Asthma severity is reflected in many aspects of the disease, including impairment and future risks, particularly for exacerbations. According to the EPR-3, however, to assess more comprehensively the severity of asthma the level of current treatment needed to maintain a level of control should be included.
Development and validation of a new instrument, the Composite Asthma Severity Index (CASI), which can quantify disease severity by taking into account impairment, risk and the amount of medication needed to maintain control. At present, there is no instrument available to measure and assess the multidimensional nature of asthma.
Twenty-six established asthma investigators, who are part of the NIH-supported Inner City Asthma Consortium (ICAC), participated in a modified Delphi consensus process to identify and weight the dimensions of asthma. Factor analysis was performed to identify independent domains of asthma using the Asthma Control Evaluation (ACE) trial. CASI was validated using the Inner City Anti-IgE Therapy for Asthma (ICATA) trial.
CASI scores include five domains: day symptoms and albuterol use, night symptoms and albuterol use, controller treatment, lung function measures, and exacerbations. At ACE enrollment, CASI ranged from 0 to 17 with a mean of 6.2. CASI was stable, with minimal change in variance after 1 year of treatment. In external validation, CASI detected a 32% larger improvement than symptoms alone.
CASI retained its discriminatory ability even with low levels of symptoms reported after months of guidelines-directed care. Thus, CASI has the ability to determine the level of asthma severity, and provide a composite clinical characterization of asthma.
Asthma; composite score; morbidity; treatment; exacerbations; symptoms; severity
Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are potential therapies for food allergy, but the optimal method of administration, mechanism of action, and duration of response remain unknown.
We sought to explore the safety and efficacy of OIT and SLIT for the treatment of cow’s milk (CM) allergy.
We randomized children with CM allergy to SLIT alone or SLIT followed by OIT. After screening double-blind, placebo-controlled food challenges and initial SLIT escalation, subjects either continued SLIT escalation to 7 mg daily or began OIT to either 1000 mg (the OITB group) or 2000 mg (the OITA group) of milk protein. They were challenged with 8 g of milk protein after 12 and 60 weeks of maintenance. If they passed the 60-week challenge, therapy was withdrawn, with challenges repeated 1 and 6 weeks later. Mechanistic correlates included end point titration skin prick testing and measurement of CM-specific IgE and IgG4 levels, basophil histamine release, constitutive CD63 expression, CD203c expression, and intracellular spleen tyrosine kinase levels.
Thirty subjects with CM allergy aged 6 to 17 years were enrolled. After therapy, 1 of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/OITB group, and 8 of 10 subjects in the OITA group passed the 8-g challenge (P = .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 of 6 subjects in the OITB group and 3 of 8 subjects in the OITA group) regained reactivity, 2 after only 1 week. Although the overall reaction rate was similar, systemic reactions were more common during OIT than during SLIT. By the end of therapy, titrated CM skin prick test results and CD63 and CD203c expression decreased and CM-specific IgG4 levels increased in all groups, whereas CM-specific IgE and spontaneous histamine release values decreased in only the OIT group.
OIT was more efficacious for desensitization to CM than SLIT alone but was accompanied by more systemic side effects. Clinical desensitization was lost in some cases within 1 week off therapy.
Food allergy; immunotherapy; milk allergy; basophil; spontaneous histamine release
For egg allergy, dietary avoidance is the only currently approved treatment. We evaluated oral immunotherapy using egg-white powder for the treatment of children with egg allergy.
In this double-blind, randomized, placebo-controlled study, 55 children, 5 to 11 years of age, with egg allergy received oral immunotherapy (40 children) or placebo (15). Initial dose-escalation, build-up, and maintenance phases were followed by an oral food challenge with egg-white powder at 10 months and at 22 months. Children who successfully passed the challenge at 22 months discontinued oral immunotherapy and avoided all egg consumption for 4 to 6 weeks. At 24 months, these children underwent an oral food challenge with egg-white powder and a cooked egg to test for sustained unresponsiveness. Children who passed this challenge at 24 months were placed on a diet with ad libitum egg consumption and were evaluated for continuation of sustained unresponsiveness at 30 months and 36 months.
