Biomass of copepods and cladocerans was estimated based on measured abundance and individual weights taken from literature. Calanus species were dominant, making up ~85% of the estimated biomass of copepods. The second most important taxon was Oithona spp. (~0.5 g dry weight (dw) m-2, ~10%), followed by Metridia spp. (~0.15 g dw m-2, 2-3%) and Pseudocalanus spp. (0.10-0.15 g dw m-2, 1-5%). Estimated biomass of cladoceran taxa (Evadne and Podon) was low (0.01 g dw m-2). Calanus spp. contributed most of the biomass of the medium size fraction (1-2 mm), whereas small copepod species (Oithona, Pseudocalanus and others) contributed to the small size fraction (<1 mm). Estimated biomass of Calanus spp. and of the sum of small copepod species were both positively correlated with measured total zooplankton biomass (R2 = 0.72 and 0.34, respectively). The biomass ratio of small copepod species to Calanus was similar in Atlantic and Arctic water masses (~0.15-0.2) but tended to increase with decreasing total biomass. This suggests a shift to relatively larger roles of small copepods as Calanus and total biomass decrease.


Antibodies that bind to fimbriae block adhesion of Streptococcus sanguis to saliva-coated hydroxyapatite.
Antibodies raised against a fimbriated, adhesive strain of Streptococcus sanguis (FW213) were found to block the adhesion of this organism to saliva-coated hydroxyapatite. Antibodies were made specific for adhesion antigens by adsorption with isogenic, nonadhesive mutants (for rabbit polyclonal adsorbed antibody) or selection based on nonreactivity with two nonadhesive mutants (for monoclonal antibody). Rabbit antibody raised against isogenic, nonfimbriated nonadhesive mutants served as a control for antibodies present, but not related to fimbriation. Adsorbed antibody and monoclonal antibody were shown to be specific for fimbriae (antigen 1), since both antibodies could be seen by immune electron microscopy to bind 3.6-nm fimbriae, reacted only with the fimbriated parent and not the mutants in a whole bacterial cell enzyme-linked immunosorbent assay, and could immunoprecipitate fimbriae from fimbrial extracts of FW213. Antibodies isolated from preimmune and mutant sera did not react with fimbriae in any of the above assays. Only adsorbed antibody and monoclonal antibody were capable of blocking the adhesion of FW213 to saliva-coated hydroxyapatite. Adsorbed antibody, purified to immunoglobulin G (IgG), was an effective inhibitor of adhesion without causing interfering cellular aggregation. Monoclonal IgG, papain-cleaved to Fab fragments to prohibit cell-to-cell cross-linking, was also a potent inhibitor of S. sanguis FW213 adhesion. Both IgG from mutant sera and Fab fragments from normal mouse IgG could not be shown to block adhesion. These data further support the hypothesis that S. sanguis fimbriae are involved in adhesion.


Social learning across psychological distance.
While those we learn from are often close to us, more and more our learning environments are shifting to include more distant and dissimilar others. The question we examine in 5 studies is how whom we learn from influences what we learn and how what we learn influences from whom we choose to learn it. In Study 1, we show that social learning, in and of itself, promotes higher level (more abstract) learning than does learning based on one's own direct experience. In Studies 2 and 3, we show that when people learn from and emulate others, they tend to do so at a higher level when learning from a distant model than from a near model. Studies 4 and 5 show that thinking about learning at a higher (compared to a lower) level leads individuals to expand the range of others that they will consider learning from. Study 6 shows that when given an actual choice, people prefer to learn low-level information from near sources and high-level information from distant sources. These results demonstrate a basic link between level of learning and psychological distance in social learning processes.


