Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs.

Organophosphorus pesticides (OPs) are implicated in human asthma. We previously demonstrated that, at concentrations that do not inhibit acetylcholinesterase activity, the OP parathion causes airway hyperreactivity in guinea pigs as a result of functional loss of inhibitory M2 muscarinic receptors on parasympathetic nerves. Because macrophages are associated with asthma, we investigated whether macrophages mediate parathion-induced M2 receptor dysfunction and airway hyperreactivity. Airway physiology was measured in guinea pigs 24 h after a subcutaneous injection of parathion. Pretreatment with liposome-encapsulated clodronate induced alveolar macrophage apoptosis and prevented parathion-induced airway hyperreactivity in response to electrical stimulation of the vagus nerves. As determined by qPCR, TNF-α and IL-1β mRNA levels were increased in alveolar macrophages isolated from parathion-treated guinea pigs. Parathion treatment of alveolar macrophages ex vivo did not significantly increase IL-1β and TNF-α mRNA but did significantly increase TNF-α protein release. Consistent with these data, pretreatment with the TNF-α inhibitor etanercept but not the IL-1β receptor inhibitor anakinra prevented parathion-induced airway hyperreactivity and protected M2 receptor function. These data suggest a novel mechanism of OP-induced airway hyperreactivity in which low-level parathion activates macrophages to release TNF-α-causing M2 receptor dysfunction and airway hyperreactivity. These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures

Asthma Prevalence, Knowledge, and Perceptions among Secondary School Pupils in Rural and Urban Costal Districts in Tanzania.

Asthma is a common chronic disease of childhood that is associated with significant morbidity and mortality. We aimed to estimate the prevalence of asthma among secondary school pupils in urban and rural areas of coast districts of Tanzania. The study also aimed to describe pupils' perception towards asthma, and to assess their knowledge on symptoms, triggers, and treatment of asthma. A total of 610 pupils from Ilala district and 619 pupils from Bagamoyo district formed the urban and rural groups, respectively. Using a modified International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire, a history of "diagnosed" asthma or the presence of a wheeze in the previous 12 months was obtained from all the studied pupils, along with documentation of their perceptions regarding asthma. Pupils without asthma or wheeze in the prior 12 months were subsequently selected and underwent a free running exercise testing. A >= 20% decrease in the post-exercise Peak Expiratory Flow Rate (PEFR) values was the criterion for diagnosing exercise-induced asthma. The mean age of participants was 16.8 (+/-1.8) years. The prevalence of wheeze in the past 12 months was 12.1% in Bagamoyo district and 23.1% in Ilala district (p < 0.001). Self-reported asthma was found in 17.6% and 6.4% of pupils in Ilala and Bagamoyo districts, respectively (p < 0.001). The prevalence of exercise-induced asthma was 2.4% in Bagamoyo, and 26.3% in Ilala (P < 0.002). In both districts, most information on asthma came from parents, and there was variation in symptoms and triggers of asthma reported by the pupils. Non-asthmatic pupils feared sleeping, playing, and eating with their asthmatic peers. The prevalence rates of self-reported asthma, wheezing in the past 12 months, and exercise-induced asthma were significantly higher among urban than rural pupils. Although bronchial asthma is a common disease, pupils' perceptions about asthma were associated with fear of contact with their asthmatic peers in both rural and urban schools

The role of ubiquitination and hepatocyte growth factor-regulated tyrosine kinase substrate in the degradation of the adrenomedullin type I receptor

Calcitonin receptor-like receptor (CLR) and the receptor activity-modifying protein 2 (RAMP2) comprise a receptor for adrenomedullin (AM). Although it is known that AM induces internalization of CLR•RAMP2, little is known about the molecular mechanisms that regulate the trafficking of CLR•RAMP2. Using HEK and HMEC-1 cells, we observed that AM-induced activation of CLR•RAMP2 promoted ubiquitination of CLR. A mutant (CLRΔ9KR), lacking all intracellular lysine residues was functional and trafficked similar to the wild-type receptor, but was not ubiquitinated. Degradation of CLR•RAMP2 and CLRΔ9KR•RAMP2 was not dependent on the duration of AM stimulation or ubiquitination and occurred via a mechanism that was partially prevented by peptidase inhibitors. Degradation of CLR•RAMP2 was sensitive to overexpression of hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), but not to HRS knockdown, whereas CLRΔ9KR•RAMP2 degradation was unaffected. Overexpression, but not knockdown of HRS, promoted hyperubiquitination of CLR under basal conditions. Thus, we propose a role for ubiquitin and HRS in the regulation of AM-induced degradation of CLR•RAMP2