After 10 months of therapy, none of the children who received placebo and 55% of those who received oral immunotherapy passed the oral food challenge and were considered to be desensitized; after 22 months, 75% of children in the oral-immunotherapy group were desensitized. In the oral-immunotherapy group, 28% (11 of 40 children) passed the oral food challenge at 24 months and were considered to have sustained unresponsiveness. At 30 months and 36 months, all children who had passed the oral food challenge at 24 months were consuming egg. Of the immune markers measured, small wheal diameters on skin-prick testing and increases in egg-specific IgG4 antibody levels were associated with passing the oral food challenge at 24 months.
These results show that oral immunotherapy can desensitize a high proportion of children with egg allergy and induce sustained unresponsiveness in a clinically significant subset. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT00461097.)
Immigrants to developed countries have low rates of aeroallergen sensitization and asthma, but less is known about both food allergy and the role of parental immigration status.
To evaluate the relationship between personal and parental nativity on the risk of food sensitization.
3550 subjects <21 years old from the National Health and Examination Survey 2005-2006 were included. Odds ratios were generated using logistic regression which adjusted for race/ethnicity, gender, age, and household income, and accounted for the complex survey design. Nativity was classified as US-born or foreign-born and the age of immigration was estimated. Head of household nativity was used as a proxy for parental nativity. Food sensitization was defined as at least one specific-IgE ≥ 0.35 kU/L to milk, egg or peanut. Aeroallergen specific sensitizations, and the presence of asthma, allergic rhinitis or eczema were also assessed.
Compared to those born outside the US, US-born children and adolescents had higher odds of sensitization to any food (OR 2.05, 95% CI 1.49-2.83, p<0.001). Among the foreign-born, those who arrived before 2 years of age had higher odds of food sensitization than those who arrived later (OR 2.68, 95% CI 1.19-6.08, p=0.02). Within the US-born group, in contrast, children of immigrants were at the highest risk (OR 1.53, 95% CI 1.05-2.24, p=0.02).
While foreign-born children and adolescents are at lower risk of food sensitization compared to those born in the US, among those born in the US, the children of immigrants are at the highest risk.
Food allergy; food sensitization; immigration; nativity; child; hay fever; asthma; eczema; aeroallergen
Data from many studies have suggested a rise in the prevalence of food allergies during the past 10 to 20 years. Currently, no curative treatments for food allergy exist, and there are no effective means of preventing the disease. Management of food allergy involves strict avoidance of the allergen in the patient's diet and treatment of symptoms as they arise. Because diagnosis and management of the disease can vary between clinical practice settings, the National Institute of Allergy and Infectious Diseases (NIAID) sponsored development of clinical guidelines for the diagnosis and management of food allergy. The guidelines establish consensus and consistency in definitions, diagnostic criteria, and management practices. They also provide concise recommendations on how to diagnose and manage food allergy and treat acute food allergy reactions. The original guidelines encompass practices relevant to patients of all ages, but food allergy presents unique and specific concerns for infants, children, and teenagers. To focus on those concerns, we describe here the guidelines most pertinent to the pediatric population.
food allergy; food hypersensitivity; infants; children; guidelines; anaphylaxis
Mechanisms of allergic transfusion reactions (ATRs) are not well understood. The aim of this study was to distinguish recipient, donor, and product-specific factors associated with ATRs.
Study Design and Methods
We conducted a retrospective cohort study of apheresis platelet (AP) products transfused from 4/2000–3/2010. The concordance rate of ATRs when split AP products were transfused to ≥2 individuals was compared to the overall ATR rate among all AP products. Per person ATR rates also were compared to the overall ATR rate.
We observed 1,616 ATRs among 93,737 transfusions, for an overall incidence of 1.72%(95%CI: 1.64–1.81%). Of the 1,616 ATRs, 630 occurred when split AP products were transfused to ≥2 recipients. Of these 630 AP products, ATRs were observed in ≥2 different recipients of the same AP collection only 6/630 times, for a concordant incidence of 0.95% (95% CI: 0.35–2.06%), which is similar to the overall ATR rate (P=0.17). On an individual level, 30.0% of recipients had ATR rates >5%, and these 30.0% accounted for 62.1% of ATRs. Donors of AP products associated with concordant ATRs donated AP products that had an ATR rate of 5.8% (95% CI 3.1–9.7%), which is higher than the overall ATR rate (P<0.001).