Human papillomavirus type 16 E6 promotes retinoblastoma protein phosphorylation and cell cycle progression.
We show that E6 proteins from benign human papillomavirus type 1 (HPV1) and oncogenic HPV16 have the ability to alter the regulation of the G(1)/S transition of the cell cycle in primary human fibroblasts. Overexpression of both viral proteins induces cellular proliferation, retinoblastoma (pRb) phosphorylation, and accumulation of products of genes that are negatively regulated by pRb, such as p16(INK4a), CDC2, E2F-1, and cyclin A. Hyperphosphorylated forms of pRb are present in E6-expressing cells even in the presence of ectopic levels of p16(INK4a). The E6 proteins strongly increased the cyclin A/cyclin-dependent kinase 2 (CDK2) activity, which is involved in pRb phosphorylation. In addition, mRNA and protein levels of the CDK2 inhibitor p21(WAF1/CIP1) were strongly down-regulated in cells expressing E6 proteins. The down-regulation of the p21(WAF1/CIP1) gene appears to be independent of p53 inactivation, since HPV1 E6 and an HPV16 E6 mutant unable to target p53 were fully competent in decreasing p21(WAF1/CIP1) levels. E6 from HPV1 and HPV16 also enabled cells to overcome the G(1) arrest imposed by oncogenic ras. Immunofluorescence staining of cells coexpressing ras and E6 from either HPV16 or HPV1 revealed that antiproliferative (p16(INK4a)) and proliferative (Ki67) markers were coexpressed in the same cells. Together, these data underline a novel activity of E6 that is not mediated by inactivation of p53.


Catalytic depolymerization of lignin in supercritical ethanol.
One-step valorization of soda lignin in supercritical ethanol using a CuMgAlOx catalyst results in high monomer yield (23 wt%) without char formation. Aromatics are the main products. The catalyst combines excellent deoxygenation with low ring-hydrogenation activity. Almost half of the monomer fraction is free from oxygen. Elemental analysis of the THF-soluble lignin residue after 8 h reaction showed a 68% reduction in O/C and 24% increase in H/C atomic ratios as compared to the starting Protobind P1000 lignin. Prolonged reaction times enhanced lignin depolymerization and reduced the amount of repolymerized products. Phenolic hydroxyl groups were found to be the main actors in repolymerization and char formation. 2D HSQC NMR analysis evidenced that ethanol reacts by alkylation and esterification with lignin fragments. Alkylation was found to play an important role in suppressing repolymerization. Ethanol acts as a capping agent, stabilizing the highly reactive phenolic intermediates by O-alkylating the hydroxyl groups and by C-alkylating the aromatic rings. The use of ethanol is significantly more effective in producing monomers and avoiding char than the use of methanol. A possible reaction network of the reactions between the ethanol and lignin fragments is discussed.


Antiepileptic medications in autism spectrum disorder: a systematic review and meta-analysis.
Electroencephalogram-recorded epileptiform activity is common in children with autism spectrum disorder (ASD), even without clinical seizures. A systematic literature search identified 7 randomized, placebo-controlled trials of antiepileptic drugs (AEDs) in ASD (total n = 171), including three of valproate, and one each of lamotrigine, levetiracetam, and topiramate. Meta-analysis revealed no significant difference between medication and placebo in four studies targeting irritability/agitation and three studies investigating global improvement, although limitations include lack of power and different medications with diverse actions. Across all seven studies, there was no significant difference in discontinuation rate between two groups. AEDs do not appear to have a large effect size to treat behavioral symptoms in ASD, but further research is needed, particularly in the subgroup of patients with epileptiform abnormalities.


