[Agreement and differences between reviewers in a peer review procedure].
In Germany the statutory pension insurance institutions have started a quality assurance programme. Our institute developed a peer review procedure for screening the process quality of rehabilitation care. The peer review was tested in a pilot study. Our article refers to the examination of interrater reliability, intrarater reliability and reviewer bias. First of all, experienced doctors were trained in reviewing reports routinely written by rehabilitation doctors at discharge of their patients. The peers had to judge on 56 process criteria belonging to six categories (e.g. case history). The reliability coefficients were calculated for the overall judgement of each category and the overall judgement of the process quality of rehabilitation care. The coefficients of interrater reliability and the coefficients of average intrarater reliability range from sufficient to good. Only few reviewers showed a general tendency to harsh or lenient rating. The objectivity of the tested peer review procedure seems definitely higher than in American studies of peer review of hospital charts.


Vibrio damsela. A cause of fulminant septicemia.
A previously healthy 70-year-old man presented with a rapidly progressive and fulminant infection due to Vibrio damsela after suffering a knife cut while filleting bluefish at the New Jersey Shore. Despite appropriate antibiotic therapy and localized wound exploration, the patient died. To our knowledge, this is the first reported case of V damsela sepsis with simultaneous isolation of the organism from both blood and wound. We are reporting this case to heighten physicians' awareness of this infection and the importance of early management with antibiotics and surgical consultation.


General practice dentists' knowledge of temporomandibular disorders in children and adolescents.
The aim of the study was to map general practice dentists' (GPDs) knowledge of temporomandibular disorders (TMD) in children and adolescents. A questionnaire was mailed to 286 Swedish dentists in the Public Dental Service and 17 TMD specialists with documented research experience. The questionnaire contained 37 statements on aetiology, diagnostics, classification, chronic pain and pain behaviour, treatment, and prognosis. Each statement was judged on a 0-10 point scale with the endpoint definitions agree or disagree. The overall response rate to the questionnaire was 87%. In 28 of all 37 statements, the TMD specialists endorsed a consensus, i.e. >75% of the specialists had the same opinion about the statement. TMD specialists differed most in opinion in the domain diagnostics and classification. In 65% of the statements, differences in knowledge between GPDs and TMD specialists were non-significant. The greatest number of significant between-group differences was found in the domain treatment and prognosis. Most of these statements were related to morphological factors. There is a high degree of consensus in TMD knowledge amongst the TMD specialists and a high degree of agreement in knowledge between GPDs and TMD specialists. In some areas, however, TMD specialists still need to reach a consensus which is founded on evidence-based TMD knowledge in children and adolescents and that can be used in undergraduate teaching. It is therefore important to develop and strengthen the undergraduate dental teaching in TMD and orofacial pain.


Bone marrow transplantation versus immunosuppressive therapy in patients with acquired severe aplastic anemia.
Standard front-line treatment for acquired aplastic anemia (AA) for patients is either immunosuppressive therapy (IST) or bone marrow transplantation (BMT), usually from an HLA identical sibling. Whereas long-term survival is comparable with either treatment, important differences remain: IST patients may have incomplete or no recovery, are exposed to late clonal disorders and relapse of the original disease. Transplantation is a curative treatment, but patients are exposed to transplant-related complications both acute and chronic, such as chronic graft versus host disease (cGvHD). In the year 2000, a study by the European Group for Blood and Marrow Transplantation (EBMT), looked at failure free survival (FFS), in patients receiving first-line BMT from an HLA identical sibling, or the first-line IST. Young patients with low neutrophil counts benefited of the first-line BMT; the opposite was true for older patients with higher neutrophil counts; and a third intermediate group of patients had comparable survival irrespective of the first-line therapy. We have now studied a more recent cohort of patients to assess whether things have changed over the years. We have found similar results, although overall survival has improved, as a consequence of changes in the IST and BMT protocols.


Mid-life occupational grade and quality of life following retirement: a 16-year follow-up of the French GAZEL study.
This article aims to contribute to the literature on life course influences upon quality of life by examining pathways linking social position in middle age to quality of life following retirement in French men and women. Data are from the GAZEL cohort study of employees at the French national gas and electricity company. A finely grained measure of occupational grade in 1989 was obtained from company records. Annual self-completion questionnaires provided information on quality of life in 2005, measured with the CASP-19 scale, and on participants' recent circumstances 2002-2005: mental health, physical functioning, wealth, social status, neighbourhood characteristics, social support and social participation. Path analysis using full information maximum likelihood estimation was performed on 11,293 retired participants. Higher occupational grade in 1989 was associated, in a graded relationship, with better quality of life 16 years later. This association was accounted for by individuals' more recent circumstances, particularly their social status, mental health, physical functioning and wealth. The graded relationship between occupational grade in mid-life and quality of life after labour market exit was largely accounted for by more recent socio-economic circumstances and state of health. The results support a pathway model for the development of social disparities in quality of life, in which earlier social position shapes individual circumstances in later life.


Pancreatic Cancer and Obesity: Molecular Mechanisms of Cell Transformation and Chemoresistance.
Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20⁻40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy.


Polyethylene glycol-modified ragweed extract: comparison of two treatment regimens.
Fifty ragweed-sensitive subjects were each administered a course of 12 injections of polyethylene glycol-modified ragweed extract. To investigate the effect of two treatment regimens, subjects were paired according to their skin sensitivity to ragweed extract and the severity of their rhinoconjunctivitis the previous year. One of each pair was randomly allocated to receive injections at weekly intervals, and the other subject was to receive injections daily until a local or systemic adverse reaction occurred and then to switch to a weekly schedule for the rest of the course. Blood was obtained immediately before each injection and at the end of the study to examine the rates of change of ragweed-specific IgE and IgG antibody levels and to evaluate whether these or other variables could be used to predict the occurrence of adverse reactions. Immediate reactions were minimal in both groups, but more late reactions occurred in subjects receiving the modified rush regimen; therefore, although the total number of injections received by the two groups was similar, the total dose of protein injected in the rush group was only half that achieved in the weekly group. Treatment induced increases in ragweed-specific IgE and IgG antibodies in both groups; the increase in IgE was similar in the two groups, but the increase in IgG was higher in the weekly group. There was a marked decrease in skin sensitivity to ragweed extract after treatment that was directly related to the IgG antibody response, and therefore, these changes were greater in the weekly group.(ABSTRACT TRUNCATED AT 250 WORDS)


Preterm newborn lamb renal and cardiovascular responses after fetal or maternal antenatal betamethasone.
The optimal dose, route of administration, and treatment-to-delivery interval necessary to induce beneficial extrapulmonary effects of glucocorticoids are not known. Pregnant ewes (127 days gestation) were randomized to receive maternal or fetal intramuscular injections of betamethasone (0.2 or 0.5 mg/kg body wt) or saline 24 h before cesarean delivery of their lambs. Three hours after delivery, low-dose maternal vs. control lamb mean arterial pressure [64 +/- 4 vs. 47 +/- 2 (SE) mmHg], glomerular filtration rate (1.7 +/- 0.2 vs. 0.7 +/- 0.1 ml.min-1.kg-1), and total renal sodium reabsorption (219 +/- 31 vs. 85 +/- 12 mueq.min-1.kg-1) were increased. Comparable increases were observed in the high-dose maternal and fetal groups without effects in the low-dose fetal group. This study provides the first quantitative data demonstrating that even short-term (24-h) antenatal betamethasone exposure alters preterm newborn cardiovascular and renal functions. These responses are route and dose dependent and are comparable to glucocorticoid-induced maturational effects after longer-term antenatal exposure.


An Interpretable and Accurate Deep-learning Diagnosis Framework Modelled with Fully and Semi-supervised Reciprocal Learning.
The deployment of automated deep-learning classifiers in clinical practice has the potential to streamline the diagnosis process and improve the diagnosis accuracy, but the acceptance of those classifiers relies on both their accuracy and interpretability. In general, accurate deep-learning classifiers provide little model interpretability, while interpretable models do not have competitive classification accuracy. In this paper, we introduce a new deep-learning diagnosis framework, called InterNRL, that is designed to be highly accurate and interpretable. InterNRL consists of a student-teacher framework, where the student model is an interpretable prototype-based classifier (ProtoPNet) and the teacher is an accurate global image classifier (GlobalNet). The two classifiers are mutually optimised with a novel reciprocal learning paradigm in which the student ProtoPNet learns from optimal pseudo labels produced by the teacher GlobalNet, while GlobalNet learns from ProtoPNet's classification performance and pseudo labels. This reciprocal learning paradigm enables InterNRL to be flexibly optimised under both fully- and semi-supervised learning scenarios, reaching state-of-the-art classification performance in both scenarios for the tasks of breast cancer and retinal disease diagnosis. Moreover, relying on weakly-labelled training images, InterNRL also achieves superior breast cancer localisation and brain tumour segmentation results than other competing methods.


Clinical characteristics of small bowel tumors diagnosed by double-balloon endoscopy: KASID multi-center study.
Small bowel tumors are relatively rare, and their confirmative diagnosis before surgery is not easy. This study was performed to investigate the clinical characteristics of patients with small bowel tumors who received double-balloon enteroscopy (DBE). Secondary end points were to evaluate the usefulness and safety of DBE for the diagnosis of patients with suspected SB tumors derived from other previous procedures. We retrospectively analyzed consecutive DBE examinations to explore the small intestine in eight university hospitals over a 5-year period. A total of 877 DBE examinations (per oral 487, per anal 390) were performed in 645 patients (405 males, mean age 48.2 years). Small bowel tumors were diagnosed in 112 patients (17.4%), of which 38 patients had benign polyps, 29 had gastrointestinal stromal tumors/leiomyomata, 18 had lymphomas, 14 had adenocarcinomas, five had metastatic or invasive cancers, five had lipomas, and three patients had cystic tumors. The main reasons for DBE among patients with small bowel tumors were obscure gastrointestinal bleeding (OGIB, 40.2%) followed by abnormal imaging study (25.2%). The concordance rate of diagnoses based on DBE with diagnoses based on small bowel follow-through, CT, and capsule endoscopy among patients with small bowel tumors was 68.9% (42/61), 75.3% (70/93), and 78.3% (18/23), respectively. Therapeutic plans were changed due to the DBE results in 64.2% of patients with small bowel tumors. Approximately one-sixth of patients who received DBE had small bowel tumors, and the most common reason for DBE among patients with small bowel tumors was OGIB. DBE is a useful method for the confirmative diagnosis of small bowel tumors and has a good clinical impact on therapeutic plans and short-term clinical results.


