A model for assembly and activation of the GM-CSF, IL-3 and IL-5 receptors: Insights from activated mutants of the common beta subunit

Granulocyte-macrophage colony stimulating factor (GM-CSF), Interleukin-3 (IL-3) and Interleukin-5 (IL-5) have overlapping, pleiotropic effects on hematopoietic cells, including neutrophils, eosinophils, monocytes and early progenitor cells. The high-affinity receptors for human GM-CSF, IL-3, and IL-5 share a common beta-subunit (h beta(c)), which is essential for signalling and plays a major role in recruiting intracellular signalling molecules. While activation of the cytoplasmic tyrosine kinase JAK2 appears to be the initiating event for signalling, the immediate events that trigger this are still unclear. We have isolated a number of activated mutants of h beta(c), which can be grouped into classes defined by their state of receptor phosphorylation, their requirement for alpha subunit as a cofactor, and their activities in primary cells and cell lines. We discuss these findings with regard to the stoichiometry, activation, and signalling of the normal GM-CSF/IL-3/IL-5 receptor complexes. Specifically, this work has implications for the role of the ligand-specific alpha-subunits in initiating the signalling through the beta-subunit, the role of beta subunit dimerization as a receptor trigger, and the function of receptor tyrosine phosphorylation in generating growth and survival signals. Based on the properties of the activated mutants and the recent structures of erythropoietin receptor (Epo-R) complexes, we propose a model in which (1) activation of h beta(c) can occur via alternative states that differ with respect to stoichiometry and subunit assembly, but which all mediate proliferative responses, and (2) each of the different classes of activated mutants mimics one of these alternative states. (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.

Erectile dysfunction in general medicine practice: prevalence and clinical correlates

Erectile dysfunction (ED) is a common problem in general medical practice affecting especially the elderly and those with cardiovascular disease and diabetes mellitus, A study was undertaken by questionnaire distributed to consecutive adult male attendees at 62 general medical practices. 1240 completed questionnaires were available for analysis. The mean age of participants was 56.4 y (range 18 - 91 y). 488 men (39.4%) reported ED: 119 (9.6%) 'occasionally', 110 (8.9%) 'often', and 231 (18.6%) 'all the time' (complete ED). Among 707 men aged 40-69 y 240 (33.9%) reported ED and 84 (11.9%) had complete ED. The prevalence of complete ED increased with age, rising from 2.0% in the 40-49 y age group to 44.9% in the 70-79 y age group. Only 11.6% of men with ED had received treatment. Hypertension, ischaemic heart disease, peripheral vascular disease and diabetes mellitus were frequently associated with ED. 40% of diabetic men aged 60 y or older had ED all the time.

Review of "Comorbidity, disability and the need for treatment for DSM-IV psychiatric disorders in an insured population"

Background: This study presents estimates of 12 month and current prevalences of DSM-IV disorders, and the related comor-bidity, disability and service utilization, derived from a national probability sample in Australia. Methods: The DSM-IV psychiatric disorders among persons aged 18 and over in the Australian population were assessed with data collected by lay interviewers using the Composite International Diagnostic Interview, other screening interviews and measures of disability and service utilization. The response rate was 78.1% and the final sample size was 10,641 adults. Results: Close to 20% reported at least one twelve month disorder and 13% a disorder current within the past 30 days. ICD-10 diagnoses were also derived, DSM-IV was the more conservative classification whether or not the new clinical significance criteria was applied. Major depression, any personality disorder, and alcohol dependence were the three most common twelve month disorders, generalized anxiety disorder replaced alcohol dependence as the third most common current disorder. The sexes has similar rates of any disorder, but women had higher rates of affective and anxiety disorders, men higher rates of substance use disorders. Prevalence of most disorders declined with age and education, and were lower among those employed or married. Respondents whose symptoms met criteria for three or more disorders in the past year had greatly increased rates of disability and of mental health consultations. The affective and somatoform disorders were associated with the highest rates of disability. Only 36% of people with a mental disorder this year had consulted for a mental problem, and most had seen a general practitioner. We identified those with a current disorder who were disabled or multiply comorbid - only half had consulted and of those who had not, more than half said they did not need treatment. Conclusions: The 12 month prevalence was lower than reported in the US National Comorbidity Survey but method factors might account for this. The relationships between prevalence and demographic variables, and between comorbidity, disability and service utilization were similar to those found in the US survey. Australia has a national health insurance scheme with total coverage and access to medical help is available to all, commonly at little or no cost. We identify the high rate of not consulting among those with a current disorder, and additional disability or multiple comorbidity, as an important public health problem. Kessler argued for more research on barriers to professional help seeking. This report reinforces his conclusion and shows that economic barriers are not the dominant issue.