Changing Epidemiology of Serious Bacterial Infections in Febrile Infants without Localizing Signs

Objective: Historically, management of infants with fever without localizing signs (FWLS) has generated much controversy, with attempts to risk stratify based on several criteria. Advances in medical practice may have altered the epidemiology of serious bacterial infections (SBIs) in this population. We conducted this study to test the hypothesis that the rate of SBIs in this patient population has changed over time. Patients and Methods: We performed a retrospective review of all infants meeting FWLS criteria at our institution from 1997–2006. We examined all clinical and outcome data and performed statistical analysis of SBI rates and ampicillin resistance rates. Results: 668 infants met criteria for FWLS. The overall rate of SBIs was 10.8%, with a significant increase from 2002–2006 (52/ 361, 14.4%) compared to 1997–2001 (20/307, 6.5%) (p = 0.001). This increase was driven by an increase in E. coli urinary tract infections (UTI), particularly in older infants (31–90 days). Conclusions: We observed a significant increase in E. coli UTI among FWLS infants with high rates of ampicillin resistance. The reasons are likely to be multifactorial, but the results themselves emphasize the need to examine urine in all febrile infants,90days and consider local resistance patterns when choosing empiric antibiotics

The Urban Environment and Childhood Asthma (URECA) birth cohort study: design, methods, and study population

<p>Abstract</p> <p>Background</p> <p>The incidence and morbidity of wheezing illnesses and childhood asthma is especially high in poor urban areas. This paper describes the study design, methods, and population of the Urban Environment and Childhood Asthma (URECA) study, which was established to investigate the immunologic causes of asthma among inner-city children.</p> <p>Methods and Results</p> <p>URECA is an observational prospective study that enrolled pregnant women in central urban areas of Baltimore, Boston, New York City, and St. Louis and is following their offspring from birth through age 7 years. The birth cohort consists of 560 inner-city children who have at least one parent with an allergic disease or asthma, and all families live in areas in which at least 20% of the population has incomes below the poverty line. In addition, 49 inner-city children with no parental history of allergies or asthma were enrolled. The primary hypothesis is that specific urban exposures in early life promote a unique pattern of immune development (impaired antiviral and increased Th2 responses) that increases the risk of recurrent wheezing and allergic sensitization in early childhood, and of asthma by age 7 years. To track immune development, cytokine responses of blood mononuclear cells stimulated <it>ex vivo </it>are measured at birth and then annually. Environmental assessments include allergen and endotoxin levels in house dust, pre- and postnatal maternal stress, and indoor air nicotine and nitrogen dioxide. Nasal mucous samples are collected from the children during respiratory illnesses and analyzed for respiratory viruses. The complex interactions between environmental exposures and immune development will be assessed with respect to recurrent wheeze at age 3 years and asthma at age 7 years.</p> <p>Conclusion</p> <p>The overall goal of the URECA study is to develop a better understanding of how specific urban exposures affect immune development to promote wheezing illnesses and asthma.</p