An observed ATR does not predict an ATR in a different recipient of a split AP product. A minority of platelet recipients accounts for the majority of ATRs. Some donors are strongly associated with ATRs. Consequently, recipient and donor factors are implicated in the mechanism of ATRs.
Allergy; transfusion reaction; platelet
Over 4000 flavonoids have been identified so far and among these, many are known to have antitumor activities. The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. Here we report the differential cytotoxic effects of two flavone isomers on human cancer cells from breast (MCF7, SK-BR-3), colon (Caco-2, HCT116), pancreas (MIA PaCa, Panc 28), and prostate (PC3, LNCaP) that vary in differentiation status and tumorigenic potential. These flavones are derived from plants of the family Asteraceae, genera Gnaphalium and Achyrocline reputed to have anti-cancer properties. Our studies indicate that 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays potent activity against more differentiated carcinomas of the colon (Caco-2), and pancreas (Panc28), whereas 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) cytototoxic action is observed on poorly differentiated carcinomas of the colon (HCT116), pancreas (Mia PaCa), and breast (SK-BR3). Both flavones induced cell death (>50%) as proven by MTT cell viability assay in these cancer cell lines, all of which are regarded as highly tumorigenic. At the concentrations studied (5–80 µM), neither flavone demonstrated activity against the less tumorigenic cell lines, breast cancer MCF-7 cells, androgen-responsive LNCaP human prostate cancer line, and androgen-unresponsive PC3 prostate cancer cells. 5,7-dihydroxy-3,6,8-trimethoxy-2-phenyl-4H-chromen-4-one (5,7-dihydroxy-3,6,8-trimethoxy flavone) displays activity against more differentiated carcinomas of the colon and pancreas, but minimal cytotoxicity on poorly differentiated carcinomas of these organs. On the contrary, 3,5-dihydroxy-6,7,8-trimethoxy-2-phenyl-4H-chromen-4-one (3,5-dihydroxy-6,7,8-trimethoxy flavone) is highly cytotoxic to poorly differentiated carcinomas of the colon, pancreas, and breast with minimal activity against more differentiated carcinomas of the same organs. These differential effects suggest activation of distinct apoptotic pathways. In conclusion, the specific chemical properties of these two flavone isomers dictate mechanistic properties which may be relevant when evaluating biological responses to flavones.
Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma.
Assess the influence of prenatal vitamin D status on immune function at birth.
In an inner-city birth cohort of 568 newborns, 520 of whom had at least one atopic parent, we measured umbilical cord (UC) plasma concentration of 25-hydroxy vitamin D (25(OH)D) and the cytokine responses of UC blood mononuclear cells (UCMCs) to stimuli including phytohemaglutinin (PHA), lipopolysaccharide (LPS), and peptidoglycan (PG). In a subset, UCMC expression of regulatory T-cell markers and the suppressive activity of CD4+CD25+ UCMCs was measured.
The 25th, 50th, and 75th percentiles of UC plasma 25(OH)D level were 15.0, 20.2, and 25.6 ng/mL, respectively. Most cytokine responses of UCMC were not correlated with UC 25(OH)D concentration; however, IFN-γ release after LPS stimulation was weakly positively correlated with UC 25(OH)D concentration (r = 0.11, p =0.01). PHA responses were not significantly correlated with 25(OH)D concentration. The UC plasma 25(OH)D concentration was inversely related to the number of CD25+ (r= -0.20, p=0.06), CD25Bright (r= -0.21, p=0.05), and CD25+FoxP3 (r= -0.29, p=0.06) cells as a proportion of CD4+ T cells in UC blood (r = -0.26, p = 0.04) but not to the suppressive activity of CD4+CD25+ cells (r=0.17, p=0.22).
