Sex differences in arterial hypertension.

There is strong evidence that sex chromosomes and sex hormones influence blood pressure (BP) regulation, distribution of cardiovascular (CV) risk factors and co-morbidities differentially in females and males with essential arterial hypertension. The risk for CV disease increases at a lower BP level in females than in males, suggesting that sex-specific thresholds for diagnosis of hypertension may be reasonable. However, due to paucity of data, in particularly from specifically designed clinical trials, it is not yet known whether hypertension should be differently managed in females and males, including treatment goals and choice and dosages of antihypertensive drugs. Accordingly, this consensus document was conceived to provide a comprehensive overview of current knowledge on sex differences in essential hypertension including BP development over the life course, development of hypertension, pathophysiologic mechanisms regulating BP, interaction of BP with CV risk factors and co-morbidities, hypertension-mediated organ damage in the heart and the arteries, impact on incident CV disease, and differences in the effect of antihypertensive treatment. The consensus document also highlights areas where focused research is needed to advance sex-specific prevention and management of hypertension

Allergy education and training for physicians.

The increasing prevalence of allergic diseases has placed a significant burden on global healthcare and society as whole. This has necessitated a rapid development of "allergy" as a specialist area. However, as allergy is so common and, for most, relatively easy to diagnose and control, all clinicians need to have basic knowledge and competence  to manage  mild disease and recognize when referral is required. The allergology specialty has not yet been recognized in many countries and even where allergy is fully recognized as a specialty, the approach to training in allergy differs significantly. In the light of recent developments in allergy diagnosis and management, there is an urgent need to harmonize core competences for physicians, as well as the standardization of core principles for medical education and post-graduate training in allergy. All physicians and allied health professionals must appreciate the multidisciplinary team (MDT) approach to allergy, which is key to achieving the highest standards in holistic care. Due to worldwide variation in resources and personnel, some MDT roles will need to be absorbed by the treating physician or other healthcare professionals. We draw particular attention to the role of psychological input for all allergy patients, dietetic input in the case of food allergy and patient education to support all patients in the supported self-management of their condition on a daily basis. A strong appreciation of these multidisciplinary aspects will help physicians provide quality patient-centered care. We consider that harmonization of allergy components within undergraduate curricula is crucial to ensure all physicians develop the appropriate allergy-related knowledge and skills, particularly in light of inconsistencies seen in the primary care management of allergy. This review from the World Allergy Organization (WAO) Education and Training Committee also outlines allergy-related competences required of physicians working with allergic patients and provides recommendations to promote harmonization of allergy training and practice worldwide

Exosome-Producing Follicle Associated Epithelium Is Not Involved in Uptake of PrPd from the Gut of Sheep (Ovis aries): An Ultrastructural Study

In natural or experimental oral scrapie infection of sheep, disease associated prion protein (PrPd) often first accumulates in Peyer's patch (PP) follicles. The route by which infectivity reaches the follicles is unknown, however, intestinal epithelial cells may participate in intestinal antigenic presentation by delivering exosomes as vehicles of luminal antigens. In a previous study using an intestinal loop model, following inoculation of scrapie brain homogenate, inoculum associated PrPd was detected by light microscopy shortly (15 minutes to 3.5 hours) after inoculation in the villous lacteals and sub-mucosal lymphatics. No PrPd was located within the follicle-associated epithelium (FAE), sub-FAE domes or the PP follicles. To evaluate this gut loop model and the transportation routes in more detail, we used electron microscopy (EM) to study intestinal tissues exposed to scrapie or control homogenates for 15 minutes to 10 days. In addition, immuno-EM was used to investigate whether exosomes produced in the FAE may possess small amounts of PrPd that were not detectable by light microscopy. This study showed that the integrity of the intestinal epithelium was sustained in the intestinal loop model. Despite prominent transcytotic activity and exosome release from the FAE of the ileal PP in sheep, these structures were not associated with transportation of PrPd across the mucosa. The study did not determine how infectivity reaches the follicles of PPs. The possibility that the infectious agent is transported across the FAE remains a possibility if it occurs in a form that is undetectable by the methods used in this study. Infectivity may also be transported via lymph to the blood and further to all other lymphoid tissues including the PP follicles, but the early presence of PrPd in the PP follicles during scrapie infection argues against such a mechanism