Tissue distribution of lignans in rats in response to diet, dose-response, and competition with isoflavones.
This paper investigates the occurrence and distribution of the lignan metabolites enterodiol (END) and enterolactone (ENL) and the isoflavone daidzein (DAID) in rat tissues by use of liquid chromatography-electrospray ionization mass spectrometry (LC-ESI/MSn) following a variety of dietary regimes. Furthermore, we examined the dose-response and distribution of END and ENL in liver, testes, prostate, and lung, and we investigated the effects of competition between lignans and isoflavones on metabolite distribution. In liver, testes, prostate, and lung tissue, dose-related increases in END concentration were observed. In the testes, coadministration of 60 mg/kg secoisolariciresinol diglycoside (SDG) with 60 mg/kg isoflavones produced alterations in the resulting metabolite profile, causing increased END concentration and decreased DAID concentration. Results indicate lignan accumulation in tissues occurs, and coadministration of lignans with isoflavones affects the metabolite profile, with effects dependent on tissue type.


CLCA4 inhibits bladder cancer cell proliferation, migration, and invasion by suppressing the PI3K/AKT pathway.
Calcium activated chloride channel A4 (CLCA4), a tumor suppressor, was shown to contribute to the progression of several human cancers, while its role in bladder carcinoma remains unclear. In this study, we showed CLCA4 expression was down-regulated in bladder carcinoma tissues and cells compared to adjacent non-tumor tissues and normal urothelial cells. Low CLCA4 expression was correlated with larger tumor size, advanced tumor stage, and poor prognosis in bladder carcinoma patients. Overexpression of CLCA4 profoundly attenuated the proliferation, growth, migratory and invasive capabilities of bladder cancer cells, whereas CLCA4 knockdown had the opposite effect. Mechanistically, CLCA4 is involved in PI3K/AKT signaling and its downstream molecules can promote bladder cancer cell proliferation. Additionally, CLCA4 could mediate the migration and invasion of bladder cancer cells by regulating epithelial-mesenchymal transition and PI3K/Akt activation. This study suggests that CLCA4 may represent a promising prognostic biomarker for bladder cancer and provides a possible mechanism for bladder cancer growth and invasion.


Oral microbiome development during childhood: an ecological succession influenced by postnatal factors and associated with tooth decay.
Information on how the oral microbiome develops during early childhood and how external factors influence this ecological process is scarce. We used high-throughput sequencing to characterize bacterial composition in saliva samples collected at 3, 6, 12, 24 months and 7 years of age in 90 longitudinally followed children, for whom clinical, dietary and health data were collected. Bacterial composition patterns changed through time, starting with "early colonizers", including Streptococcus and Veillonella; other bacterial genera such as Neisseria settled after 1 or 2 years of age. Dental caries development was associated with diverging microbial composition through time. Streptococcus cristatus appeared to be associated with increased risk of developing tooth decay and its role as potential biomarker of the disease should be studied with species-specific probes. Infants born by C-section had initially skewed bacterial content compared with vaginally delivered infants, but this was recovered with age. Shorter breastfeeding habits and antibiotic treatment during the first 2 years of age were associated with a distinct bacterial composition at later age. The findings presented describe oral microbiota development as an ecological succession where altered colonization pattern during the first year of life may have long-term consequences for child´s oral and systemic health.


The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition.
Malignant tumors often display an aberrant energy metabolism that relies primarily on glycolysis to produce adenosine triphosphate (ATP) the so-called Warburg effect or aerobic glycolysis. Thus, the elucidation of this energetic alteration in malignant tumors is important in the search for more effective therapeutics against malignant cancers, the most deadly human disease. To investigate whether attenuated glycolytic activity modulates tumor progression, the effects of silencing the first and rate-limiting glycolytic enzyme hexokinase (HK) isozymes HK1 and HK2 were examined. There was an inverse correlation between the expression of HK1 and HK2 in human cancer cells. In cervical carcinoma cells, the HK1 but not HK2 knockdown induced a phenotypic change characteristic of epithelial-mesenchymal transition, which accelerated tumor growth and metastasis both in vitro and in vivo analyses. Notably, the silencing of HK1 disrupted aerobic respiration and increased glycolysis, but it had no effect on ATP generation. These metabolic changes were associated with higher HK2 and lactate dehydrogenase 1 expression but a lower citrate synthase level. Particularly, the HK1 knockdown induced aberrant energy metabolism that was almost recapitulated by HK2 overexpression. Moreover, the HK1-silenced cells showed strong glucose-dependent growth and 2-deoxyglucose (2-DG) induced cell proliferation inhibition. These results clearly indicate that the silencing of HK1, but not HK2, alters energy metabolism and induces an EMT phenotype, which enhances tumor malignancy, but increases the susceptibility of cancer cells to 2-DG inhibition. In addition, this work also suggests that the glycolytic inhibitors should be used only to treat cancers with elevated glycolytic activity.


The Art of Influencing Consumer Choices: A Reflection on Recent Advances in Decision Neuroscience.
In recent years, our knowledge concerning the neurobiology of choice has increased tremendously. Research in the field of decision-making has identified important brain mechanisms by which a representation of the subjective value of an option is built based on previous experience, retrieved and compared to that of other available options in order to make a choice. One body of research, in particular, has focused on simple value-based choices (e.g., choices between two types of fruits) to study situations very similar to our daily life decisions as consumers. The use of neuroimaging techniques has deepened and refined our knowledge of decision processes. Additionally, computational approaches have helped identifying and describing the mechanisms underlying newly found components of the decisional process. They provide mechanistic explanations for diverse biases that can drive decision makers away from their own preferences or from rational choices. It is now clear that both attentional and affective factors can exert robust effects on an individual's decisions. Because these factors can be manipulated externally, academic research and theories are of great interest to the marketing industry. This approach is becoming increasingly effective in manipulating consumer behavior and has the potential to become even more effective in the future. Another line of research has revealed differences in the decision-making neural circuitry that underlie sub-optimal choice behavior, rendering some individuals particularly vulnerable to marketing strategies. As neuroscientists, we wonder whether relevant institutions should direct their efforts toward raising citizens' awareness, demanding more transparency on marketing applications and regulate the most pervasive communication techniques in marketing, in view of their current use and of recent research progress.


An unusual radiographic finding in pulmonary parenchymal endometriosis.
Thoracic endometriosis is an uncommon disorder. In most cases, the diagnosis is based on history alone and radiographic findings depend on the menstrual cycle. CT findings include ill-defined or well-defined opacities, nodular lesions, cavities, cystic changes and bullous formation. We report a case of pulmonary parenchymal endometriosis with an unusual radiographic finding.


Ba(2+)-sensitive K+ channels in basal membrane of confluent Madin-Darby canine kidney cells.
A method is described for gaining access to the basolateral membranes of confluent Madin-Darby canine kidney (MDCK) cells by surgical reflection of the cell layer overlying fluid-filled domes. Single-channel recordings from cell-attached inside-out and outside-out configurations revealed two K+ channels located in the basal membranes of the highly differentiated monolayers. With 140 mmol/l KCl in pipette, the intermediate-conductance K+ channel displayed outward rectification in cell-attached configuration with channel conductances of 65 pS for outward part and 17 pS for inward part. In excised-patch recording, this channel had a conductance of 92 pS with 140 mmol/l KCl on the extracellular side of the patch and 5 mmol/l KCl on the cytosolic side. The maximum conductance obtained in symmetrical KCl (140 mmol/l) solution was 140 pS. Ba2+ (1 mmol/l) and tetraethylammonium (5 mmol/l) blocked this channel reversibly. Channel open probability (Po) was reduced from 0.41 at cytosolic pH 7.4 to 0.14 at pH 6.8 and increased to 0.64 at pH 8.0. The channel activity was significantly inhibited by elevation of intracellular Ca2+. A small-conductance K+ channel was also observed mainly in excised patches with single-channel conductance of 48 pS in symmetrical KCl solutions. However, the activity of this channel was partially obscured by the intermediate-conductance K+ channel and further analysis was not possible. A physiological role of these channels in mediating K+ recycling through the monolayer is suggested.


Generation of three control iPS cell lines for sickle cell disease studies by reprogramming erythroblasts from individuals without hemoglobinopathies.
Sickle cell disease (SCD) is one of the most prevalent and severe monogenetic disorders. Previously, we generated iPS cell lines from SCD patients. Here, we generated iPS cell lines from three age-, ethnicity- and gender-matched healthy individuals as control cell lines. Cell reprogramming was performed using erythroblasts expanded from PBMC by a non-integrative method. SCD-iPSC controls expressed pluripotency markers, presented a normal karyotype, were able to differentiate into the three germ layers in embryoid body spontaneous differentiation and confirmed to be integration-free. The cell lines generated here may be used as matched healthy controls for SCD studies.