Conclusion and Clinical Relevance
UC 25(OH)D concentration was not correlated with most UCMC cytokine responses to multiple stimuli. There was a suggestion of a weakly positive correlation with IFN-γ release after LPS stimulation. The proportions of CD25+, CD25bright, and CD25+FoxP3 cells to total CD4+ T cells were inversely correlated with UC 25(OH)D concentration. Our findings suggest that higher vitamin D levels at birth may be associated with a lower number of T regulatory cells. Vitamin D status in utero may influence immune regulation in early life.
The Centers for Disease Control and Prevention recently recommended the expansion of human immunodeficiency virus (HIV) antibody testing. However, antibody tests have longer “window periods” after HIV acquisition than do nucleic acid amplification tests (NAATs).
Public Health–Seattle & King County offered HIV antibody testing to men who have sex with men (MSM) using the OraQuick Advance Rapid HIV-1/2 Antibody Test (OraQuick; OraSure Technologies) on oral fluid or finger-stick blood specimens or using a first- or second-generation enzyme immunoassay. The enzyme immunoassay was also used to confirm reactive rapid test results and to screen specimens from OraQuick-negative MSM prior to pooling for HIV NAAT. Serum specimens obtained from subsets of HIV-infected persons were retrospectively evaluated by use of other HIV tests, including a fourth-generation antigen-antibody combination assay.
From September 2003 through June 2008, a total of 328 (2.3%) of 14,005 specimens were HIV antibody positive, and 36 (0.3%) of 13,677 antibody-negative specimens were NAAT positive (indicating acute HIV infection). Among 6811 specimens obtained from MSM who were initially screened by rapid testing, OraQuick detected only 153 (91%) of 169 antibody-positive MSM and 80% of the 192 HIV-infected MSM detected by the HIV NAAT program. HIV was detected in serum samples obtained from 15 of 16 MSM with acute HIV infection that were retrospectively tested using the antigen-antibody combination assay.
OraQuick may be less sensitive than enzyme immunoassays during early HIV infection. NAAT should be integrated into HIV testing programs that serve populations that undergo frequent testing and that have high rates of HIV acquisition, particularly if rapid HIV antibody testing is employed. Antigen-antibody combination assays may be a reasonably sensitive alternative to HIV NAAT.
Purpose. To determine the factors that are associated with Mexican Americans' preference for ventilator support, given a supposed terminal diagnosis. Methods. 100 Mexican Americans, aged 60–89, were recruited and screened for MMSE scores above 18. Eligible subjects answered a questionnaire in their preferred language (English/Spanish) concerning ventilator use during terminal illness. Mediator variables examined included demographics, generation, religiosity, occupation, self-reported depression, self-reported health, and activities of daily living. Results. Being first or second generation American (OR = 0.18, CI = 0.05–0.66) with no IADL disability (OR = 0.11, CI = 0.02–0.59) and having depressive symptoms (OR = 1.43, CI = 1.08–1.89) were associated with preference for ventilator support. Implications. First and second generation older Mexican Americans and those functionally independent are more likely to prefer end-of-life ventilation support. Although depressive symptoms were inversely associated with ventilator use at the end of life, scores may more accurately reflect psychological stress associated with enduring the scenario. Further studies are needed to determine these factors' generalizability to the larger Mexican American community.
The URECA study was established to investigate the immunologic and environmental causes of asthma in inner-city children.
To evaluate potential atopic outcomes in the first12 months and their relationships to environmental exposures and immune development.
A birth cohort of 560 children with at least one parent with allergy or asthma was established in Baltimore, Boston, New York, and St. Louis. Wheezing is assessed every 3 months, allergen-specific IgE yearly, mononuclear cell cytokine responses at birth and yearly; environmental assessments include dust allergen and endotoxin, maternal stress, and indoor nicotine and nitrogen dioxide.
Key outcomes in the first year include wheeze in 49%, ≥2 episodes of wheeze 23%, eczema 30%, and detectable IgE to milk, egg, and/or peanut in 32% and to cockroach in 4%. Household dust revealed levels >2mcg/g to cockroach in 40%, mite 19%, cat 25%, and mouse 29%, and 66% of homes housed at least one smoker. Positive associations were detected between multiple wheeze and cotinine, maternal stress, and maternal depression, while cytokine responses to a variety of innate, adaptive, and mitogenic stimuli were inversely related to eczema.