Psychophysiological phenotypes of cognition: The P3 and SW components

As part of a large ongoing project, the Memory, Attention and Problem Solving (MAPS) study, we investigated whether genetic variability explains some of the variance in psychophysiological correlates of brain function, namely, the P3 and SW components of event-related potentials (ERPs). These ERP measures are minute time recordings of brain processes and, because they reflect fundamental cognitive processing, provide a unique window on the millisecondto- millisecond transactions that occur at the cognitive level and taking place in the human brain. The extent to which the variance in P3 and SW components is influenced by genetic factors was examined in 350 identical and nonidentical twin pairs aged 16 years. ERPs were recorded from 15 scalp electrodes during the performance of a visuospatial delayed response task that engages working memory. Multivariate genetic analyses using MX were used to estimate genetic and environmental influences on individual differences in brain functioning and to identify putative genetic factors common to the ERP measures and psychometric IQ. For each of the ERP measures, correlation among electrode sites was high, a spatial pattern was evident, and a large part of the genetic variation in the ERPs appeared to be mediated by a common genetic factor. Moderate within-pair concordance in MZ pairs was found for all ERP measures, with higher correlations found for P3 than SW, and the MZ twin pair correlations were approximately twice the DZ correlations, suggesting a genetic influence. Correlations between ERP measures and psychometric IQ were found and, although moderately low, were evident across electrode site. The analyses show that the ERP components, P3 and SW, are promising phenotypes of the neuroelectrical activity of the brain and have the potential to be used in linkage and association analysis in the search for QTLs influencing cognitive function.

A randomized trial of a problem-based learning approach for teaching epidemiology

Purpose. To conduct a controlled trial of traditional and problem-based learning (PBL) methods of teaching epidemiology. Method. All second-year medical students (n = 136) at The University of Western Australia Medical School were offered the chance to participate in a randomized controlled trial of teaching methods fur an epidemiology course. Students who consented to participate (n = 80) were randomly assigned to either a PBL or a traditional course. Students who did not consent or did not return the consent form (n = 56) were assigned to the traditional course, Students in both streams took identical quizzes and exams. These scores, a collection of semi-quantitative feedback from all students, and a qualitative analysis of interviews with a convenience sample of six students from each stream were compared. Results. There was no significant difference in performances on quizzes or exams between PBL and traditional students. Students using PBL reported a stronger grasp of epidemiologic principles, enjoyed working with a group, and, at the end of the course, were more enthusiastic about epidemiology and its professional relevance to them than were students in the traditional course. PBL students worked more steadily during the semester but spent only marginally more time on the epidemiology course overall. Interviews corroborated these findings. Non-consenting students were older (p < 0.02) and more likely to come from non-English-speaking backgrounds (p < 0.005). Conclusions. PBL provides an academically equivalent but personally far richer learning experience. The adoption of PBL approaches to medical education makes it important to study whether PBL presents particular challenges for students whose first language is not the language of instruction.