Tumor diagnosis preceding Alzheimer's disease onset: is there a link between cancer and Alzheimer's disease?
Studies reporting an inverse association between Alzheimer's disease (AD) and cancer are scant. Available data are mostly based on ancillary findings of mortality data or obtained from studies evaluating frequency of neoplasms in AD patients independently if they occurred before or after AD. Moreover, some studies estimated frequencies of neoplasms in demented individuals, who were not necessarily AD patients. We estimated frequency of tumors preceding the onset of AD in AD patients and compared it to that of age- and gender-matched AD-free individuals. Occurrence of tumors preceding AD onset was assessed through a semi-structured questionnaire. Tumors were categorized as benign, malignant, or of uncertain classification and as endocrine-related or not. Odds ratios (OR), used as measure of the association between the two diseases, were adjusted for tumor categories and known risk factors for AD and tumors. We included 126 AD patients and 252 matched controls. Tumor frequency before AD onset was 18.2% among cases and 24.2% among controls. There was a suggestive trend of an overall inverse association between the two diseases (adjusted OR 0.6; 95% CI 0.4-1.1; p = 0.11). Risk for neoplasms was significantly reduced only for women (adjusted OR, 0.5; 95% CI 0.3-0.9; p = 0.03) and for endocrine related tumors (adjusted OR, 0.5; 95% CI 0.2-1; p = 0.04). Our study confirms the inverse association reported in previous epidemiological studies. Though our findings might be explained by processes playing an opposite role in tumors development and neurodegeneration, they are also suggestive for a possible role of estrogen.


Adaptation to ionizing radiation induced by prior exposure to very low doses.
In human and animal cells, an adaptive response has been found to make cells somewhat refractory to the induction of chromosomal damage by high doses applied subsequently. These responses can also be induced in vivo by irradiating animals with low, or chronic doses. In regard to cytogenetic damage, and presumably those mutations that are cytogenetic in origin, the induced response leads to the repair, or rejoining, of broken chromosome ends, which means that chromosome aberrations, deletional (or null) mutations, DNA double-strand breaks, and even cellular survival that is dependent upon the genetic (cytogenetic) integrity of the cell can be endpoints that will show an adaptive response to ionizing radiations.


Endoscopic Versus Microscopic Transsphenoidal Approach for Pituitary Adenomas: Comparison of Outcomes During the Transition of Methods of a Single Surgeon.
The transition from microscopic to fully endoscopic transsphenoidal surgery requires a surgeon to assess how the change in technique will affect the extent of tumor resection (EOR), outcomes, and complications. We compared a single surgeon's experience transitioning from one technique to the other and examined the operative outcomes and EOR between microscopic versus endoscopic transsphenoidal surgery. Retrospective data analysis of adult patients who were treated surgically for a pituitary adenoma between August 2005 and May 2015 by a single neurosurgeon, who was originally trained and practiced in the microscopic transsphenoidal approach. Patient demographics, perioperative conditions, tumor characteristics, operative times, volumetric EOR, postoperative outcome, and the endoscopic learning curve were evaluated. One hundred and nine patients underwent microscopic transsphenoidal surgery and 275 patients underwent a fully endoscopic approach. The patient characteristics were similar in the 2 groups. Operative room time was significantly shorter in the endoscopic group than in the microscopic group (180.2 vs. 215.6 minutes; P < 0.001). The endoscopic and microscopic groups had similar volumetric EOR (85.1% vs. 82.8%; P = 0.371) as well as residual tumor volume (1.06 cm3 vs. 1.15 cm3; P = 0.765). The mean length of hospital stay was 2.4 days in the endoscopic group and 3.2 days in the microscopic group (P = 0.03). During the transition from the microscopic to the endoscopic approach, similar surgical outcomes and EOR were achieved in the 2 cohorts. In our experience, the endoscopic approach offers the advantage of shorter operative times and lengths of hospital stays after the surgeon has developed more experience with the technique.


Pharmacokinetics of piroxantrone in a phase I trial of piroxantrone and granulocyte-colony stimulating factor.
Piroxantrone is an anthrapyrazole derivative with broad antitumor activity in vitro. In previous phase I trials, the dose-limiting toxicity of this agent was myelosuppression. Therefore, a phase I and pharmacokinetic study of a 1-h infusion of piroxantrone in combination with granulocyte-colony stimulating factor was conducted. In this article, we report the results of the pharmacokinetic analysis. Thirty-seven patients were studied over a dosage range of 150 to 555 mg/m2. The plasma elimination of piroxantrone was biexponential with a mean (+/- SD) t1/2 alpha of 3.2 +/- 2.7 min and a mean (+/- SD) t1/2 beta of 82 +/- 92 min. Clearance was 840 +/- 230 ml/min/m2. A limited sampling strategy was developed to allow the estimation of total drug exposure (area under the plasma concentration-time curve) from the plasma piroxantrone concentrations at 30, 60, and 120 min after the start of the infusion. The pharmacokinetic behavior of a presumed piroxantrone metabolite not previously described in plasma was also characterized. Based on in vitro cytotoxicity studies with partially purified extract of this compound, we do not believe that it contributes to the antitumor effects of piroxantrone at the concentrations observed in plasma. Finally, piroxantrone elimination was linear over the nearly 4-fold dose range studied, indicating that when dose adjustments are made, systemic drug exposure will remain predictable.


From bad to worse: Symbolic equivalence and opposition in fear generalisation.
The present study compared the impact of symbolic equivalence and opposition relations on fear generalisation. In a procedure using nonsense words, some stimuli became symbolically equivalent to an aversively conditioned stimulus while others were symbolically opposite. The generalisation of fear to symbolically related stimuli was then measured using behavioural avoidance, retrospective unconditioned stimulus expectancy and stimulus valence ratings. Equivalence relations facilitated fear generalisation while opposition relations constrained generalisation. The potential clinical implications of symbolic generalisation are discussed.


GP treatment decisions for patients with depression: an observational study.
GPs are prescribing more antidepressants than previously, but not in accordance with guidelines. The reasons why they prescribe are not well understood. To explore associations between GP treatment and severity of depression, patients' life difficulties, previous history of illness and treatment, and patient attitudes. Observational study in two phases, 3 years apart. Seven practices in Southampton, UK. Adult attenders who consented were screened for depression in the waiting room. After the consultation, the 17 participating GPs completed questionnaires on the perceived presence and severity of depression, patients' life difficulties, previous problems and treatment, patient attitudes towards antidepressants, and their treatment decisions. Patients returned postal questionnaires on sociodemographics, life events, physical health, and attitudes towards antidepressants. Of 694 patients screened in the two phases, the GPs rated 101 (15%) as depressed, acknowledged depression in 44 cases (6%), and offered treatment in 27 (4%), including antidepressants in 14 (2%). Offers of antidepressants were more likely in both phases where the GPs rated the depression as moderate rather than mild, and where they perceived a positive patient attitude to antidepressants. However, GP ratings of severity did not agree well with the validated screening instrument, and their assessments of patients' attitudes to treatment were only moderately related to patients' self-reports. In line with current guidelines, GPs base prescribing decisions on the perceived severity of depression, taking patients' preferences into account, but they do not accurately identify which patients are likely to benefit from treatment. Better ways to assess depression severity and patient attitudes towards antidepressants are needed in order to target treatment more appropriately.


Photosynthesis, photorespiration, and light signalling in defence responses.
Visible light is the basic energetic driver of plant biomass production through photosynthesis. The constantly fluctuating availability of light and other environmental factors means that the photosynthetic apparatus must be able to operate in a dynamic fashion appropriate to the prevailing conditions. Dynamic regulation is achieved through an array of homeostatic control mechanisms that both respond to and influence cellular energy and reductant status. In addition, light availability and quality are continuously monitored by plants through photoreceptors. Outside the laboratory growth room, it is within the context of complex changes in energy and signalling status that plants must regulate pathways to deal with biotic challenges, and this can be influenced by changes in the highly energetic photosynthetic pathways and in the turnover of the photosynthetic machinery. Because of this, defence responses are neither simple nor easily predictable, but rather conditioned by the nutritional and signalling status of the plant cell. This review discusses recent data and emerging concepts of how recognized defence pathways interact with and are influenced by light-dependent processes. Particular emphasis is placed on the potential roles of the chloroplast, photorespiration, and photoreceptor-associated pathways in regulating the outcome of interactions between plants and pathogenic organisms.


Drug repurposing and emerging adjunctive treatments for schizophrenia.
Schizophrenia is a frequent disorder, which substantially impairs patients' quality of life. Moreover, the burden of illness for patients, their families and for the society, in general, is substantial. Nevertheless, the understanding of the pathophysiology of this syndrome, concise diagnostic methods and more effective and tolerable treatments are still lacking. Thus, innovative approaches and the exploration of new territories are required. An overview of repurposed drugs and emerging treatments for schizophrenia is presented, focusing on randomized, controlled trials and meta-analyses. Despite many years of drug research, several needs in the treatment of schizophrenia including the safety and tolerability, stage-dependent and personalized approaches, as well as drug delivery and sustainability have not been addressed sufficiently. Given the current failure of a number of mechanistically new drugs, repurposed compounds may serve as alternative and/or adjunctive agents for schizophrenic patients and for treatment refractory patients in particular. Anti-inflammatory drugs (e.g., acetylsalicylic acid, celecoxib and minocycline), as well as N-acetylcysteine, a precursor of the major antioxidant glutathione, hormones (e.g., estrogen, raloxifene and oxytocin), glutamatergic (e.g., glycine and d-serine) and nicotinergic compounds, 'nutraceuticals' (e.g., ω-3 fatty acids) and cannabidiol, an endocannabinoidmodulator, represent promising agents in this field.


Host-Pathogen Interactions: I. A Correlation Between alpha-Galactosidase Production and Virulence.
Resistance or susceptibility of Red Kidney, Pinto and Small White beans (Phaseolus vulgaris) to the alpha, beta, and gamma strains of Colletotrichum lindemuthianum was either confirmed or established. These fungal strains secrete alpha-galactosidase, beta-galactosidase and beta-xylosidase when grown on cell walls isolated from the hypocotyls of any of the above bean varieties. These enzymes effectively degrade cell walls isolated from susceptible 5-day old hypocotyls but degrade only slightly the walls isolated from resistant 18-day old hypocotyls. The amounts of the beta-galactosidase and beta-xylosidase secreted by the 3 fungal strains are relatively low and are approximately equivalent. The secretion of these 2 enzymes is not dependent upon the bean variety from which the hypocotyl cell walls used as a carbon source were isolated. However, the fungal strains secrete greater amounts of alpha-galactosidase when grown on hypocotyl cell walls isolated from susceptible plants than when grown on walls from resistant plants. Virulent isolates of the fungus, when grown on hypocotyl cell walls isolated from a susceptible plant, secrete more alpha-galactosidase than do attenuated (avirulent) isolates of the same fungal strain grown under the same conditions. The alpha-galactosidase secreted by each of the fungal strains is capable of removing galactose from the hypocotyl cell walls of each bean variety tested. Galactose is removed from the cell walls of each variety at the same rate regardless of whether the cell walls were isolated from a susceptible or resistant plant.


