Patient, clinician and logistic barriers to blood pressure control among adult hypertensives in rural district hospitals in Rwanda: a cross-sectional study.

BACKGROUND: Hypertension management in rural, resource-poor settings is difficult. Detailed understanding of patient, clinician and logistic factors which pose barriers to effective blood pressure control could enable strategies to improve control to be implemented. METHODS: This cross-sectional, multifactorial, observational study was conducted at four rural Rwandan district hospitals, examining patient, clinician and logistic factors. Questionnaires were administered to consenting adult outpatient hypertensive patients, obtaining information on sociodemographic factors, past management for hypertension, and adherence (by Morisky Medication Adherence 8-item Scale (MMAS-8). Treating clinicians identified local difficulties in providing hypertension management from a standard World Health Organisation list and nominated their preferred treatment regimens. Blood pressure measurements and other clinical data were collected during the study visit and used to determine blood pressure control, according to goals from JNC-8 guidelines. Medication availability and cost at each hospital's pharmacy were reviewed as logistic barriers to treatment. RESULTS: The 112 participating patients were 80% female, with only 41% having completed primary education. Self-reported adherence by the MMAS-8 was high in 77% (86/112) and significantly associated) with literacy, lack of medication side effects and the particular hospital and pharmacy attended (all p < 0.05). However, of 89 patients with blood pressure data, only 26 (29%) had achieved goal blood pressure. No patient factor were statistically associated with poor blood pressure control. Among 30 participating clinicians, deficiencies in knowledge were evident; 43% (13/30) and 37% (11/30) chose a loop diuretic as their prescribed medication and as an ideal medication, respectively, for a newly diagnosed hypertensive patient without comorbidities, counter to JNC 8 recommendations, and 50% (15/30) identified clinician non-adherence to hypertension guidelines as a barrier. In the pharmacies, common anti-hypertensive medications were affordably available (> 6 out of 8 examined medications available in all pharmacies, cost

IgG1+ B-cell immunity predates IgE responses in epicutaneous sensitization to foods.

BACKGROUND: The generation of IgE-mediated food allergy in humans is silent and only diagnosed upon manifestation of clinical symptoms. While experimental models have been used to investigate some mechanisms of allergic sensitization, the generation of humoral immunity and memory remains to be elucidated. Here, we defined the evolution of allergen-specific B-cell responses during epicutaneous sensitization to foods. METHODS: Wild-type and genetic knockout animals, and drug or antibody strategies for cell depletion and immunoglobulin signaling blockade were used to investigate epicutaneous sensitization and disease progression; we analyzed allergen-specific germinal centers and IgG1+ memory B cells by flow cytometry, evaluated humoral responses, and determined clinical reactivity (anaphylaxis). RESULTS: Epicutaneous sensitization caused microscopic skin damage, inflammation, and recruitment of activated dendritic cells to the draining lymph nodes. This process generated allergen-specific IgG1+ germinal center B cells, serum IgG1, and anaphylaxis that was mediated by the alternative pathway. Whether we used peanut and/or ovalbumin from the egg white for sensitization, the allergen-specific IgG1+ memory compartment predominantly exhibited an immature, pro-germinal center phenotype (PDL-2- CD80- CD35+ CD73+ ). Subsequent subclinical exposures to the allergen induced IgE+ germinal center B cells, serum IgE, and likely activated the classical pathway of anaphylaxis. CONCLUSIONS: Our data demonstrate that IgG1+ B-cell immunity against food allergens in epicutaneous sensitization precedes the generation of IgE responses. Therefore, the assessment of allergen-specific cellular and humoral IgG1+ immunity may help to identify individuals at risk of developing IgE-mediated food allergy and hence provide a window for therapeutic interventions.

Comprehensive metabolomics identifies the alarmin uric acid as a critical signal for the induction of peanut allergy.

BACKGROUND: Food allergy, in particular peanut allergy, is a growing concern in Western countries. The prevalence of allergy to peanut, which currently stands at 1.4%, nearly tripled between 1997 and 2008. Allergic sensitization is a particularly difficult process to study as it is clinically silent. We sought to identify key pathways and mediators critically involved in the induction of allergic sensitization to peanut. METHODS: Comprehensive metabolomics analysis with liquid chromatography-mass spectrometry was used to detect metabolite changes in mice (C57BL/6) undergoing sensitization. Loss-of-function and gain-of-function studies were performed in mice subjected to two models of peanut sensitization and anaphylaxis that involved either oral or epicutaneous sensitization. Flow cytometric analyses on dendritic cells (DCs) in vitro and in vivo were used to investigate the mechanisms of immune activation. RESULTS: Elevated levels of uric acid (UA) were detected in mice undergoing sensitization as well as in peanut-allergic children who were not challenged with peanut. In mice, the depletion of UA during sensitization prevented the development of peanut-specific immunoglobulins IgE and IgG1 as well as anaphylaxis while exogenous delivery of UA crystals (monosodium urate, MSU) restored the allergic phenotype. Monosodium urate enhanced CD86 and OX40L expression on DCs, independent of Toll-like receptors 2 and 4, the NLRP3 inflammasome, and IL-1ß, via a PI3K signaling pathway. CONCLUSION: Overproduction of the UA alarmin in the local microenvironment plays a critical role in the induction of peanut-allergic sensitization, likely due to its ability to activate DCs. These finding suggest that cellular damage or tissue injury may be an essential requisite for the development of allergic sensitization to foods.