Optimal Control of Nonlinear Switched Systems: Computational Methods and Applications

A switched system is a dynamic system that operates by switching between different subsystems or modes. Such systems exhibit both continuous and discrete characteristics—a dual nature that makes designing effective control policies a challenging task. The purpose of this paper is to review some of the latest computational techniques for generating optimal control laws for switched systems with nonlinear dynamics and continuous inequality constraints. We discuss computational strategiesfor optimizing both the times at which a switched system switches from one mode to another (the so-called switching times) and the sequence in which a switched system operates its various possible modes (the so-called switching sequence). These strategies involve novel combinations of the control parameterization method, the timescaling transformation, and bilevel programming and binary relaxation techniques. We conclude the paper by discussing a number of switched system optimal control models arising in practical applications

SAD phasing using iodide ions in a high-throughput structural genomics environment

The Seattle Structural Genomics Center for Infectious Disease (SSGCID) focuses on the structure elucidation of potential drug targets from class A, B, and C infectious disease organisms. Many SSGCID targets are selected because they have homologs in other organisms that are validated drug targets with known structures. Thus, many SSGCID targets are expected to be solved by molecular replacement (MR), and reflective of this, all proteins are expressed in native form. However, many community request targets do not have homologs with known structures and not all internally selected targets readily solve by MR, necessitating experimental phase determination. We have adopted the use of iodide ion soaks and single wavelength anomalous dispersion (SAD) experiments as our primary method for de novo phasing. This method uses existing native crystals and in house data collection, resulting in rapid, low cost structure determination. Iodide ions are non-toxic and soluble at molar concentrations, facilitating binding at numerous hydrophobic or positively charged sites. We have used this technique across a wide range of crystallization conditions with successful structure determination in 16 of 17 cases within the first year of use (94% success rate). Here we present a general overview of this method as well as several examples including SAD phasing of proteins with novel folds and the combined use of SAD and MR for targets with weak MR solutions. These cases highlight the straightforward and powerful method of iodide ion SAD phasing in a high-throughput structural genomics environment

Detection of Progeny Immune Responses after Intravenous Administration of DNA Vaccine to Pregnant Mice

A number of factors influence the development of tolerance, including the nature, concentration and mode of antigen presentation to the immune system, as well as the age of the host. The studies were conducted to determine whether immunizing pregnant mice with liposome-encapsulated DNA vaccines had an effect on the immune status of their offspring. Two different plasmids (encoding antigens from HIV-1 and influenza virus) were administered intravenously to pregnant mice. At 9.5 days post conception with cationic liposomes, injected plasmid was present in the tissues of the fetus, consistent with trans-placental transfer. When the offspring of vaccinated dams were immunized with DNA vaccine, they mounted stronger antigen-specific immune responses than controls and were protected against challenge by homologous influenza virus after vaccination. Moreover, such immune responses were strong in the offspring of mothers injected with DNA plasmid 9.5 days after coitus. These results suggest that DNA vaccinated mothers confer the antigen-specific immunity to their progeny. Here we describe the methods in detail as they relate to our previously published work

Axis I and II disorders as long-term predictors of mental distress: a six-year prospective follow-up of substance-dependent patients