Efficacy and safety of intensified antiplatelet therapy on the basis of platelet reactivity testing in patients after percutaneous coronary intervention: systematic review and meta-analysis.
ADP-specific platelet function assays were shown to predict thrombotic events, and might be helpful to select candidates for more potent antiplatelet therapy. We aimed to determine the efficacy and safety of giving intensified antiplatelet therapy on the basis of platelet reactivity testing for patients undergoing percutaneous coronary intervention (PCI). Electronic databases were searched to find prospective, randomized trials that reported the clinical impact of using an intensified antiplatelet protocol (repeated loading or elevated maintenance doses of clopidogrel, prasugrel or glycoprotein IIb/IIIa inhibitor) on the basis of ADP-specific platelet reactivity testing (VerifyNow, Multiplate, VASP or light transmission aggregometry) compared to standard-dose clopidogrel. Evaluated efficacy measures included cardiovascular death, non-fatal myocardial infarction and definite/probable stent thrombosis (ST), while major bleeding events were recorded as safety endpoint. Between 2008 and 2011, 10 clinical trials comprising 4213 randomized patients were identified. Compared to standard antiplatelet therapy, the intensified protocol was associated with a significant reduction in cardiovascular mortality, ST and myocardial infarction (p<0.01 for all). There was no difference in the rate of major bleeding events between intensified and standard groups (p=0.44). Although the observed effects regarding mortality, ST and bleeding were not heterogeneous, meta-regression analysis revealed that the net clinical benefit of the intensified treatment significantly depended on the risk of ST with standard-dose clopidogrel (p=0.023). Intensifying antiplatelet therapy on the basis of platelet reactivity testing reduces cardiovascular mortality and ST after PCI; however, the net benefit of this approach depends on the risk of ST with standard-dose clopidogrel.


Structural centrosome aberrations promote non-cell-autonomous invasiveness.
Centrosomes are the main microtubule-organizing centers of animal cells. Although centrosome aberrations are common in tumors, their consequences remain subject to debate. Here, we studied the impact of structural centrosome aberrations, induced by deregulated expression of ninein-like protein (NLP), on epithelial spheres grown in Matrigel matrices. We demonstrate that NLP-induced structural centrosome aberrations trigger the escape ("budding") of living cells from epithelia. Remarkably, all cells disseminating into the matrix were undergoing mitosis. This invasive behavior reflects a novel mechanism that depends on the acquisition of two distinct properties. First, NLP-induced centrosome aberrations trigger a re-organization of the cytoskeleton, which stabilizes microtubules and weakens E-cadherin junctions during mitosis. Second, atomic force microscopy reveals that cells harboring these centrosome aberrations display increased stiffness. As a consequence, mitotic cells are pushed out of mosaic epithelia, particularly if they lack centrosome aberrations. We conclude that centrosome aberrations can trigger cell dissemination through a novel, non-cell-autonomous mechanism, raising the prospect that centrosome aberrations contribute to the dissemination of metastatic cells harboring normal centrosomes.


[Registration of various classes of otoacoustic emission in definition of acoustic sensitivity in different forms of neurosensory hypoacusis].
To establish correlations between parameters of otoacoustic emission and audiometric thresholds, we have examined 30 ears (28 patients) with high-frequency neurosensory hypoacusis. The analysis of the findings was made in microstructural frequency resolution. It was discovered that peaks of spontaneous otoacoustic emission correspond by frequency range to minimal thresholds of audibility in all the cases. Minimal values of audibility thresholds correlate also by frequency with maximal values of amplitudes of the response signal of delayed evoked otoacoustic emission with good sigmal/noise in all the examinees as well. 23 ears demonstrated 'mirrow' correlation of pure-tone audiogram with DP-gram - a rise in behavioral thresholds corresponds to amplitude-lowering response signals in frequency range 3-6 kHz.


Polypharmacy and health outcomes in atrial fibrillation: a systematic review and meta-analysis.
To undertake a systematic review and meta-analysis examining the impact of polypharmacy on health outcomes in atrial fibrillation (AF). PubMed and Embase databases were searched from inception until 31 July 2019. Studies including post hoc analyses of prospective randomised controlled trials or observational design that examined the impact of polypharmacy on clinically significant outcomes in AF including mortality, hospitalisations, stroke, bleeding, falls and quality of life were eligible for inclusion. A total of six studies were identified from the systematic review, with three studies reporting on common outcomes and used for a meta-analysis. The total study population from the three studies was 33 602 and 37.2% were female. Moderate and severe polypharmacy, defined as 5-9 medicines and >9 medicines, was observed in 42.7% and 20.7% of patients respectively, and was associated with a significant increase in all-cause mortality (Hazard ratio [HR] 1.36, 95% CI 1.20 to 1.54, p<0.001; HR 1.84, 95% CI 1.40 to 2.41, p<0.001, respectively), major bleeding (HR 1.32, 95% CI 1.14 to 1.52, p<0.001; HR 1.68, 95% CI 1.35 to 2.09, p<0.001, respectively) and clinically relevant non-major bleeding (HR 1.12, 95% CI 1.03 to 1.22, p<0.01; HR 1.48, 95% CI 1.33 to 1.64, p<0.01, respectively). There was no statistically significant association between polypharmacy and stroke or systemic embolism or intracranial bleeding. Among other examined outcomes, polypharmacy was associated with cardiovascular death, hospitalisation, reduced quality of life and poorer physical function. Polypharmacy is highly prevalent in the AF population and is associated with numerous adverse outcomes. CRD42018105298.


Association of baseline physical activity participation with participant characteristics and outcomes following education and exercise-therapy in people with knee osteoarthritis: A GLA:D® Australia prospective cohort study.
To investigate whether participants with knee osteoarthritis classified as 'more' or 'less' physically active at baseline differ in characteristics and/or outcomes at baseline and at 3 and 12 months following the commencement of an education and exercise-therapy program. Prospective cohort study using the GLA:D® Australia registry. The University of California, Los Angeles Physical Activity Scale (UCLA) participant data dichotomised as 'more' (≥7) or 'less' active (≤6). Groups were compared using chi-square (obesity [baseline only], comorbidity prevalence, medication consumption, fear of damage from physical activity); and linear mixed model regression (12-item Injury Osteoarthritis Outcome Score [KOOS-12], pain [visual analogue scale], health-related quality of life [QoL] [EQ-5D-5L]) statistics, adjusted for age, sex and baseline physical activity at 3 and 12 months. We included 1059 participants (70% female). At baseline, 267 (25%) were classified as 'more' active, increasing to 29% and 30% at 3 and 12 months, respectively. At baseline, compared to the 'less' active group, the 'more' active group had a lower proportion of participants who were obese ('more' = 21% vs. 'less' = 44%), had comorbidities (58% vs. 74%) and consumed medications (71% vs. 85%); lower pain intensity (37 vs. 47); and higher KOOS-12 (59 vs. 50), and health-related QoL (0.738 vs. 0.665) scores. When accounting for age, sex and baseline physical activity, improvements seen in knee-related burden and health-related QoL were not different between groups at 3 or 12 months. Compared to the 'less' active group, the proportion of participants not consuming medication remained higher in the 'more' active group at 3 ('more' 45% vs. 'less' 28%) and 12 months (43% vs. 32%). 'More' active people with knee osteoarthritis were less likely to be obese, had fewer comorbidities, lower medication consumption, knee-related burden and pain intensity, and higher health-related QoL than 'less' active participants at all timepoints.


Stem cell therapy: a potential for the perils of pancreatitis.
Acute and chronic pancreatitis carry a significant disease burden and there is no definite treatment that exists for either. They are associated with local and systemic inflammation and lead to numerous complications. Stem cell therapy has been explored for other disease processes and is a topic of research that has gained momentum with regards to implications for acute and chronic pancreatitis. They not only carry the potential to aid in regeneration but also prevent pancreatic injury as well as injury of other organs and hence the resultant complications. Stem cells appear to have immunomodulatory properties and clinical potential as evidenced by numerous studies in animal models. This review article discusses the types of stem cells commonly used and the properties that show promise in the field of pancreatitis.


An evaluation of the value of choice with preschool children.
The current study examined the reinforcing effects of choosing among alternatives in a four-part evaluation. In the first study, initial-link responses in a concurrent-chains arrangement resulted in access to terminal links in which the completion of an academic task resulted in (a) the choice of a reinforcer (choice), (b) the delivery of an identical reinforcer (no choice), or (c) no material reinforcer (control). Three patterns of responding emerged: persistent preference for choice (3 participants); initial preference for choice, which did not persist (2 participants); and preference for no choice (1 participant). Additional evaluations determined if preference for choice could be enhanced (Study 2) or established (Study 3) by including more stimuli from which to choose. Choice-link selections systematically increased for all participants when more items were available from which to choose. Study 4 identified the precise value of the opportunity to choose by progressively increasing the response requirement during the choice terminal links for 3 children and determining the point at which these children stopped selecting the choice link. All children continued to select the choice link even when the work required in the choice link was much greater than that arranged in the no-choice link.


