Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: A paradigm of human autoimmunity

Pemphigus encompasses a group of organ specific, antibody mediated autoimmune diseases of the skin characterized by keratinocyte detachment that leads to the development of blisters and erosions, which can become life-threatening. The pathogenic autoantibodies recognize desmogleins, which are members of the desmosomal cadherin family of cell adhesion molecules. Desmoglein 3 is targeted in pemphigus vulgaris while desmoglein 1 is targeted in pemphigus foliaceus and its endemic form, fogo selvagem. This review will briefly define the salient features of pemphigus and the proposed steps in pathogenesis. We will then summarize the most recent advances in three important areas of investigation: (i) epidemiologic, genetic, and immunologic features of fogo selvagem, (ii) molecular mechanisms of injury to the epidermis, and (iii) novel therapeutic strategies targeting specific steps in disease pathogenesis. The advances in each of these three seemingly separate areas contribute to the overall understanding of the pemphigus disease model. These recent advancements also underscore the dynamic interplay between the treatment of patients in a clinical setting and basic science research, which has led to an integrative understanding disease pathogenesis and treatment and allow pemphigus to serve as a paradigm of human autoimmunity

Signal Transmission in the Auditory System

Contains table of contents for Section 3, an introduction and reports on nine research projects.National Institutes of Health Grant 5 T32 NS07047National Institutes of Health Grant 5 P01 NS13126National Institutes of Health Grant 8 R01 DC00194National Institutes of Health Grant 5 R01 NS25995National Institutes of Health Grant 8 R01 DC00238National Institutes of Health Grant 5 R01 NS20322National Institutes of Health Grant 5 R01 DC00235National Institutes of Health Grant 5 R01 NS20269National Institutes of Health Grant 1 P01 NS23734Johnson and Johnson FoundationUnisys Corporation Doctoral Fellowshi

Cytochrome P450-catalyzed hydroxylation of taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5a-o1: the first oxygenation step in taxol biosynthesis

AbstractBackground: The structural complexity of taxol dictates continued reliance on biological production methods, which may be improved by a detailed understanding of taxol biosynthesis, especially the rate-limiting steps. The biosynthesis of taxol involves the cyclization of the common isoprenoid intermediate geranylgeranyl diphosphate to taxa-4(5),11(12)-diene followed by extensive, largely oxidative, modification of this diterpene olefin. We set out to define the first oxygenation step in taxol biosynthesis.Results: Microsomal enzymes from Taxus stem and cultured cells were used to define the first hydroxylation of taxadiene. We confirmed the structure of the reaction product (taxa-4(20),11(12)-dien-5α-ol) by synthesizing this compound. The responsible biological catalyst was characterized as a cytochrome P450 (heme thiolate protein). In vivo studies confirmed that taxadienol is a biosynthetic intermediate and indicated that the hydroxylation step that produces this product is slow relative to subsequent metabolic transformations.Conclusions: The structure of the first oxygenated intermediate on the taxol pathway establishes that the hydroxylation reaction proceeds with an unusual double bond migration that limits the mechanistic possibilities for subsequent elaboration of the oxetane moiety of taxol. The reaction is catalyzed by a cytochrome P450, suggesting that the seven remaining oxygenation steps in taxol biosynthesis may involve similar catalysts. Because the first oxygenation step is slow relative to subsequent metabolic transformations, it may be possible to speed taxol biosynthesis by isolating and manipulating the gene for the taxadiene-5-hydroxylase that catalyzes this reaction

Reorganization of the somatosensory cortex in hemiplegic cerebral palsy associated with impaired sensory tracts

Functional neuroimaging studies argue that sensory deficits in hemiplegic cerebral palsy (HCP) are related to deviant somatosensory processing in the ipsilesional primary somatosensory cortex (S1). A separate body of structural neuroimaging literature argues that these deficits are due to structural damage of the ascending sensory tracts (AST). The relationship between the functional and structural integrity of the somatosensory system and the sensory performance is largely unknown in HCP. To address this relationship, we combined findings from magnetoencephalography (MEG) and probabilistic diffusion tractography (PDT) in 10 children with HCP and 13 typically developing (TD) children. With MEG, we mapped the functionally active regions in the contralateral S1 during tactile stimulation of the thumb, middle, and little fingers of both hands. Using these MEG-defined functional active regions as regions of interest for PDT, we estimated the diffusion parameters of the AST. Somatosensory function was assessed via two-point discrimination tests. Our MEG data showed: (i) an abnormal somatotopic organization in all children with HCP in either one or both of their hemispheres; (ii) longer Euclidean distances between the digit maps in the S1 of children with HCP compared to TD children; (iii) suppressed gamma responses at early latencies for both hemispheres of children with HCP; and (iv) a positive correlation between the Euclidean distances and the sensory tests for the more affected hemisphere of children with HCP. Our MEG-guided PDT data showed: (i) higher mean and radian diffusivity of the AST in children with HCP; (ii) a positive correlation between the axial diffusivity of the AST with the sensory tests for the more affected hemisphere; and (iii) a negative correlation between the gamma power change and the AD of the AST for the MA hemisphere. Our findings associate for the first time bilateral cortical functional reorganization in the S1 of HCP children with abnormalities in the structural integrity of the AST, and correlate these abnormalities with behaviorally-assessed sensory deficits