Chemopreventive role of arabinoxylan rice bran, MGN-3/Biobran, on liver carcinogenesis in rats.
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and one of the most lethal. MGN-3/Biobran is a natural product derived from rice bran hemicelluloses and has been reported to possess a potent anticancer effect in a clinical study of patients with HCC. The current study examines the mechanisms by which Biobran protects against chemically induced hepatocarcinogenesis in rats. The chemical carcinogen used in this study is N-nitrosodiethylamine (NDEA) plus carbon tetrachloride (CCl4). Rats were treated with this carcinogen, and the animals were pretreated or posttreated with Biobran via intraperitoneal injections until the end of the experiment. Treatment with Biobran resulted in: 1) significant alleviation of liver preneoplastic lesions towards normal hepatocellular architecture in association with inhibition of collagen fiber deposition; 2) arrest of cancer cells in the sub-G1 phase of the cell cycle; 3) increased DNA fragmentation in cancer cells; 4) down-regulated expression of Bcl-2 and up-regulated expression of p53, Bax, and caspase-3; and 5) protection against carcinogen-induced suppression of IkappaB-alpha (IκB-α) mRNA expression and inhibition of nuclear factor kappa-B (NF-κB/p65) expression. Additionally, the effect of Biobran treatment was found to be more significant when supplemented prior to carcinogen-induced hepatocarcinogenesis as compared to posttreatment. We conclude that Biobran inhibits hepatocarcinogenesis in rats by mechanisms that include induction of apoptosis, inhibition of inflammation, and suppression of cancer cell proliferation. Biobran may be a promising chemopreventive and chemotherapeutic agent for liver carcinogenesis.


Plasma Pharmacokinetics of High-Dose Oral versus Intravenous Rifampicin in Patients with Tuberculous Meningitis: a Randomized Controlled Trial.
Higher doses of intravenous rifampicin may improve outcomes in tuberculous meningitis but are impractical in high-burden settings. We hypothesized that plasma rifampicin exposures would be similar between oral dosing of 35 mg/kg of body weight and intravenous dosing of 20 mg/kg, which has been proposed for efficacy trials in tuberculous meningitis. We performed a randomized parallel-group pharmacokinetic study nested within a clinical trial of intensified antimicrobial therapy for tuberculous meningitis. HIV-positive participants with tuberculous meningitis were recruited from South African hospitals and randomized to one of three rifampicin dosing groups: standard (oral 10 mg/kg), high dose (oral 35 mg/kg), and intravenous (20 mg/kg). Intensive pharmacokinetic sampling was done on day 3. Data were described using noncompartmental analysis, and exposures were compared by geometric mean ratios (GMRs). Forty-six participants underwent pharmacokinetic sampling (standard dose, n = 17; high-dose oral, n = 15; intravenous, n = 14). The median CD4 count was 130 cells/mm3 (interquartile range [IQR], 66 to 253 cells/mm3). The rifampicin geometric mean area under the concentration-time curve from 0 to 24 h (AUC0-24) values were 42.9 μg · h/ml (95% confidence interval [CI], 24.5 to 75.0 μg · h/ml) for the standard dose, 295.2 μg · h/ml (95% CI, 189.9 to 458.8 μg · h/ml) for the high oral dose, and 206.5 μg · h/ml (95% CI, 154.6 to 275.8 μg · h/ml) for intravenous administration. The rifampicin AUC0-24 GMR was 1.44 (90% CI, 0.84 to 2.21) and the maximal concentration of drug in serum (Cmax) GMR was 0.89 (90% CI, 0.63 to 1.23) for high-dose oral administration with respect to intravenous dosing. The plasma rifampicin AUC0-24 was higher after an oral 35-mg/kg dose than with intravenous administration at a 20-mg/kg dose over the first few days of tuberculosis (TB) treatment. The findings support oral rifampicin dosing in future tuberculous meningitis trials.