Efficient decolorization of real dye wastewater and bioelectricity generation using a novel single chamber biocathode-microbial fuel cell.
Large scale applications of microbial fuel cells (MFCs) have been severely hindered by several problems such as high internal resistance, low power output, expensive materials, and complicated configuration. To address these issues, a granular activated carbon based single chamber microbial fuel cell (GACB-SCMFC) has been designed using GAC-biocathodes without using any expensive materials for the simultaneous decolorization of real dye wastewater and electricity generation. The GACB-SCMFC produced a power density of 8 W/m(3) which indicates the GAC-biocathode can be a good alternative to platinum and other chemical catalysts. The dye wastewater was primarily treated at the anode and further polishing steps were occurred at the aerobic cathode. Toxicity measurement shows that the effluent after GACB-SCMFC operation was much less toxic compared to the original dye wastewater. Additional advantage of the GACB-SCMFC is that pH was automatically adjusted from 12.2 to 8 during 48 h of hydraulic retention time (HRT).


Phy-Mer: a novel alignment-free and reference-independent mitochondrial haplogroup classifier.
All current mitochondrial haplogroup classification tools require variants to be detected from an alignment with the reference sequence and to be properly named according to the canonical nomenclature standards for describing mitochondrial variants, before they can be compared with the haplogroup determining polymorphisms. With the emergence of high-throughput sequencing technologies and hence greater availability of mitochondrial genome sequences, there is a strong need for an automated haplogroup classification tool that is alignment-free and agnostic to reference sequence. We have developed a novel mitochondrial genome haplogroup-defining algorithm using a k-mer approach namely Phy-Mer. Phy-Mer performs equally well as the leading haplogroup classifier, HaploGrep, while avoiding the errors that may occur when preparing variants to required formats and notations. We have further expanded Phy-Mer functionality such that next-generation sequencing data can be used directly as input. Phy-Mer is publicly available under the GNU Affero General Public License v3.0 on GitHub (https://github.com/danielnavarrogomez/phy-mer). firstname.lastname@example.com Supplementary data are available at Bioinformatics online.


Correction of coherence gate curvature in high numerical aperture optical coherence imaging.
We present a method for correcting coherence gate curvature caused by scanning-induced path length variations in spectral-domain high-NA optical coherence imaging systems. These variations cause curvature artifacts in optical coherence tomography and effectively restrict the field of view in optical coherence microscopy (OCM). Here we show that the coherence gate curvature can be measured and corrected by recovering the phase of the analytic signal from a calibration image. This phase information can be used directly to process OCM images allowing the coherence gate curvature, as well as any order of system dispersion, to be corrected in a computationally efficient manner. We also discuss the use of various image quality metrics that can be used to adjust the calibrated phase in order to keep the coherence and confocal gates aligned in tissue.


Rapid activation and partial inactivation of inositol trisphosphate receptors by inositol trisphosphate.
During superfusion of permeabilized hepatocytes, submaximal concentrations of inositol 1,4,5-trisphosphate (InsP3) evoked quantal Ca2+ mobilization: a rapid acceleration in the rate of 45Ca2+ release abruptly followed by a biphasic decline to the basal rate before the InsP3-sensitive stores had fully emptied. During the fast component of the decay, the Ca2+ permeability of the stores fell rapidly by 40% (t1/2 = 250 ms) to a state indistinguishable from that evoked by preincubation with InsP3 under conditions that prevented Ca2+ mobilization. This change was accompanied by a decrease in the InsP3 dissociation rate: the response declined more quickly when InsP3 was removed during the initial stages of a response than later. We suggest that InsP3 directly causes its receptor to rapidly switch (t1/2 = 250 ms) between a low-affinity (Kd approximately 1 microM) active, and a higher-affinity (Kd approximately 100 nM) less active, conformation, and that this transition underlies the fast component of the decaying phase of Ca2+ release. Ca2+ continues to leak through the unchanging less active state of the receptor until those stores that responded initially are completely empty, accounting for the slow phase of the response. The requirements for activation of InsP3 receptors are more stringent (InsP3 and then Ca2+ binding) than those for partial inactivation (InsP3 binding); rapid inactivation is therefore likely to determine whether the cytosolic [Ca2+] reaches the threshold for regenerative Ca2+ signals.


The status of emergency medicine in Makira Ulawa Province, Solomon Islands.
This Perspective reports on the challenges that face a solo doctor in a provincial hospital in the Solomon Islands following the civil disturbances of 1998-2003. The Health Service is seriously constrained by a paucity of funding, supplies and personnel. In spite of that, a rudimentary service can be provided and lives can be saved using simple techniques and basic resources. Further training of nurses, midwives and doctors is required. Emergency medicine, as a generalist discipline, provides a foundation to improve the delivery of care to the acutely ill and injured in these circumstances.


A study to promote breast feeding in the Helsinki Metropolitan area in Finland.
the aim of this study was to assess the impact of providing intensified support for breast feeding during the perinatal period. a quasi-experimental design with non-equivalent control group. three public maternity hospitals (two study, one control) in the Helsinki Metropolitan area in Finland. a convenience sample of 705 mothers (431 in the intervention group, 274 in the control group). in this study, families in the intervention group had access to intensified breast feeding support from midpregnancy, whereas those in the control group had access to normal care. Intensified support included lectures and workshops to health professionals, and families in the intervention group had access to more intensive support and counselling for breast feeding and a breast feeding outpatient clinic. Additionally, an internet-based intervention was only used in the intervention group, but not in the control group. Mothers in the control group received normal care from the midwifery and nursing professionals who were to continue their work normally. The data were analysed statistically. altogether 705 women participated in the study. In the intervention group (n=431), 76% of the women breast fed exclusively throughout the hospital stay, compared to 66% of the mothers in the control group (n=274). In multivariate analysis, the likelihood of exclusive breast feeding at the time of responding (at hospital discharge or after that at home) was increased by the mother not being treated for an underlying illness or medical problem during pregnancy, being in the intervention group, having normal vaginal childbirth, high breast feeding confidence, positive attitude towards breast feeding, good coping with breast feeding, and 24-hour presence of the infant's father in the ward. the low exclusive breast feeding rates of newborns could be increased by using intensified breast feeding support. Mothers' health problems during pregnancy can decrease exclusive breast feeding. Mothers with health problems or other than normal childbirth should receive extra breast feeding support, and the presence of fathers in the ward should be encouraged. Intensified breast feeding counselling and support helps mothers to breast feed exclusively. This support should be available in a variety of forms, so that mothers can choose the type of support they need. As breast feeding counselling and support is intensified, more mothers succeed with exclusive breast feeding.


A metadata classification schema for semantic content analysis of videos.
Simple ancillary metadata, such as those encompassed by the 15 elements of the Dublin Core, may be sufficient and entirely appropriate for basic coarse-granularity cross-domain resource discovery. However, they are insufficient and inappropriate for content description of complex data types such as videos, which require more detailed relational models. We propose a metadata classification schema for the characterization of items and events in videos that permits subsequent query by content. Following MPEG-7 nomenclature, metadata intrinsic to the information content of the video are defined as either structural or semantic, where structural metadata are numerical feature primitives produced by analysing the colour, shape, texture, structure and motion within the video frames, whereas semantic metadata describe the locations and timings of individual items and particular actions or events in the video, and are thus of higher information value. In this paper, the semantic metadata required to describe the visual information content of videos are defined and classified into four distinct classes: Media Entities; Content Items; Events; and Supplementary Items, and three types of property tables are defined: Identity Tables; Spatio-Temporal Position Tables; and Event Tables, in which these metadata may be stored in a relational database.


piRNAs of Caenorhabditis elegans broadly silence nonself sequences through functionally random targeting.
Small noncoding RNAs such as piRNAs are guides for Argonaute proteins, enabling sequence-specific, post-transcriptional regulation of gene expression. The piRNAs of Caenorhabditis elegans have been observed to bind targets with high mismatch tolerance and appear to lack specific transposon targets, unlike piRNAs in Drosophila melanogaster and other organisms. These observations support a model in which C. elegans piRNAs provide a broad, indiscriminate net of silencing, competing with siRNAs associated with the CSR-1 Argonaute that specifically protect self-genes from silencing. However, the breadth of piRNA targeting has not been subject to in-depth quantitative analysis, nor has it been explained how piRNAs are distributed across sequence space to achieve complete coverage. Through a bioinformatic analysis of piRNA sequences, incorporating an original data-based metric of piRNA-target distance, we demonstrate that C. elegans piRNAs are functionally random, in that their coverage of sequence space is comparable to that of random sequences. By possessing a sufficient number of distinct, essentially random piRNAs, C. elegans is able to target arbitrary nonself sequences with high probability. We extend this approach to a selection of other nematodes, finding results which elucidate the mechanism by which nonself mRNAs are silenced, and have implications for piRNA evolution and biogenesis.


Only a Minority of the Inhibitory Inputs to Cerebellar Golgi Cells Originates from Local GABAergic Cells.
Cerebellar Golgi cells (GoCs) efficiently control the spiking activity of granule cells through GABAA receptor-mediated tonic and phasic inhibition. Recent experiments provided compelling evidence for the extensive interconnection of GoCs through electrical synapses, but their chemical inhibitory synaptic inputs are debated. Here, we investigated the GABAergic synaptic inputs of GoCs using in vitro electrophysiology and quantitative light microscopy (LM) and electron microscopy (EM). We characterized GABAA receptor-mediated IPSCs in GoCs and Lugaro cells (LuCs), and found that IPSCs in GoCs have lower frequencies, smaller amplitudes, and much slower decay kinetics. Pharmacological and LM immunolocalization experiments revealed that GoCs express α3, whereas LuCs express α1 subunit-containing GABAA receptors. The selective expression and clustered distribution of the α3 subunit in GoCs allowed the quantitative analysis of GABAergic synapses on their dendrites in the molecular layer (ML). EM and LM experiments in rats, and wild-type and GlyT2-GFP transgenic mice revealed that only one third of axon terminals establishing GABAergic synapses on GoC dendrites contain GlyT2, ruling out LuCs, globular cells, and any noncortical glycinergic inputs as major inhibitory sources. We also show that axon terminals of stellate/basket cells very rarely innervate GlyT2-GFP-expressing GoCs, indicating that only a minority of the inhibitory inputs to GoCs in the ML originates from local interneurons, and the majority of their inhibitory inputs exclusively releases GABA.