<p>Abstract</p> <p>Background</p> <p>A high prevalence of lifetime psychiatric disorders among help-seeking substance abusers has been clearly established. However, the long-term course of psychiatric disorders and mental distress among help-seeking substance abusers is still unclear. The aim of this research was to examine the course of mental distress using a six-year follow-up study of treatment-seeking substance-dependent patients, and to explore whether lifetime Axis I and II disorders measured at admission predict the level of mental distress at follow-up, when age, sex, and substance-use variables measured both at baseline and at follow-up are controlled for. </p> <p>Methods</p> <p>A consecutive sample of substance dependent in- and outpatients (n = 287) from two counties of Norway were assessed at baseline (T1) with the Composite International Diagnostic Interview (Axis I), Millon's Clinical Multiaxial Inventory (Axis II), and the Hopkins Symptom Checklist (HSCL-25 (mental distress)). At follow-up (T2), 48% (137/287 subjects, 29% women) were assessed with the HSCL-25, the Alcohol Use Disorders Identification Test, and the Drug Use Disorders Identification Test. </p> <p>Results</p> <p>The stability of mental distress is a main finding and the level of mental distress remained high after six years, but was significantly lower among abstainers at T2, especially among female abstainers. Both the number of and specific lifetime Axis I disorders (social anxiety disorder, generalized anxiety disorder, and somatization disorder), the number of and specific Axis II disorders (anxious and impulsive personality disorders), and the severity of substance-use disorder at the index admission were all independent predictors of a high level of mental distress at follow-up, even when we controlled for age, sex, and substance use at follow-up.</p> <p>Conclusion</p> <p>These results underscore the importance of diagnosing and treating both substance-use disorder and non-substance-use disorder Axis I and Axis II disorders in the same programme.</p

Impact of comorbid psychiatric disorders on the outcome of substance abusers: a six year prospective follow-up in two Norwegian counties

BACKGROUND: Most help-seeking substance abusers have comorbid psychiatric disorders. The importance of such disorders for the long-term course of substance abuse is, however, still unclear. The aim of this paper is to describe six-year outcomes regarding death and relapse among alcoholics and poly-substance abusers and to analyse the predictive value of lifetime psychiatric disorders on relapse. METHODS: A consecutive sample of substance-dependent patients who received treatment in two counties in Norway (n = 287) was followed up after approximately six years. Information on socio-demographics, Axis I (CIDI) and II disorders (MCMI-II) and mental distress (HSCL-25) was gathered at baseline. At follow-up, detailed information regarding socio-demographics, use of substances (AUDIT and DUDIT) and mental distress (HSCL-25) was recorded (response rate: 63%). RESULTS: At six-year follow-up, 11% had died, most often male alcoholics (18%). Among the surviving patients, 70% had drug or alcohol related problems the year prior to follow-up. These patients were, classified as "relapsers". There were no significant differences in the relapse rate between women and men and among poly-substance abusers and alcoholics. The relapsers had an earlier onset of a substance use disorder, and more frequently major depression and agoraphobia. Multivariate analysis indicated that both psychiatric disorders (major depression) and substance use factors (early onset of a substance use disorder) were independent predictors of relapse. CONCLUSION: For reducing the risk of long-term relapse, assessment and treatment of major depression (and agoraphobia) are important. In addition, we are in need of a comprehensive treatment and rehabilitation program that also focuses on the addictive behaviour

Analysis of the CD1 Antigen Presenting System in Humanized SCID Mice

CD1 molecules are glycoproteins that present lipids and glycolipids for recognition by T cells. CD1-dependent immune activation has been implicated in a wide range of immune responses, however, our understanding of the role of this pathway in human disease remains limited because of species differences between humans and other mammals: whereas humans express five different CD1 gene products (CD1a, CD1b, CD1c, CD1d, and CD1e), muroid rodents express only one CD1 isoform (CD1d). Here we report that immune deficient mice engrafted with human fetal thymus, liver, and CD34+ hematopoietic stem cells develop a functional human CD1 compartment. CD1a, b, c, and d isoforms were highly expressed by human thymocytes, and CD1a+ cells with a dendritic morphology were present in the thymic medulla. CD1+ cells were also detected in spleen, liver, and lungs. APCs from spleen and liver were capable of presenting bacterial glycolipids to human CD1-restricted T cells. ELISpot analyses of splenocytes demonstrated the presence of CD1-reactive IFN-γ producing cells. CD1d tetramer staining directly identified human iNKT cells in spleen and liver samples from engrafted mice, and injection of the glycolipid antigen α-GalCer resulted in rapid elevation of human IFN-γ and IL-4 levels in the blood indicating that the human iNKT cells are biologically active in vivo. Together, these results demonstrate that the human CD1 system is present and functionally competent in this humanized mouse model. Thus, this system provides a new opportunity to study the role of CD1-related immune activation in infections to human-specific pathogens