This high risk cohort of inner-city infants is exhibiting high rates of wheeze, eczema, and allergic sensitization. Low cytokine responses at birth may be a risk factor for eczema, while a variety of adverse environmental exposures contribute to the risk of wheezing in infancy. These findings provide evidence of specificity in the interactions between immune development, environmental exposures, and the development of early features that may predict future asthma.
Immune development; birth cohort; atopy; asthma; cytokines; allergen exposure; inner-city
Peanut allergy is typically severe, life-long and prevalent.
To identify factors associated with peanut sensitization.
We evaluated 503 infants 3–15 months of age (mean, 9.4 months) with likely milk or egg allergy but no previous diagnosis of peanut allergy. A total of 308 had experienced an immediate allergic reaction to cow’s milk and/or egg and 204 had moderate to severe atopic dermatitis and a positive allergy test to milk and/or egg. A peanut IgE level of ≥ 5 kUA/L was considered likely indicative of peanut allergy.
A total of 140 (27.8%) infants had PN-IgE levels ≥5 kUA/L. Multivariate analysis including clinical, laboratory and demographic variables showed frequent peanut consumption during pregnancy (OR 2.9, 95% CI 1.7–4.9, p < 0.001), IgE levels to milk (p = 0.001) and egg (p < 0.001), male sex (p = 0.02) and non-white race (p = 0.02) to be the primary factors associated with peanut IgE ≥5 kUA/L. Frequency of peanut consumption during pregnancy and breast feeding showed a dose-response association with peanut IgE ≥ 5 kUA/L, but only consumption during pregnancy was a significant predictor. Among 71 infants never breastfed, frequent consumption of peanut during pregnancy was strongly associated with peanut IgE ≥ 5 kUA/L (OR-4.99, 95% CI-1.69–14.74, p < 0.004).
In this cohort of infants with likely milk or egg allergy, maternal ingestion of peanut during pregnancy was strongly associated with a high level of peanut sensitization.
food allergy; sensitization; atopy; peanut allergy
Rationale: We identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony–stimulating factor (GM-CSF) receptor function, and increased GM-CSF.
Objectives: Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction.
Methods: We screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls.
Measurement and Main Results: Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-lung lavage therapy.
Conclusions: CSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-lung lavage.
GM-CSF receptor; genetic disease; surfactant; alveolar macrophage; whole lung lavage
Cardiovascular disease is a leading cause of morbidity and mortality in the United States, and its prevention and treatment remain a priority for the medical community. Ethnic variations account for some differences in the prevalence of hypertension and blood pressure (BP) control rates among Hispanics, indicating the need for culturally appropriate management models. Aggressive treatment strategies are key to achieving optimal BP control in high-risk Hispanic patients. Hypertension in this ethnic group continues to be a major health concern. Of note, when provided access to comprehensive care, Hispanics demonstrate similar response rates to treatment as the majority of non-Hispanic whites. This highlights the importance of effective, culturally responsive hypertension management among high-risk Hispanic patients for achieving observable, positive health outcomes.
HIV infection has been implicated in dysregulation of the autonomic nervous system.
Cross-sectional study examining the relationship between the presence of persistent detectable HIV viral load with autonomic function, measured by heart rate variability (HRV). Non-virologic suppression (NVS) was defined as having a detectable viral load for at least 3 months prior to autonomic function testing. HRV was measured during the following 4 maneuvers: resting and paced respirations and sustained handgrip and tilt. Inferences on parasympathetic and sympathetic modulations were determined by analyzing time and frequency domains of HRV.
57 participants were enrolled in 3 groups: 22 were HIV-infected participants with HIV virologic suppression (VS; undetectable HIV viral load), 9 were HIV-infected participants who had NVS, and 26 were HIV seronegative controls. There were lower time domain parameters in the HIV-infected group as a whole compared to controls. There were no significant differences in time domain parameters among HIV-infected participants. There were no differences in frequency domain parameters during any of the maneuvers between controls and all HIV-infected participants, nor between the NVS and VS groups.