Propolis and its constituents against cardiovascular risk factors including obesity, hypertension, atherosclerosis, diabetes, and dyslipidemia: A comprehensive review.
Cardiovascular diseases (CVDs) are some of the major causes of death worldwide. The modern lifestyle elevates the risk of CVDs. CVDs have several risk factors such as obesity, dyslipidemia, atherosclerosis, hypertension, and diabetes. Using herbal and natural products plays a pivotal role in the treatment of different diseases such as CVDs, diabetes, and metabolic syndrome. Propolis, a natural resinous mixture, is made by honey bees. Its main components are phenolics and terpenoid compounds such as caffeic acid phenethyl ester, chrysin, and quercetin. In this review, multiple studies regarding the pharmacological impacts of propolis and its constituents with their related mechanisms of action against mentioned CVD risk factors have been discussed in detail. Here, we used electronic databases or search engines such as Scopus, Web of Science, Pubmed, and Google Scholar without time limitations. The primary components of propolis are phenolics and terpenoid compounds such as caffeic acid phenethyl ester, chrysin and quercetin. Propolis and its constituents have been found to exhibit anti-obesity, anti-hypertension, anti-dyslipidemic, anti-atherosclerosis, and anti-diabetic effects. The vast majority of studies discussed in this review demonstrate that propolis and its constituents could have therapeutic effects against mentioned CVD risk factors via several mechanisms such as antioxidant, anti-inflammatory, reducing adipogenesis, HMG-CoA reductase inhibitory effect, inhibition of the ACE, increasing insulin secretion, NO level, etc.


A Pharmacokinetic Study of Mix-160 by LC-MS/MS: Oral Bioavailability of a Dosage Form of Citroflavonoids Mixture.
This study was performed to evaluate and compare the pharmacokinetic parameters between two dosage formulations of hesperidin and naringenin: mixture and tablet. Our objective was to determine that the flavonoid tablet does not significantly modify the pharmacokinetic parameters compared with the mixture. For this study, we administered 161 mg/kg of either mixture (Mix-160) or tablet composed of hesperidin and by intragastric administration. Blood microsamples were collected from tail vein up to 24 h. Serum flavonoid extraction was performed by solid phase extraction and analyzed by LC-MS/MS of triple quadrupole (QqQ). Serum concentration vs. time plot showed that data fitted for a first-order model. The pharmacokinetic parameters were calculated by a noncompartmental model. The results showed that the absorption constant is higher than the elimination constant. The first concentration was found at five minutes, and minimal concentration at 24 h after administration, suggesting a enterohepatic recirculation phenomena and regulation of liver cytochromes' activity. We did not find meaningful differences between the pharmacokinetic parameters of both samples. We concluded that tablet form did not interfere with the bioavailability of hesperidin and naringenin, and it could be a suitable candidate for developing a drug product.


[Bacterial skin flora, host defense and skin infections].
Resident skin flora consists of coagulase-negative staphylococci, micrococci, aerobic and anaerobic coryneform organisms (i.e. propionibacterium acnes) as well as gram-negative rods (i.e. acinetobacter). Their growth is favoured by increased temperature and humidity and modified by body location, age, sex and chronic diseases (i.e. diabetes mellitus). Occupation, hospitalization, soaps and disinfectants as well as medications exert promoting and inhibiting influences, too. In addition, environment gains significant importance due to trauma and implants as well as contact with animals, infected persons and carriers. Whereas bacteria attach by adhesins and succeed other bacteria by factors of pathogeneity such as exotoxins, exoenzymes, bacteriocins and various interference mechanisms, skin exerts its resistance and defense by means of the intact horny layer, proliferation and desquamation, lipids and fatty acids as well as sweat, in addition, by means of IgA and the specific skin immune system with complex interactions between Langerhans-, TH-, TS- and cytotoxic T-cells, interleukins and cytokines. Furthermore the non-specific defense system (complement, NK-cells, granulocytes, mononuclear phagocytic system, inflammation) is involved. Finally, skin infections caused by resident bacterial flora are briefly discussed.


Rates of endoscopy and endoscopic findings among people with frequent symptoms of gastroesophageal reflux in the community.
Epidemiological studies have confirmed that gastroesophageal symptoms are highly prevalent. However, studies linking epidemiology with clinical or chart data are scarce. We aimed to determine the frequency of endoscopy and endoscopic findings, as well as predictors of health-care utilization, among people with reflux symptoms in the community. A previous survey of 2,118 Olmsted County, MN, residents in 1993 identified 242 subjects with frequent reflux symptoms (at least weekly) who received care at a medical center in the county. Data were abstracted from Mayo Clinic records between 1988 and 1998. Overall, 130 of the 242 (54%, 95% CI 47-60%) had sought care for reflux. Twenty-five patients (10%) had visited a gastroenterologist; 47 (19%) had an upper endoscopy (EGD), 64 (26%) had an upper GI X-ray, and one had an ambulatory 24-h esophageal pH study. Long segment Barrett's esophagus was detected in 4 (9%) of those having an EGD and adenocarcinoma was found in one patient with Barrett's. Three patients had surgery for gastroesophageal reflux disease. Thirteen patients (5%) died, but no deaths were due to esophageal reflux or adenocarcinoma. Age, higher education, frequent heartburn, and dysphagia were all significant, independent predictors of consulting. Although many people in the community have frequent reflux symptoms, few have investigations, and deaths were unrelated to reflux disease or its complications. Data from referral clinic or endoscopy series should not be extrapolated to the large numbers of people in the community with symptoms of reflux.


Graduate follow-up in the US Air Force family practice residency programs.
Between June 30, 1973, and June 30, 1982, 216 family physicians completed residency training in family practice residencies sponsored by the US Air Force. The primary purpose of this study was to measure the adequacy of the graduates' residency training program. One hundred seventy-nine (83 percent) of the graduates responded to an extensive eight-page survey. The study assessed all Air Force program graduates as a whole as well as each program separately. Seventy-four percent of the respondents are still in the Air Force. All but one are board certified, and 19 have been recertified. Of the 179 respondents, 37.0 percent are involved in teaching medical students of family practice residents, only 5.0 percent are dissatisfied with their present hospital privileges, 43.5 percent felt that their residency training was superior to that provided by civilian family practice residency, 53.7 percent felt the training was equal, and 2.8 percent felt the training was inferior. Practice satisfaction and continuing medical education needs were also addressed in the study.


Nationwide time trends in dispensed prescriptions of psychotropic medication for children and adolescents in Denmark.
The analysis of time trends in dispensed prescriptions of psychotropic medications for children and adolescents in Denmark. The entire data set of the Danish prescription register covering stimulants, antidepressants, antipsychotics, and anxiolytics used in children and adolescents over a 15-year time span from 1996 to 2010 was analyzed. Both non-adjusted age-standardized prevalence rates and adjusted age-standardized prevalence rates considering the increase in patient numbers over time were calculated, and time trends were assessed based on 105908 patient-years. For stimulants, antidepressants, and antipsychotics, the non-adjusted prevalence rates increased significantly. These trends were strongest for the stimulants. However, all adjusted prevalence rates were much lower with the anxiolytics even declining significantly. The prevalence rates of stimulants and antipsychotics were significantly higher among males than females, whereas females received significantly more antidepressants. The increase in prescription rates for both antidepressants and antipsychotics was mainly due to increased use among the 14- to 17-year-olds. Stratification by diagnoses revealed significantly increasing prevalence rates of dispensed antidepressants and antipsychotics in six major diagnostic indications. Although increasing, the unadjusted Danish prevalence rates of dispensed prescriptions of psychotropics for children and adolescents are still lower than in many other Western countries.


Molecular and functional characterization of ferredoxin NADP(H) oxidoreductase from Gracilaria chilensis and its complex with ferredoxin.
Ferredoxin NADP(H) oxidoreductases (EC 188.8.131.52) (FNR) are flavoenzymes present in photosynthetic organisms; they are relevant for the production of reduced donors to redox reactions, i.e. in photosynthesis, the reduction of NADP+ to NADPH using the electrons provided by Ferredoxin (Fd), a small FeS soluble protein acceptor of electrons from PSI in chloroplasts. In rhodophyta no information about this system has been reported, this work is a contribution to the molecular and functional characterization of FNR from Gracilaria chilensis, also providing a structural analysis of the complex FNR/Fd. The biochemical and kinetic characterization of FNR was performed from the enzyme purified from phycobilisomes enriched fractions. The sequence of the gene that codifies for the enzyme, was obtained using primers designed by comparison with sequences of Synechocystis and EST from Gracilaria. 5'RACE was used to confirm the absence of a CpcD domain in FNRPBS of Gracilaria chilensis. A three dimensional model for FNR and Fd, was built by comparative modeling and a model for the complex FNR: Fd by docking. The kinetic analysis shows KMNADPH of 12.5 M and a k cat of 86 s-1, data consistent with the parameters determined for the enzyme purified from a soluble extract. The sequence for FNR was obtained and translated to a protein of 33646 Da. A FAD and a NADP+ binding domain were clearly identified by sequence analysis as well as a chloroplast signal sequence. Phycobilisome binding domain, present in some cyanobacteria was absent. Transcriptome analysis of Gch revealed the presence of two Fd; FdL and FdS , sharing the motif CX5CX2CX29X. The analysis indicated that the most probable partner for FNR is FdS. The interaction model produced, was consistent with functional properties reported for FNR in plants leaves, and opens the possibilities for research in other rhodophyta of commercial interest.