Systemic gene therapy rescues retinal dysfunction and hearing loss in a model of Norrie disease.
Deafness affects 5% of the world's population, yet there is a lack of treatments to prevent hearing loss due to genetic causes. Norrie disease is a recessive X-linked disorder, caused by NDP gene mutation. It manifests as blindness at birth and progressive sensorineural hearing loss, leading to debilitating dual sensory deprivation. To develop a gene therapy, we used a Norrie disease mouse model (Ndptm1Wbrg ), which recapitulates abnormal retinal vascularisation and progressive hearing loss. We delivered human NDP cDNA by intravenous injection of adeno-associated viral vector (AAV)9 at neonatal, juvenile and young adult pathological stages and investigated its therapeutic effects on the retina and cochlea. Neonatal treatment prevented the death of the sensory cochlear hair cells and rescued cochlear disease biomarkers as demonstrated by RNAseq and physiological measurements of auditory function. Retinal vascularisation and electroretinograms were restored to normal by neonatal treatment. Delivery of NDP gene therapy after the onset of the degenerative inner ear disease also ameliorated the cochlear pathology, supporting the feasibility of a clinical treatment for progressive hearing loss in people with Norrie disease.


Environmental filtering of body size and darker coloration in pollinator communities indicate thermal restrictions on bees, but not flies, at high elevations.
Bees and flies are the two most dominant pollinator taxa in mountain environments of the Southwest USA. Communities of both taxa change dramatically along elevation gradients. We examined whether bee and fly traits would also change along elevation gradients and if so, do they change in a predictable way related to a decrease in temperature as elevation increases. We used insect body size and darkness traits as proxies for energetic requirements and indicators of cold tolerance in order to assess patterns of bee and fly community trait differences along an elevation gradient. We examined 1,922 individuals of bees and flies sampled along an elevation gradient ranging from 2,400 meters to 3,200 meters and from 9.6 °C to 5.2 °C mean annual temperature. We examined bees and flies separately using community weighted means (site-level trait values weighted by species abundance) and estimates of environmental filtering (quantified as the inverse of the standardized range of trait values). Bees and flies exhibited two somewhat distinct patterns; (1) Community weighted mean body volume and darkness of bees increased sharply at the highest elevation, and the intensity of environmental filtering also increased with elevation. This was due to both a change among bee populations within a species as well as species replacement at the highest elevation. (2) Community weighted mean body volume and darkness of flies also increased moderately with increasing elevation, but did not exhibit patterns of significant environmental filtering. In fact, the intensity of environmental filtering as indicated by the range of fly body volume weakened with elevation. The increase in filter intensity at high elevations exhibited by bees suggests a significant limitation on the breadth of viable functional strategies for coping with extreme cold, at least within this regional species pool. Flies, on the other hand, do not appear to be limited by high elevations, indicating that the shift from bee to fly dominance at high elevations may be due, at least in part, to greater environmental constraints on bee adaptation to colder environments.


Detection of Putative Stem-cell Markers in Invasive Ductal Carcinoma of the Breast by Immunohistochemistry: Does It Improve Prognostic/Predictive Assessments?
Experimental evidences from the last 2 decades supports the existence of a special type of neoplastic cell with stem-like features [cancer stem cell (CSC)] and their role in the pathophysiology and therapeutic resistance of breast cancer. However, their clinical value in human breast cancer has not been fully determined. An immunohistochemistry panel of 10 putative CSC markers (CD34, C-KIT, CD10, SOX-2, OCT 3/4, p63, CD24, CD44, CD133, and ESA/EPCAM) was applied to 74 cases of breast cancer, followed in a Regional Cancer Center of Minas Gerais State, Brazil, from 2004 to 2006. Possible associations between CSC markers and classic variables of clinicopathologic relevance were investigated. The most frequently positive CSC markers were CD44, CD24, CD133, and ESA (the others were present in <15% of the cases). Two CSC profiles were defined: CD24/CD44 (CSC-1) and CD133/ESA (CSC-2). CSC-1 was significantly associated to patients older than 40 years, tumors of <2.0 cm in diameter, early clinical stages (P<0.05), and increased death risk of 4 times (P=0.03; 95% confidence interval, 1.09-14.41). CSC-2 was related to increased relapse risk of 3.75 times (P=0.04; 95% confidence interval, 1.02-13.69). The detection of the most frequently positive CSC markers by immunohistochemistry is of clinicopathologic and prognostic relevance.