The land assembly problem revisited

As in the standard land assembly problem, a developer wants to buy two adjacent blocks of land belonging to two different owners. The value of the two blocks of land to the developer is greater than the sum of the individual values of the blocks for each owner. Unlike the land assembly literature, however, our focus is on the incentive that each lot owner has to delay the start of negotiations, rather than on the public goods nature of the problem. An incentive for delay exists, for example, when owners perceive that being last to sell will allow them to capture a larger share of the joint surplus from the development. We show that competition at point of sale can cause equilibrium delay, and that cooperation at point of sale will eliminate delay. This suggests that strategic delay is another source for the inefficient allocation of land, in addition to the public-good type externality pointed out by Grossman and Hart [Bell Journal of Economics 11 (1980) 42] and O'Flaherty [Regional Science and Urban Economics 24 (1994) 287]. (C) 2004 Elsevier B.V. All rights reserved.

Is your vision consistent? A method for checking, based on scenario concepts

Common sense tells us that the future is an essential element in any strategy. In addition, there is a good deal of literature on scenario planning, which is an important tool in considering the future in terms of strategy. However, in many organizations there is serious resistance to the development of scenarios, and they are not broadly implemented by companies. But even organizations that do not rely heavily on the development of scenarios do, in fact, construct visions to guide their strategies. But it might be asked, what happens when this vision is not consistent with the future? To address this problem, the present article proposes a method for checking the content and consistency of an organization`s vision of the future, no matter how it was conceived. The proposed method is grounded on theoretical concepts from the field of future studies, which are described in this article. This study was motivated by the search for developing new ways of improving and using scenario techniques as a method for making strategic decisions. The method was then tested on a company in the field of information technology in order to check its operational feasibility. The test showed that the proposed method is, in fact, operationally feasible and was capable of analyzing the vision of the company being studied, indicating both its shortcomings and points of inconsistency. (C) 2007 Elsevier Ltd. All rights reserved.

First detection of lead in black paper from intraoral film An environmental concern

Lead (Pb) contamination in the black paper that recovers intraoral films (BKP) has been investigated. BKP samples were collected from the Radiology Clinics of the Dental School of Ribeirao Preto, University of Sao Paulo, Brazil. For sake of comparison, four different methods were used. The results revealed the presence of high lead levels, well above the maximum limit allowed by the legislation. Pb contamination levels achieved after the following treatments: paper digestion in nitric acid, microwave treatment, DIN38414-54 method and TCLP method were 997 mu g g(-1), 189 mu g g(-1), 20.8 mu g g(-1), and 54.0 mu g g(-1), respectively. Flame atomic absorption spectrometry (FAAS) and inductively coupled plasma mass spectrometry (ICP-MS) were employed for lead determination according to the protocols of the applied methods. Lead contamination in used BKP was confirmed by scanning electron microscopy coupled with energy dispersive X-ray microanalysis (SEM-EDS). All the SEM imaging was carried out in the secondary electron mode (SE) and backscattered-electron mode (QBSD) following punctual X-ray fluorescence spectra. Soil contamination derived from this product revealed the urgent need of addressing this problem. These elevated Pb levels, show that a preliminary treatment of BKP is mandatory before it is disposed into the common trash. The high lead content of this material makes its direct dumping into the environment unwise. (C) 2009 Elsevier B.V. All rights reserved.

A Delphi study of district nursing research priorities in Australia

This study, using a Delphi approach, sought the opinion of a self-selected panel of 320 district nurses regarding research priorities for district nursing in Australia. Over three rounds of questionnaires, the 419 research clinical problem areas requiring research as suggested by the panel were each rated in importance by the panel and then ranked through analysis from high to low average rating scores, thereby, whittling down the list to the top 15% (68) research questions and to a final list of the top 10 research priorities overall. Research questions focusing on discharge planning are dominant in these top 10 priorities, with documentation issues the second most common focus. Other foci in the top 10 priorities are staffing, aged care, palliative care, and assessment. The organization-specific top 10 research priorities focus on wound care, funding, education, and communication issues. Additionally, the top 68 priorities, which are either finitely practice-based or contextual-issues research questions, were categorized into 20 themes. The results will hopefully lead to scarce human and financial resources being directed to practice-relevant research programs that will facilitate improved health for district nursing (primarily home-nursing) clients in Australia and elsewhere. (c) 2005 Elsevier Inc. All rights reserved.