Multiple growth factors regulate coronary embryonic vasculogenesis.
Mechanisms regulating coronary vascularization are not well understood. To test hypotheses regarding the influence of key growth factors and their interactions, we studied vascular tube formation (vasculogenesis) in collagen gels onto which quail embryonic ventricles were placed and incubated in the presence of growth factors or inhibitors. Vasculogenesis in this model is dependent on tyrosine kinase receptors, since tube formation was totally blocked by genestein. Tube formation was attenuated when anti-bFGF or anti-VEGF neutralizing antibodies were added to the medium and nearly completely inhibited when the both were added. The attenuation associated with anti-VEGF was due primarily to a decrease in assembly of endothelial cells, while that associated with bFGF was primarily due to a reduction in endothelial cells. Soluble tie-2, the receptor for angiopoietins, also had an inhibitory effect and, when added with either anti-bFGF or anti-VEGF, markedly attenuated tube formation. At optimal doses, tube formation was enhanced 6.5-fold by bFGF and 2.5-fold by VEGF over the controls. Each of these growth factors was dependent upon the other for optimal induction of tube formation, since neutralizing antibodies to one markedly reduced the potency of the other. VEGF potency was also markedly reduced when soluble tie-2 was added to the medium. Tube formation was virtually totally blocked by exogenous TGF-beta at doses > 1 ng/ml, while neutralizing TGF-beta antibodies enhanced tube formation 2-fold in the 30 ng-30 microg range. These data provide the first documentation of multiple growth factor regulation of coronary tube formation.


Primary low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) arising in dura.
We report 2 cases of low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type presenting as primary lesions in the intracranial dura. Both patients are female, and, prior to biopsy were felt to have subdural hematoma and meningioma based on preoperative MRI scans. Histologically, both cases showed a diffuse proliferation of small centrocyte-like cells or monocytoid B cells admixed with a moderate number of large transformed cells. Reactive germinal center formation was present, as was plasmacytoid differentiation in one case. These histologic features are identical to those associated with low-grade MALT lymphomas arising at other more typical sites. Clinically, both patients were found to have stage IE disease at diagnosis without evidence of lymphoma outside of the central nervous system. Immunophenotypically, the lymphomas expressed B-cell-associated antigens CD20 and CD79a without coexpression of CD5, CD10, or CD23, and 1 of the 2 cases tested showed monoclonal rearrangement of the immunoglobulin heavy chain gene without rearrangement of bcl-1 or bcl-2. MALT lymphomas have recently been described in the dura and are postulated to arise in association with meningoepithelial cells. It is important that this entity be recognized and distinguished from other small B-cell non-Hodgkin's lymphomas such as mantle cell lymphoma, small lymphocytic lymphoma, or follicular small cleaved cell lymphomas, since localized low grade MALT lymphomas are usually clinically indolent proliferations which may require only minimally aggressive therapy.


[Avermectins: biotechnological features of the producing strain of Streptomyces avermitilis VKM As 1301].
The monosporic plating of the avermectin-producing strain Streptomyces avermitilis VKM Ac-1301 with low activity showed the heterogeneity of the population. By selection of natural mutants the authors obtained a strain synthesizing up to 60 micrograms avermectin B1 per ml of culture liquid. The maximum avermectin yield was observed in the medium containing 7% glucose after 100-120 h of culture growth.


A histomorphometric evaluation of heparin-induced bone loss after discontinuation of heparin treatment in rats.
Although it is well established that long-term heparin therapy causes osteoporosis, it is unknown whether heparin-induced bone loss is reversible when heparin treatment is stopped. To address this question, we randomized rats to once daily subcutaneous injections of either unfractionated heparin (1.0 U/g or 0.5 U/g) or saline for 28 days and then followed the rats for an additional 28 days off treatment. Based on histomorphometric analysis of the distal third of the right femur proximal to the epiphyseal growth plate, 1.0 U/g heparin caused a 30% loss in cancellous bone volume over the first 28 days. This was accompanied by a 137% increase in osteoclast surface and a 60% decrease in both osteoblast and osteoid surface. One month after cessation of heparin treatment, no recovery in these parameters was observed. Similarly, serum levels of alkaline phosphatase, a biochemical marker of bone formation, which continued to decrease over the course of heparin treatment, showed no signs of recovery in the subsequent 28 days off treatment. To explore the mechanism responsible for the prolonged effect of heparin on bone, we repeated the experiment giving 125I-labeled heparin in place of unlabeled heparin. 125I-labeled heparin was found to accumulate in bone during the course of its administration, and be retained in bone for at least 56 days after stopping heparin treatment. These findings suggest that heparin-induced osteoporosis is not rapidly reversible because heparin is sequestered in bone for an extended period.


The emergence of cardiometabolic disease risk in Chinese children and adults: consequences of changes in diet, physical activity and obesity.
Strong secular declines in physical activity, increased fat and salt intake, and increased obesity, especially abdominal obesity, mark China's recent nutrition transition. The China Health and Nutrition 2009 Survey collected anthropometry, blood pressure and fasting blood samples from more than 9,000 individuals ≥ 7 years of age. We focus on elevated blood pressure and plasma markers of diabetes, inflammation and dyslipidemia. We used international definitions of cardiometabolic risk and estimated age- and sex-specific prevalence ratios for each outcome for high waist circumference or overweight. We used logistic regression to assess each risk factor's association with diet, physical activity, overweight and abdominal obesity. Cardiometabolic risk prevalence was high in all age groups Prevalence ratios for most risk factors were nearly doubled for overweight or high waist circumference groups. Prevalence ratios were higher in younger than older adults. Low physical activity consistently predicted higher cardiometabolic risk across most outcomes and age-sex groups. The co-occurrence of overweight and high waist circumference was highly predictive of dyslipidemia, elevated glycated haemoglobin and diabetes. High prevalence of cardiometabolic risk factors and their strong association with weight status and abdominal obesity in young adults portend increases in cardiometabolic morbidity and mortality. Early interventions will be required to reverse trends.


The Association between Pretreatment anemia and Overall Survival in Advanced Non-small Cell lung Cancer: A Retrospective Cohort Study Using Propensity Score Matching.
Background: The purpose of this study was to investigate whether pretreatment anemia was an independent risk factor for survival in patients with advanced non-small cell lung cancer (NSCLC) after adjusting for other covariates. Methods: We used propensity score matching (PSM) to minimize the influence of confounding factors and used χ2 (categorical variables), Student's t-test (normal distribution), or Mann-Whitney U test (skewed distribution) to analyze the differences among the Hb groups. Cox regression and Kaplan-Meier analyses were used to assess the association between anemia and survival. P values < 0.05 (two-sided) were considered statistically significant. Results: The average age of the 758 selected participants was 58.2±11 years, and 210 patients (27.7%) had anemia. In the multivariate analysis, anemia was associated with a poor prognosis in the unmatched cohort (Hazards ratio (HR)=1.3, 95% (confidence interval (CI): 1.1-1.6; p= 0.008), and the matched cohort (HR=1.7, 95% CI: 1.3-2.3; p <0.001), emerging as an independent risk and prognostic factor in advanced NSCLC patients. In the Kaplan-Meier curve, the average survival time of anemic and non-anemic patients was 9.3 months (95% CI: 7.9-11.4 months) vs. 14.1 months (95% CI: 12-16.3 months) (p=0.0073) in the unmatched cohort. After propensity score matching, the average survival time of anemic and non-anemic patients was 10.9 months (95% CI: 8.8-12.9. months) vs. 17.8 months (95% CI: 16.0-23.3 months) (p <0.001). Conclusion: Pretreatment anemia was an independent risk and prognostic factor for survival in patients with advanced NSCLC. Large-scale studies are required to confirm our findings.


Neuroinflammation and Behavioral Deficit in Rotenone-Induced Neurotoxicity in Rats and the Possible Effects of Butanolic Extract of Centaurea africana.
Many studies have used rotenone (ROT) to create an experimental animal model of Parkinson's disease (PD) because of its ability to induce similar behavioral and motor deficits. PD is the most common age-related motoric neurodegenerative disorder. Neuroinflammation and apoptosis play an important role in the pathogenesis of this disease. This study investigated the effect of butanolic (n-BuOH) extract of Centaurea africana (200 mg/kg, 16 days) on a ROT-induced neurotoxicity model in male Wistar albino rats. Estimation of Tumor Necrosis Factor (TNF-α) and Nitric Oxide (NO) levels along with the myeloperoxidase (MPO) activity in brains was carried out in order to evaluate neuro-inflammation. Oxidative stress, Caspase 3 activity (apoptosis), and behavioral alterations were also evaluated. In behavior assessment, using Ludolph Movement Analysis Scale, all ROT treated animals showed a decreased locomotor activity. The mitochondrial dysfunction induced by ROT was expressed by a decreased activity of complex I of the mitochondrial respiratory chain and increased lipid peroxidation and caspase 3. Co-treatment with the n-BuOH extract significantly restored the activity of complex I (65.41 %) compared to treatment with ROT alone. The n-BuOH extract also reduced the neuroinflammation in rat brains by reducing MPO activity (75.12 %), NO levels (77.43 %), and TNF-α (71.48 %) compared to the group treated with ROT. The obtained results indicated that C. africana n-BuOH extract exhibited a protective effect in rats.


The role of PTEN in the progression and survival of prostate cancer.
PTEN (phosphatase and tensin homologue deleted on chromosome-10), a dual specificity phosphatase, is a tumor suppressor gene whose inactivation has been associated with many different types of cancer including prostate cancer. Prostate adenocarcinoma is one of the most commonly diagnosed malignancies afflicting the male population in both the United States and Europe. The frequency of PTEN inactivation appears to increase during the progression of prostatic cancer. The physical loss of the PTEN genetic locus in prostate cancer progression has been well characterized, however the molecular implication of this loss of PTEN remains enigmatic. The purpose of this review is to describe the functional role of PTEN in the molecular pathogenesis of prostatic disease. We review the function of PTEN discussing its association with the phosphoinositol 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) signal transduction pathways. Additionally, we discuss the role of PTEN in the regulation of apoptotic pathways involving the anti-apoptotic gene bcl-2 and the pro-apoptotic ligand TRAIL. We also review the mechanisms that can lead to the loss of PTEN function. We describe genetic inactivation including loss of heterozygosity, haploinsufficiency and mutation. We conclude by outlining epigenetic loss including methylation, post-translational modifications and oxidative stress.