Movement patterns of catfishes (Ariidae) in a tropical semi-arid estuary.
From December 2005 to November 2006, 216 samples were taken from the main channel of the Goiana Estuary, representing a total sampled area of 23 ha. Ariidae species were the most abundant in density (1600 individuals ha(-1), 53%) and biomass (18,813 g ha(-1), 63%). Cathorops spixii was the most abundant in density (1340 individuals ha(-1)) and biomass (14,203 g ha(-1)). The variables: number of species, total density and biomass, showed significant interactions between the factors of areas and seasons (P < 0.01). The highest total density (7394 individuals ha(-1)) and biomass (70,292 g ha(-1)) occurred in the middle and upper estuaries, respectively, during the early-rainy season. The density of C. spixii differed significantly between areas and seasons (P < 0.01), while Cathorops agassizii differed significantly only between seasons (P < 0.01). The biomass differed significantly for the species C. spixii, C. agassizii and Sciades herzbergii between seasons, and C. spixii and C. agassizii between areas. Also, the density and biomass of C. spixii and C. agassizii showed interaction between areas and seasons. Only the biomass of S. herzbergii showed interaction between areas and seasons (P < 0.01). This indicates that seasonal variations influenced the distribution of Ariidae species in the different areas of the Goiana Estuary. Moreover, canonical correspondence analysis highlighted a strongly significant correlation (P < 0.01) between the seasonal variations of the environmental gradients (salinity and water temperature) and distribution of catfishes. The management and conservation of estuaries should take into account the life cycle of these species in different estuarine areas and hydrological seasons.


The Education of the Deaf Child: For Integration or Autonomy?
It is argued that Oralism and Total Communication underestimate the profound nature of deafness and the potential value of fundamental research. The evolution of these philosophies is described, and changes in philosophy are discussed.


New Perspectives on Circulating Ferritin: Its Role in Health and Disease.
The diagnosis of iron disturbances usually includes the evaluation of serum parameters. Serum iron is assumed to be entirely bound to transferrin, and transferrin saturation-the ratio between the serum iron concentration and serum transferrin-usually reflects iron availability. Additionally, serum ferritin is commonly used as a surrogate of tissue iron levels. Low serum ferritin values are interpreted as a sign of iron deficiency, and high values are the main indicator of pathological iron overload. However, in situations of inflammation, serum ferritin levels may be very high, independently of tissue iron levels. This presents a particularly puzzling challenge for the clinician evaluating the overall iron status of the patient in the presence of an inflammatory condition. The increase in serum ferritin during inflammation is one of the enigmas regarding iron metabolism. Neither the origin, the mechanism of release, nor the effects of serum ferritin are known. The use of serum ferritin as a biomarker of disease has been rising, and it has become increasingly diverse, but whether or not it contributes to controlling the disease or host pathology, and how it would do it, are important, open questions. These will be discussed here, where we spotlight circulating ferritin and revise the recent clinical and preclinical data regarding its role in health and disease.


[Correlation of electromyography and clinical results after bicondylar knee joint prosthesis implantation].
To investigate clinical findings in patients receiving bicondylar sledge prostheses, and their correlation with electromyographic measurements in comparison with healthy volunteers. An average of 31.9 months after implantation of a bicondylar sledge prosthesis, 15 patients were clinically examined and compared with 11 control subjects. Electromyographic measurements of the rectus femoris, vastus medialis and lateralis, semitendinosus, biceps femoris, tibialis anterior, and gastrocnemius muscles were obtained. All clinical scores were significantly poorer in the patient group. The activity of the vastus lateralis was significantly reduced. The activity in the lower leg of the operated side was significantly higher than in the control group. Significant differences were found in the tibialis anterior and gastrocnemius muscles between controls and patients. Analysis of the correlation between the clinical scores and the electromyographic measurements showed no significance. The clinical results correlated only slightly with the electromyographic activity of the muscles investigated. The commonly presumed quadriceps insufficiency was not confirmed.