The common p450 oxidoreductase variant A503V is not a modifier gene for 21-hydroxylase deficiency

Context: 21-hydroxylase deficiency (21OHD) is a common genetic disorder caused by mutations in the CYP21A2 gene, which encodes the adrenal 21-hydroxylase, microsomal P450c21. CYP21A2 gene mutations generally correlate well with impaired P450c21 enzymatic activity and the clinical findings in 21OHD, but occasional discrepancies between genotype and phenotype suggest the effects of modifier genes. Mutations in P450 oxidoreductase (POR), the protein that transfers electrons from reduced nicotinamide adenine dinucleotide phosphate to all microsomal P450s, can ameliorate the 21OHD phenotype and, therefore, could be a modifier gene. Objectives: We sought to identify POR variants in patients with 21OHD having discordant phenotype and genotype, and to evaluate their effect on 21-hydroxylase activity. Patients and Methods: We determined the CYP21A2 genotypes of 313 Brazilian patients with 21OHD and correlated the genotype and phenotype. The POR gene was sequenced in 17 patients with discordant genotype and phenotype. Wild-type and A503V POR, and P450c21 were expressed in bacteria and reconstituted in vitro. Activities were assayed by conversion of [C-14] progesterone to deoxycorticosterone and [H-3]17-hydroxyprogesterone to 11-deoxycortisol, and assessed by thin layer chromatography and phosphorimaging. Results: The A503V POR variant was found in 10 of 30 alleles, the same ratio as in the normal population. There were no significant differences in Michaelis constant, maximum velocity and maximum velocity/Michaelis constant of 21-hydroxylase activity supported by wild-type and A503V POR. Conclusion: The only POR missense polymorphism found in atypical 21OHD patients was A503V. Although A503V reduces P450c17 enzymatic activity, it does not influence P450c21 activity, indicating that POR A503V does not modify the 21OHD phenotype.

Acute care surgeon South American model

Background In the World Health Organization book by Murray and Lopez (The Global Burden of Disease), the authors make the point that there are major regional differences across the world for death from injury. In the European market economies, injuries accounted for 6% of all deaths, of which the majority were the result of road traffic accidents. In stark contrast, in Latin America and the Caribbean, injuries account for 12-13% of all deaths, and most of these are the result of violence. An estimated 30% of all male deaths are from external causes, and road traffic accidents are the number two cause of death. Within South American countries, trauma is the second most common cause of death in Columbia, Venezuela, Ecuador, and Brazil. In other South American countries, it is the third or fourth most common cause of death. If one examines the Disability Adjusted Life Years, South America is the third highest in the world. Death from injury primarily affects people in the middle- and low-income group. Traffic accidents and suicide are the main causes of trauma in the high-income population. South America is made up of developing and poor countries that have trauma as a very important cause of death and disability. Methods The author has reviewed information on injury from the World Health Organization, Pan American Health Organization, and Brazilian Health Ministry. In addition, a search of injury was performed through MEDLINE. Results and Conclusions The results of this review show that trauma is a major public health problem in South America. At the present time, there is a lack of statewide system development. In addition, there are difficulties in training surgeons to cope with these problems.

The intersection problem for K_4-e designs

A G-design of order n is a pair (P,B) where P is the vertex set of the complete graph K-n and B is an edge-disjoint decomposition of K-n into copies of the simple graph G. Following design terminology, we call these copies ''blocks''. Here K-4 - e denotes the complete graph K-4 with one edge removed. It is well-known that a K-4 - e design of order n exists if and only if n = 0 or 1 (mod 5), n greater than or equal to 6. The intersection problem here asks for which k is it possible to find two K-4 - e designs (P,B-1) and (P,B-2) of order n, with \B-1 boolean AND B-2\ = k, that is, with precisely k common blocks. Here we completely solve this intersection problem for K-4 - e designs.