T helper cell IL-4 drives intestinal Th2 priming to oral peanut antigen, under the control of OX40L and independent of innate-like lymphocytes.

Intestinal T helper type 2 (Th2) immunity in food allergy results in IgG1 and IgE production, and antigen re-exposure elicits responses such as anaphylaxis and eosinophilic inflammation. Although interleukin-4 (IL-4) is critically required for allergic sensitization, the source and control of IL-4 during the initiation of Th2 immunity in vivo remains unclear. Non-intestinal and non-food allergy systems have suggested that natural killer-like T (NKT) or γδ T-cell innate lymphocytes can supply the IL-4 required to induce Th2 polarization. Group 2 innate lymphoid cells (ILCs) are a novel IL-4-competent population, but their contribution to initiating adaptive Th2 immunity is unclear. There are also reports of IL-4-independent Th2 responses. Here, we show that IL-4-dependent peanut allergic Th2 responses are completely intact in NKT-deficient, γδ T-deficient or ILC-deficient mice, including antigen-specific IgG1/IgE production, anaphylaxis, and cytokine production. Instead, IL-4 solely from CD4(+) Th cells induces full Th2 immunity. Further, CD4(+) Th cell production of IL-4 in vivo is dependent on OX40L, a costimulatory molecule on dendritic cells (DCs) required for intestinal allergic priming. However, both Th2 cells and ILCs orchestrated IL-13-dependent eosinophilic inflammation. Thus, intestinal Th2 priming is initiated by an autocrine/paracrine acting CD4(+) Th cell-intrinsic IL-4 program that is controlled by DC OX40L, and not by NKT, γδ T, or ILC cells.

Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood.

The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c+ CD11b+ inflammatory dendritic cell and CD8α+ plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.

Evaluation of allergic lung inflammation by computed tomography in a rat model in vivo.

The ability of micro-computed tomography (CT) to noninvasively evaluate allergic pulmonary inflammation in an experimental model was investigated. In addition, two image segmentation methods and the value of respiratory gating were investigated in the context of this model. Brown Norway rats were exposed to one of four doses of house dust mite (HDM) extract (0, 0.15, 15 or 150 microg) delivered intratracheally every 24 h for 10 days. CT scanning was performed at baseline and after several longitudinal HDM exposures. Both thoracic- and lung-segmentation methods yielded similar results when standardisation practices were employed. While tissue histology correlated well with CT images, cell counts from bronchoalveolar lavage depicted greater inflammation than did density measures from CT images. Evidence from representative CT slices and transaxial density distribution indicated that inflammation was primarily associated with major airways and extended into the periphery from these focal points. Respiratory gating demonstrated that images of the inspiratory state provided greater contrast of inflammatory processes. Lastly, decreases in tidal volumes indicated significant mechanical respiratory changes in animals exposed to both 15 and 150 microg. In summary, CT image segmentation can extract pertinent data on in vivo allergic airway/lung inflammation. Furthermore, respiratory gating provides additional contrast and insight into these quantification practices.

Ontogeny of hepatic type I insulin-like growth factor receptors in the rat.

We studied the pre- and postnatal developmental regulation of the hepatic type I IGF receptor in the rat. Fetal rat liver membranes bound IGF-I throughout the latter part of gestation (d 17 to 21). After birth, binding diminished rapidly, reaching barely detectable levels by the 13th postnatal d. However, the presence of type I IGF receptors was readily demonstrated by affinity-labeling throughout the immediate postnatal period and in adult rats. Furthermore, IGF-I-dependent autophosphorylation of type I receptors could be seen in both fetal and adult liver membranes. Fasting for 48 h in adult rats led to a 2- to 3-fold increase in affinity-labeled type I IGF receptors. In contrast, nutrient deprivation to the fetus, via maternal fasting, did not alter fetal hepatic IGF-I binding or affinity-labeling of the type I receptor. These results support a role for the IGF and the type I IGF receptor in the autocrine/paracrine regulation of hepatic growth through the latter stages of gestation in the rat. The demonstration of enzymatically active type I IGF receptors in adult liver, and their increased expression in fasted adult rats is consistent with an autocrine/paracrine role for hepatic IGF-I in the adult.

The importance of eye movements in the analysis of simple patterns.

How important are eye movements to visual pattern analysis? Previous findings indicate that at least one visual task (counting) is seriously impaired without them. We asked whether a comparable limitation applies to pattern recognition. Subjects were presented with pairs of randomly generated arrays composed of black and white pixels. The subjects indicated whether the arrays were identical or differed by one pixel. In one experiment, they were instructed to use normal eye movements, in another they were required to fixate on a point between the arrays. When eye movements were permitted, subjects' performance showed evidence for a search in which the discrepant pixel was eventually found, given adequate inspection time. When fixation was required, search was less efficient and the discrepant pixel was sometimes not found, despite prolonged inspection time. These results were independent of target size over a wide range. Our findings indicate that eye movements play a crucial role in pattern analysis that is not related to resolution.