Dose validation and study design criteria in current cimetidine studies.
A large dose validation study compared cimetidine 800 mg at bedtime, a dose known to provide maximum acid suppression through the night, with placebo, cimetidine 400 mg, and 1,600 mg in the treatment of acute duodenal ulcer. The study was also designed to assess the effects of smoking and ulcer size on duodenal ulcer healing. Results of the study indicated that both smoking and ulcer size negatively correlated with ulcer healing. Cimetidine 800 mg (75%) was superior to placebo (45%) and cimetidine 400 mg (60%) (P less than 0.05) in terms of ulcer healing. There was no statistically significant difference between cimetidine 800 mg and 1,600 mg (81%). Up to 80% of the patients treated with cimetidine 800 mg had some degree of pain relief after the first dose. Cimetidine 800 mg was superior to placebo with respect to both daytime and nighttime pain relief at all assessment points and was superior to 400 mg during the first week. There was no difference in pain relief between 800 mg and 1,600 mg at any assessment period. It was clear that cimetidine 800 mg is the most appropriate dosage in the acute therapy of duodenal ulcer, combining optimal healing with maximum pain relief.


Acetaldehyde-induced interleukin-1beta and tumor necrosis factor-alpha production is inhibited by berberine through nuclear factor-kappaB signaling pathway in HepG2 cells.
Alcoholic liver disease (ALD) is one of the most common liver diseases in the world. Increased levels of proinflammatory cytokines, including interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha), have been correlated with the patients affected by ALD. However, the direct effect of alcohol in the induction of IL-1beta and TNF-alpha has not been clarified. In this study, we demonstrated that acetaldehyde, the metabolic product of ethanol, was able to induce IL-1beta and TNF-alpha production in HepG2 cells. Nuclear factor-kappaB (NF-kappaB), the transcription factor involved in the regulation of cytokine production, was also activated by acetaldehyde through inhibitory kappaB-alpha (IkappaB-alpha) phosphorylation and degradation. However, the NF-kappaB inhibitors, such as aspirin, cyclosporin A and dexamethasone, inhibited both the acetaldehyde-induced NF-kappaB activity and the induced cytokine production. Therefore, these data suggested that acetaldehyde stimulated IL-1beta and TNF-alpha production via the regulation of NF-kappaB signaling pathway. By screening 297 controlled Chinese medicinal herbs supervised by Committee on Chinese Medicine and Pharmacy at Taiwan, we found that Coptis chinensis (Huang-Lien) and Phellodendron amurense (Huang-Po) were capable of inhibiting acetaldehyde-induced NF-kappaB activity. Berberine, the major ingredient of these herbs, abolished acetaldehyde-induced NF-kappaB activity and cytokine production in a dose-dependent manner. Moreover, its inhibitory ability was through the inhibition of induced IkappaB-alpha phosphorylation and degradation. In conclusion, we first linked the acetaldehyde-induced NF-kappaB activity to the induced proinflammatory cytokine production in HepG2 cells. Our findings also suggested the potential role of berberine in the treatment of ALD.


Berry integrity and extraction of skin and seed proanthocyanidins during red wine fermentation.
In this study, microscale fermentations were conducted on Vitis vinifera L. cv. Merlot. Five treatments were established varying from 0-100% crushed fruit (25% increments x 5 replicates). Caps were kept submerged throughout the experiment, and fermentation temperatures were maintained at 25 degrees C. Samples were collected throughout fermentation and from the free run and press wine at the time of pressing. Proanthocyanidins were determined by acid-catalyzed depolymerization in the presence of phloroglucinol, followed by reversed phase, high performance liquid chromatography (RP-HPLC). Total proanthocyanidin extraction increased with time in all treatments. In addition, crushing increased the rate at which proanthocyanidins were extracted. When the extraction of skin and seed proanthocyanidins were monitored separately, skin proanthocyanidin extraction rate exceeded that for seed proanthocyanidins and followed a Boltzmann sigmoid extraction model. The highest proanthocyanidin concentration for skin (435 mg/L) and seed (344 mg/L) was observed for the 75% crushed fruit treatment at the time of pressing (17 days). The highest skin proanthocyanidin proportion (79%) was observed for the 75% crushed fruit treatment on day 9 with a total proanthocyanidin concentration of 439 mg/L. For all treatments, skin proanthocyanidin extraction reached a plateau concentration prior to pressing, with the plateau concentration increasing with crushing. Seed proanthocyanidin concentration increased throughout maceration.