Shopping Centres and Intangible Consumption in Global Cities

In global markets, shopping centres are becoming important agents, defining the kind and quality of intangible features of supplies, not only establishing the assortments, but also affecting the consumption behaviour atmosphere that theydetermine in all its aspects. In this way, shopping malls are responsible for the quality of the intangible consumption process which has a profound impact on people and on the community that people live in. That is why shopping centres, both physical and virtual (i.e. e-commerce sites and other kinds of virtual marketplaces), are significant in big towns, where commercial density is high. By defining the intangible aspects of consumption, shopping centres determine thedevelopment of a particular geographical area (normally surrounding a big city) because they are able to concentrate demand, and they play an active role in establishing the choice alternatives, which means forging the consumption habits and expectations of populations and cities

Impact of tobacco control policy on quitting and nicotine dependence among women in five European countries.

Objective: To describe differences in and factors associated with former smoking and nicotine dependence among women in Ireland, Sweden, France, Italy and the Czech Republic. Methods: A cross-sectional, random digit dial telephone survey of 5000 women, aged 18 years and older, conducted in 2008. Analyses were conducted using logistic regression models. Results: Respondents from Ireland and Sweden had statistically significantly higher odds of having quit smoking within the 5 years before survey administration compared with respondents from the Czech Republic. Current smokers from Ireland, Sweden, France and Italy are more nicotine dependent than those from the Czech Republic. Conclusions: Respondents from countries with stronger tobacco control policies were more likely to have quit smoking compared with those living in the Czech Republic. However, respondents in countries with some of the strongest policies (Ireland, Sweden, France and Italy) had higher odds of smoking within 30 min of waking, an established indicator of nicotine dependence. More research in this area is warranted, but this study suggests that now that the Czech Republic is beginning to implement strong tobacco control policy, they will probably achieve a rapid decline in population-level smoking. Ireland, Sweden, France, Italy and other countries with established, strong tobacco control policies would do well to consider what additional programmes they can put in place to help their highly nicotine-dependent population of smokers successfully quit

Effects of Intensive Primary Care on High-Need Patient Experiences: Survey Findings from a Veterans Affairs Randomized Quality Improvement Trial

BackgroundIntensive primary care programs aim to coordinate care for patients with medical, behavioral, and social complexity, but little is known about their impact on patient experience when implemented in a medical home.ObjectiveDetermine how augmenting the VA's medical home (Patient Aligned Care Team, PACT) with a PACT-Intensive Management (PIM) program influences patient experiences with care coordination, access, provider relationships, and satisfaction.DesignCross-sectional analysis of patient survey data from a five-site randomized quality improvement study.ParticipantsTwo thousand five hundred sixty-six Veterans with hospitalization risk scores ≥ 90th percentile and recent acute care.InterventionPIM offered patients intensive care coordination, including home visits, accompaniment to specialists, acute care follow-up, and case management from a team staffed by primary care providers, social workers, psychologists, nurses, and/or other support staff.Main measuresPatient-reported experiences with care coordination (e.g., health goal assessment, test and appointment follow-up, Patient Assessment of Chronic Illness Care (PACIC)), access to healthcare services, provider relationships, and satisfaction.Key resultsSeven hundred fifty-nine PIM and 768 PACT patients responded to the survey (response rate 60%). Patients randomized to PIM were more likely than those in PACT to report that they were asked about their health goals (AOR = 1.26; P = 0.046) and that they have a VA provider whom they trust (AOR = 1.35; P = 0.005). PIM patients also had higher mean (SD) PACIC scores compared with PACT patients (2.91 (1.31) vs. 2.75 (1.25), respectively; P = 0.022) and were more likely to report 10 out of 10 on satisfaction with primary care (AOR = 1.25; P = 0.048). However, other effects on coordination, access, and satisfaction did not achieve statistical significance.ConclusionsAugmenting VA's patient-centered medical home with intensive primary care had a modestly positive influence on high-risk patients' experiences with care coordination and provider relationships, but did not have a significant impact on most patient-reported access and satisfaction measures