Leukocyte counts in urine reflect the risk of concomitant sepsis in bacteriuric infants: A retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>When urine infections are missed in febrile young infants with normal urinalysis, clinicians may worry about the risk – hitherto unverified – of concomitant invasion of blood and cerebrospinal fluid by uropathogens. In this study, we determine the extent of this risk.</p> <p>Methods</p> <p>In a retrospective cohort study of febrile 0–89 day old infants evaluated for sepsis in an urban academic pediatric emergency department (1993–1999), we estimated rates of bacteriuric sepsis (urinary tract infections complicated by sepsis) after stratifying infants by urine leukocyte counts higher, or lower than 10 cells/hpf. We compared the global accuracy of leukocytes in urine, leukocytes in peripheral blood, body temperature, and age for predicting bacteruric sepsis. The global accuracy of each test was estimated by calculating the area under its receiver operating characteristic curve (AUC). Chi-square and Fisher exact tests compared count data. Medians for data not normally distributed were compared by the Kruskal-Wallis test.</p> <p>Results</p> <p>Two thousand two hundred forty-nine young infants had a normal screening dipstick. None of these developed bacteremia or meningitis despite positive urine culture in 41 (1.8%). Of 1516 additional urine specimens sent for formal urinalysis, 1279 had 0–9 leukocytes/hpf. Urine pathogens were isolated less commonly (6% vs. 76%) and at lower concentrations in infants with few, compared to many urine leukocytes. Urine leukocytes (AUC: 0.94) were the most accurate predictors of bacteruric sepsis. Infants with urinary leukocytes < 10 cells/hpf were significantly less likely (0%; CI:0–0.3%) than those with higher leukocyte counts (5%; CI:2.6–8.7%) to have urinary tract infections complicated by bacteremia (N = 11) or bacterial meningitis (N = 1) – relative risk, 0 (CI:0–0.06) [RR, 0 (CI: 0–0.02), when including infants with negative dipstick]. Bands in peripheral blood had modest value for detecting bacteriuric sepsis (AUC: 0.78). Cases of sepsis without concomitant bacteriuria were comparatively rare (0.8%) and equally common in febrile young infants with low and high concentrations of urine leukocytes.</p> <p>Conclusion</p> <p>In young infants evaluated for fever, leukocytes in urine reflect the likelihood of bacteriuric sepsis. Infants with urinary tract infections missed because of few leukocytes in urine are at relatively low risk of invasive bacterial sepsis by pathogens isolated from urine.</p

The Consent Paradox: Accounting for the Prominent Role of Consent in Data Protection

The concept of consent is a central pillar of data protection. It features prominently in research, regulation, and public debates on the subject, in spite of the wide-ranging criticisms that have been levelled against it. In this paper, I refer to this as the consent paradox. I argue that consent continues to play a central role not despite but because the criticisms of it. I analyze the debate on consent in the scholarly literature in general, and among German data protection professionals in particular, showing that it is a focus on the informed individual that keeps the concept of consent in place. Critiques of consent based on the notion of “informedness” reinforce the centrality of consent rather than calling it into question. They allude to a market view that foregrounds individual choice. Yet, the idea of a data market obscures more fundamental objections to consent, namely the individual’s dependency on data controllers’ services that renders the assumption of free choice a fiction

Effect of a web-based chronic disease management system on asthma control and health-related quality of life: study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Asthma is a prevalent and costly disease resulting in reduced quality of life for a large proportion of individuals. Effective patient self-management is critical for improving health outcomes. However, key aspects of self-management such as self-monitoring of behaviours and symptoms, coupled with regular feedback from the health care team, are rarely addressed or integrated into ongoing care. Health information technology (HIT) provides unique opportunities to facilitate this by providing a means for two way communication and exchange of information between the patient and care team, and access to their health information, presented in personalized ways that can alert them when there is a need for action. The objective of this study is to evaluate the acceptability and efficacy of using a web-based self-management system, My Asthma Portal (MAP), linked to a case-management system on asthma control, and asthma health-related quality of life.</p> <p>Methods</p> <p>The trial is a parallel multi-centered 2-arm pilot randomized controlled trial. Participants are randomly assigned to one of two conditions: a) MAP and usual care; or b) usual care alone. Individuals will be included if they are between 18 and 70, have a confirmed asthma diagnosis, and their asthma is classified as not well controlled by their physician. Asthma control will be evaluated by calculating the amount of fast acting beta agonists recorded as dispensed in the provincial drug database, and asthma quality of life using the Mini Asthma Related Quality of Life Questionnaire. Power calculations indicated a needed total sample size of 80 subjects. Data are collected at baseline, 3, 6, and 9 months post randomization. Recruitment started in March 2010 and the inclusion of patients in the trial in June 2010.</p> <p>Discussion</p> <p>Self-management support from the care team is critical for improving chronic disease outcomes. Given the high volume of patients and time constraints during clinical visits, primary care physicians have limited time to teach and reinforce use of proven self-management strategies. HIT has the potential to provide clinicians and a large number of patients with tools to support health behaviour change.</p> <p>Trial Registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN34326236">ISRCTN34326236</a>.</p