Comparison of three anti-coccidioides antibody enzyme immunoassay kits for the diagnosis of coccidioidomycosis.
Coccidioidomycosis is a common cause of community-acquired pneumonia in endemic areas of the southwestern United States. Clinical presentations range from self-limited disease to severe, disseminated disease. As such, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic testing has variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from patients with coccidioidomycosis and controls were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies using the MVista Coccidioides antibody detection EIA and two commonly used commercial enzyme immunoassay (EIA) kits: the IMMY Omega EIA and the Meridian Premier EIA. The sensitivity of the IgG antibody detection was 87.4% using the MVista test compared to 46.6% for IMMY and 70.9% for Meridian. The sensitivity for IgM antibody detection was 61.2% for the MVista test, 22.3% for IMMY and 29.1% for Meridian. For IgG antibody detection, specificity was 90% for the MVista EIA, 94.6% for IMMY, 96.4% for Meridian. For IgM antibody detection, specificity was 95.3% for the MVista test 98.2% for IMMY and 99.1% for Meridian. The MVista Coccidioides antibody EIA offers improved sensitivity, including among high-risk patient populations, for the detection of IgG and IgM antibodies in comparison to other currently available EIAs.


Mean-field dynamos in random Arnold-Beltrami-Childress and Roberts flows.
We study magnetic field evolution in flows with fluctuating in time governing parameters in electrically conducting fluid. We use a standard mean-field approach to derive equations for large-scale magnetic field for the fluctuating Arnold-Beltrami-Childress (ABC) flow as well as for the fluctuating Roberts flow. The derived mean-field dynamo equations have growing solutions with growth rate of the large-scale magnetic field which is not controlled by molecular magnetic diffusivity. Our study confirms the Zeldovich idea that the nonstationarity of the fluid flow may remove the obstacle in the large-scale dynamo action of classic stationary flows.


Recommendations for the classification and nomenclature of the DNA-beta satellites of begomoviruses.
The symptom-modulating, single-stranded DNA satellites (known as DNA-beta) associated with begomoviruses (family Geminiviridae) have proven to be widespread and important components of a large number of plant diseases across the Old World. Since they were first identified in 2000, over 260 full-length sequences (approximately 1,360 nucleotides) have been deposited with databases, and this number increases daily. This has highlighted the need for a standardised, concise and unambiguous nomenclature for these components, as well as a meaningful and robust classification system. Pairwise comparisons of all available full-length DNA-beta sequences indicate that the minimum numbers of pairs occur at a sequence identity of 78%, which we propose as the species demarcation threshold for a distinct DNA-beta. This threshold value divides the presently known DNA-beta sequences into 51 distinct satellite species. In addition, we propose a naming convention for the satellites that is based upon the system already in use for geminiviruses. This maintains, whenever possible, the association with the helper begomovirus, the disease symptoms and the host plant and provides a logical and consistent system for referring to already recognised and newly identified satellites.