Canine major histocompatibility complex genes DQA and DQB in Irish setter dogs.
Information about genetic variation within the canine major histocompatibility complex (MHC) class II genes is limited. In common with most other vertebrate species the canine MHC, or DLA, includes genes which are homologous to human DR, DQ, and DP. Recently, at least one functional DLA DQ gene-pair has been characterized, but so far systematic screening efforts have been lacking. In the present study, we sequenced both cDNA and genomic clones derived from DLA DQ genes of Irish setter dogs. This breed was of interest, since it shows a high prevalence of gluten sensitive enteropathy (GSE), which may be a useful animal model for celiac disease (CD) of man. Interestingly, few of the alleles found in Irish setters were identical to those previously detected in other breeds. Three novel DLA DQA and four novel DLA DQB alleles were discovered in 19 unrelated dogs. Strong association between certain HLA DQ alleles and CD of man prompted us to screen the DQ alleles of members of a family of gluten-sensitive Irish setter dogs. No haplotypes or alleles were shared by all affected dogs, but one frequent haplotype in this family was also detected in an unrelated gluten-sensitive Irish setter; this haplotype was absent in the healthy dogs. This observation warrants further investigation by screening the DQ alleles of a large population of unrelated gluten-sensitive Irish setters.


Binding and Activation of Serotonergic G-Protein Coupled Receptors by the Multimodal Antidepressant Vortioxetine.
G-protein coupled receptors (GPCRs) are important pharmacological targets. Despite substantial progress, important questions still remain concerning the details of activation: how can a ligand act as an agonist in one receptor but as an antagonist in a homologous receptor, and how can agonists activate a receptor despite lacking polar functional groups able to interact with helix 5 as is the case for the related adrenergic receptors? Studying vortioxetine (VXT), an important multimodal antidepressant drug, may elucidate both questions. Herein, we present a thorough in silico analysis of VXT binding to 5-HT1A, 5-HT1B, and 5-HT7 receptors and compare it with available experimental data. We are able to rationalize the differential mode of action of VXT at different receptors, but also, in the case of the 5-HT1A receptor, we observe the initial steps of activation that inform about an activation mechanism that does not involve polar interaction with helix 5. The results extend our current understanding of agonist and antagonist action at aminergic GPCRs.


Severe aortic stenosis detection by deep learning applied to echocardiography.
Early diagnosis of aortic stenosis (AS) is critical to prevent morbidity and mortality but requires skilled examination with Doppler imaging. This study reports the development and validation of a novel deep learning model that relies on two-dimensional (2D) parasternal long axis videos from transthoracic echocardiography without Doppler imaging to identify severe AS, suitable for point-of-care ultrasonography. In a training set of 5257 studies (17 570 videos) from 2016 to 2020 [Yale-New Haven Hospital (YNHH), Connecticut], an ensemble of three-dimensional convolutional neural networks was developed to detect severe AS, leveraging self-supervised contrastive pretraining for label-efficient model development. This deep learning model was validated in a temporally distinct set of 2040 consecutive studies from 2021 from YNHH as well as two geographically distinct cohorts of 4226 and 3072 studies, from California and other hospitals in New England, respectively. The deep learning model achieved an area under the receiver operating characteristic curve (AUROC) of 0.978 (95% CI: 0.966, 0.988) for detecting severe AS in the temporally distinct test set, maintaining its diagnostic performance in geographically distinct cohorts [0.952 AUROC (95% CI: 0.941, 0.963) in California and 0.942 AUROC (95% CI: 0.909, 0.966) in New England]. The model was interpretable with saliency maps identifying the aortic valve, mitral annulus, and left atrium as the predictive regions. Among non-severe AS cases, predicted probabilities were associated with worse quantitative metrics of AS suggesting an association with various stages of AS severity. This study developed and externally validated an automated approach for severe AS detection using single-view 2D echocardiography, with potential utility for point-of-care screening.


Detection of lipoatrophy in human immunodeficiency virus-1-infected children treated with highly active antiretroviral therapy.
Highly active antiretroviral therapy has been associated with lipodystrophy in adults. Much is unknown about its characteristics, especially in children. To obtain an objective case definition of the lipodystrophy syndrome. This was a cross-sectional study. One investigator rated clinical lipodystrophy. Body composition was measured using body mass index, skin fold thickness and circumference of arm, leg, waist and hip. Samples for human immunodeficiency virus (HIV)-1 RNA, CD4 cell count, fasting lipids and glucose variables were drawn. HIV-infected children with lipodystrophy were compared with HIV-infected children without lipodystrophy (controls). Thirty-four children were included: 28 controls, 2 nonassigned, and 4 with the lipoatrophic phenotype. Lipohypertrophy or mixed syndrome were not observed. All children with lipoatrophy were pubertal; they had used stavudine and didanosine longer. Children with lipoatrophy had significantly smaller arm and leg circumference, and their skin folds were thinner. The torso-to-arm ratio was 3 times higher in lipoatrophic children, but the difference did not reach significance. The waist-to-hip ratio was higher (P = 0.005). None of the laboratory values differed significantly between the two groups, but all children with lipoatrophy had an increased C-peptide level above the upper limit of normal. All children with lipoatrophy could be distinguised from controls by an increased C-peptide level, a waist-to-hip ratio z score of 1 standard deviation or higher and a sum of skin folds z score below -1 standard deviation. All children with lipoatrophy can be distinguished by using anthropometric measurements and C-peptide measurement in serum. This method is simple, readily available and inexpensive.


The Caggins Synergy Nursing Model.
The Caggins Synergy Nursing Model (CSNM) is a conceptual framework which was developed by the author during her doctoral coursework at Texas Woman's University-Houston. The conceptualization of the phenomena described in the CSNM represents an integration of several theoretical frameworks and the sequencing of concepts based on the influence of other theoretical frameworks. The theoretical and conceptual frameworks that were integrated and had the most influence during the development of the model were Rogers' (1970) life process model, Akers' (1970) conceptual framework for professional cohesion, and Cattell's (1948) group syntality theory. The CSNM supports the use of the nursing process and is applicable to the analysis of group interaction.


An Analysis of Warm-Up Strategies at a Cross-Country Skiing National Championship.
To provide a descriptive analysis of the warm-up (WU) strategies employed by cross-country skiers prior to distance and sprint competitions at a national championship and to compare the skiers' planned and executed WUs prior to the respective competitions. Twenty-one national- and international-level skiers (11 women and 10 men) submitted WU plans prior to the distance and sprint competitions, and after the competitions, reported any deviations from the plans. Skiers used personal monitors to record heart rate (HR) during WU, races, and cooldown. Quantitative statistical analyses were conducted on WU durations, durations in HR-derived intensity zones, and WU loads. Qualitative analyses were conducted on skiers' WU plans and their reasons for deviating from the plans. Skiers' planned WUs were similar in content and planned time in HR-derived intensity zones for both the distance and sprint competitions. However, 45% of the women and 20% of the men reported that their WU was not carried out as planned, with reasons detailed as being due to incorrect intensities and running out of time. WU activities including skiing across variable terrain, muscle-potentiating exercises, and heat-maintenance strategies were missing from the skiers' planned routines. Skiers favored a long, traditional WU approach for both the sprint and distance events, performing less high-intensity and more moderate-intensity exercise during their WUs than planned. In addition, elements likely relevant to successful performance in cross-country skiing were missing from WU plans.


Multiple pharmacokinetic parameter prediction for a series of cephalosporins.
The goal of quantitative structure-pharmacokinetic relationship analyses is to develop useful models that can predict one or more pharmacokinetic properties of a particular compound. In the present study, a multiple-output artificial neural network model was constructed to predict human half-life, renal and total body clearance, fraction excreted in urine, volume of distribution, and fraction bound to plasma proteins for a series of cephalosporins. Descriptors generated solely from drug structure were used as inputs for the model, and the six pharmacokinetic parameters were simultaneously predicted as outputs. The final 10 descriptor model contained sufficient information for successful predictions using both internal and external test compounds. Descriptors were found to contribute to individual pharmacokinetic parameters to differing extents, such that descriptor importance was independent of the relationships between pharmacokinetic parameters. This technique provides the advantage of simultaneous prediction of multiple parameters using information obtained by nonexperimental means, with the potential for use during the early stages of drug development.


A progressive review of Sandhana kalpana (Biomedical fermentation): An advanced innovative dosage form of Ayurveda.
Sandhana kalpana (biomedical fermented formulations) are one of the best dosage forms of Ayurveda in practice since thousands of years. In order to prepare these medicaments, certain sets of conditions are prearranged, which lead to fermentation. Thus, products bequeath with self-generated ethyl alcohol, which potentiate these preparations (Asava-Arishta), pharmaceutically and therapeutically. Commonly, medicinal and commercial components of these formulations are prompting many researchers to contribute in manufacturing, quality control, safety, and efficacy of these formulations. To cope up with this, literature related to Asava-Arishta has been surveyed from the Vedic period to recent publications of Government of India, ie, Ayurvedic Formulary of India, and presented briefly here. In this review paper, we have discussed pioneering facts such as nature and amount of carbohydrate, type of containers, optimum temperature, variety and relevance of initiator of fermentation, manufacturing, regulatory rules, and business aspects of Asava-Arishta. After going through this basic information, any academician or researcher may show a way to further strengthen this dosage form.


[Cell therapy in treating age-related intervertebral disc pathology].
Pathology of the spine significantly affects the quality of life and is associated with a high rate of disability. Prevalence of the pathology of the spine increases with advanced age. It may have various causes and is associated with a wide spectrum of significant and variable symptoms. Low back pain (back pain) is the most common syndrome. It is mostly caused by the degeneration of the intervertebral discs, associated with unspecific and irreversible structural alterations in the latter. Surgical treatment of degenerative disc disease (DDD) is symptomatic, thus requiring a development of alternative approaches. In the current review, the principles of regenerative cellular therapy and cell replacement therapy of DDD are analyzed. Various cell types utilized as cellular therapy substrates are compared.