Expression of activated mutants of the human interleukin-3/interleukin-5 granulocyte-macrophage colony-stimulating factor receptor common beta subunit in primary hematopoietic cells induces factor-independent proliferation and differentiation

To date, several activating mutations have been discovered in the common signal-transducing subunit (h beta c) of the receptors for human granulocyte-macrophage colony-stimulating factor, interleukin-3, and interleukin-5. Two of these, Fl Delta and 1374N, result in a 37 amino acid duplication and a single amino acid substitution in the extracellular domain of h beta c, respectively. A third, V449E, results in a single amino acid substitution in the transmembrane domain, Previous studies comparing the activity of these mutants in different hematopoietic cell lines imply that the transmembrane and extracellular mutations act by different mechanisms and suggest the requirement for cell type-specific molecules in signalling. To characterize the ability of these mutant hpc subunits to mediate growth and differentiation of primary cells and hence investigate their oncogenic potential, we have expressed all three mutants in primary murine hematopoietic cells using retroviral transduction. It is shown that, whereas expression of either extracellular hpc mutant confers factor-independent proliferation and differentiation on cells of the neutrophil and monocyte lineages only, expression of the transmembrane mutant does so on these lineages as well as the eosinophil, basophil, megakaryocyte, and erythroid lineages, Factor-independent myeloid precursors expressing the transmembrane mutant display extended proliferation in liquid culture and in some cases yielded immortalized cell lines. (C) 1997 by The American Society of Hematology.

Molecular characterization of the Hepatitis B virus genotypes in Colombia: A Bayesian inference on the genotype F

Hepatitis B is a worldwide health problem affecting about 2 billion people and more than 350 million are chronic carriers of the virus. Nine HBV genotypes (A to I) have been described. The geographical distribution of HBV genotypes is not completely understood due to the limited number of samples from some parts of the world. One such example is Colombia, in which few studies have described the HBV genotypes. In this study, we characterized HBV genotypes in 143 HBsAg-positive volunteer blood donors from Colombia. A fragment of 1306 bp partially comprising HBsAg and the DNA polymerase coding regions (S/POL) was amplified and sequenced. Bayesian phylogenetic analyses were conducted using the Markov Chain Monte Carlo (MCMC) approach to obtain the maximum clade credibility (MCC) tree using BEAST v.1.5.3. Of all samples, 68 were positive and 52 were successfully sequenced. Genotype F was the most prevalent in this population (77%) - subgenotypes F3 (75%) and Fib (2%). Genotype G (7.7%) and subgenotype A2 (15.3%) were also found. Genotype G sequence analysis suggests distinct introductions of this genotype in the country. Furthermore, we estimated the time of the most recent common ancestor (TMRCA) for each HBV/F subgenotype and also for Colombian F3 sequences using two different datasets: (i) 77 sequences comprising 1306 bp of S/POL region and (ii) 283 sequences comprising 681 bp of S/POL region. We also used two other previously estimated evolutionary rates: (i) 2.60 x 10(-4) s/s/y and (ii) 1.5 x 10(-5) s/s/y. Here we report the HBV genotypes circulating in Colombia and estimated the TMRCA for the four different subgenotypes of genotype F. (C) 2010 Elsevier B.V. All rights reserved.

Common mental disorders during pregnancy: prevalence and associated factors among low-income women in Sao Paulo, Brazil

To estimate the prevalence of common mental disorders (CMD) and factors associated with these disorders among pregnant women of low socio-economic status (SES) in Sao Paulo. We performed a cross-sectional study with 831 women in their 20th to 30th weeks of pregnancy, who were attending antenatal clinics in primary care in Sao Paulo, Brazil. CMD were assessed with the Clinical Interview Schedule-Revised. Crude and adjusted prevalence ratios and 95% CI were calculated to examine the association between CMD and exposure variables. The prevalence of CMD was 20.2% (95% CI 17.5 to 23.0). Age at current pregnancy and at first delivery, current obstetric complications, not having friends in the community, living in a crowded household, lower occupational status and history of previous psychiatric treatment were all independently associated with increased prevalence of CMD. CMD is highly prevalent among pregnant women of low SES seen in primary care settings in Sao Paulo. A combination of distal and proximal psychosocial factors increase the risk for CMD. Primary health care professionals need to be aware of how common CMD in such settings and properly trained to deal with CMD during pregnancy.