Use of adoptive transfer of T-cell-antigen-receptor-transgenic T cell for the study of T-cell activation in vivo.
Adoptive transfer of TCR-transgenic T cells uniformly expressing an identifiable TCR of known peptide/MHC specificity can be used to monitor the in vivo behavior of antigen-specific T cells. We have used this system to show that naive T cells are initially activated within the T-cell zones of secondary lymphoid tissue to proliferate in a B7-dependent manner. If adjuvants or inflammatory cytokines are present during this period, enhanced numbers of T cells accumulate, migrate into B-cell-rich follicles, and acquire the capacity to produce IFN-gamma and help B cells produce IgG2a. If inflammation is absent, most of the initially activated antigen-specific T cells disappear without entering the follicles, and the survivors are poor producers of IL-2 and IFN-gamma. Our results indicate that inflammatory mediators play a key role in regulating the anatomic location, clonal expansion, survival and lymphokine production potential of antigen-stimulated T cells in vivo.


The collection and interpretation of epidemiological data about the cardiovascular risks associated with the use of steroid contraceptives.
A variety of epidemiological approaches have been used to assess the safety of steroid contraceptives. Each study design has its own strengths and weaknesses, especially with respect to susceptibility to bias and confounding. Randomized controlled trials provide the strongest evidence of a cause and effect relationship, but the low incidence of cardiovascular disease in women of reproductive age precludes the use of this study design to examine these clinical endpoints. Consequently, observational cohort and case-control studies have provided the most useful clinical information about the main cardiovascular effects of steroid contraceptives. Data from epidemiological research need to be interpreted carefully taking into consideration which of the potential biases or sources of confounding are likely to have affected a particular study, and what effect these may have on any inferences from the study. Additional factors that need to be considered before deciding whether a causal relationship exists include evidence that the exposure preceded the disease, the strength of association, consistency of findings with other studies, presence of dose gradients, and agreement with animal or laboratory research. Even if a casual link is thought to be plausible, the public health implications may be minimal; absolute (attributable) risks are required in order to assess these. An understanding of these epidemiological issues will enable clinicians to advise their clients whether steroid contraceptives alter the risk of cardiovascular disease and, if so, the clinical significance of such changes.


Prostacyclin, thromboxane A2, and hypertension.
Prostacyclin and thromboxane A2, products of separate branches of the arachidonic acid cascade, can have opposing effects on kidney function and on the vascular musculature. Prostacyclin acts as a vasodilator while thromboxane A2 has a vasoconstrictor effect and the balance between these two compounds appears to contribute to the homeostatic regulation of normal blood pressure. In the hypertensive state, this balance is disrupted and, at least in animal models of hypertension, there is excessive production of both. The increase in prostacyclin formation may be a reaction to the elevated blood pressure, possibly due to mechanical stimulation of the vascular smooth muscle cells in the blood vessel wall. However, the increase in thromboxane A2 may be more directly involved in the development and maintenance of hypertension. Not only is thromboxane A2 a vasoconstrictor but it can also stimulate the growth and proliferation of vascular smooth muscle cells which may account for the vascular hypertrophy seen in hypertension. Both of these actions would increase total peripheral resistance and contribute to hypertension. Whether prostacyclin and thromboxane A2 are in fact involved as causative agents in essential hypertension must await future research.


[Empty body weight gain, protein, fat and energy deposit and utilization of metabolizable energy for energy deposit in black and white bulls. 2. Protein, fat and energy deposit].
The protein, fat and energy deposition determined in 6 series of individual feeding experiments with different energy supply on slaughter steps (altogether 458 animals) and whole body analysis were generalized in this publication on nonlinear regression analyses. The protein deposition per kg empty body weight gain is influenced by empty body weight, it takes off with increase of the empty body weight. At low empty body weight (100-200 kg) the protein deposition per kg empty body weight gain is small increased with increasing of empty body weight gain, at high empty body weight it is reduced continuously. The fat deposition per kg empty body weight gain increases progressively with the empty body weight and with the empty body weight gain respectively. The energy deposition per kg empty body weight gain increases with increase of empty body weight and of empty body weight gain. It showed the same development like the fat deposition. The protein, fat and energy deposition per kg live weight gain are calculated and tabulated in dependence on the live weight and the live weight gain.