There were differences in autonomic function between HIV-infected individuals and HIV seronegative controls, but not between the NVS and VS groups.
acquired immune deficiency syndrome; autonomic dysfunction; heart rate variability; HIV; viremia
Rationale: Stress-elicited disruption of immunity begins in utero.
Objectives: Associations among prenatal maternal stress and cord blood mononuclear cell (CBMC) cytokine responses were prospectively examined in the Urban Environment and Childhood Asthma Study (n = 557 families).
Methods: Prenatal maternal stress included financial hardship, difficult life circumstances, community violence, and neighborhood/block and housing conditions. Factor analysis produced latent variables representing three contexts: individual stressors and ecological-level strains (housing problems and neighborhood problems), which were combined to create a composite cumulative stress indicator. CBMCs were incubated with innate (lipopolysaccharide, polyinosinic-polycytidylic acid, cytosine-phosphate-guanine dinucleotides, peptidoglycan) and adaptive (tetanus, dust mite, cockroach) stimuli, respiratory syncytial virus, phytohemagglutinin, or medium alone. Cytokines were measured using multiplex ELISAs. Using linear regression, associations among increasing cumulative stress and cytokine responses were examined, adjusting for sociodemographic factors, parity, season of birth, maternal asthma and steroid use, and potential pathway variables (prenatal smoking, birth weight for gestational age).
Measurements and Main Results: Mothers were primarily minorities (Black [71%], Latino [19%]) with an income less than $15,000 (69%). Mothers with the highest cumulative stress were older and more likely to have asthma and deliver lower birth weight infants. Higher prenatal stress was related to increased IL-8 production after microbial (CpG, PIC, peptidoglycan) stimuli and increased tumor necrosis factor-α to microbial stimuli (CpG, PIC). In the adaptive panel, higher stress was associated with increased IL-13 after dust mite stimulation and reduced phytohemagglutinin-induced IFN-γ.
Conclusions: Prenatal stress was associated with altered innate and adaptive immune responses in CBMCs. Stress-induced perinatal immunomodulation may impact the expression of allergic disease in these children.
psychological stress; cord blood; cytokines; innate; adaptive
Rationale: Granulocyte/macrophage colony–stimulating factor (GM-CSF) autoantibodies (GMAb) are strongly associated with idiopathic pulmonary alveolar proteinosis (PAP) and are believed to be important in its pathogenesis. However, levels of GMAb do not correlate with disease severity and GMAb are also present at low levels in healthy individuals.
Objectives: Our primary objective was to determine whether human GMAb would reproduce PAP in healthy primates. A secondary objective was to determine the concentration of GMAb resulting in loss of GM-CSF signaling in vivo (i.e., critical threshold).
Methods: Nonhuman primates (Macaca fascicularis) were injected with highly purified, PAP patient-derived GMAb in dose-ranging (2.2–50 mg) single and multiple administration studies, and after blocking antihuman immunoglobulin immune responses, in chronic administration studies maintaining serum levels greater than 40 μg/ml for up to 11 months.
Measurements and Main Results: GMAb blocked GM-CSF signaling causing (1) a milky-appearing bronchoalveolar lavage fluid containing increased surfactant lipids and proteins; (2) enlarged, foamy, surfactant-filled alveolar macrophages with reduced PU.1 and PPARγ mRNA, and reduced tumor necrosis factor-α secretion; (3) pulmonary leukocytosis; (4) increased serum surfactant protein-D; and (5) impaired neutrophil functions. GM-CSF signaling varied inversely with GMAb concentration below a critical threshold of 5 μg/ml, which was similar in lungs and blood and to the value observed in patients with PAP.
Conclusions: GMAb reproduced the molecular, cellular, and histopathologic features of PAP in healthy primates, demonstrating that GMAb directly cause PAP. These results have implications for therapy of PAP and help define the therapeutic window for potential use of GMAb to treat other disorders.
alveolar macrophages; surfactant homeostasis; autoimmunity; neutrophils; anti–granulocyte/macrophage colony–stimulating factor therapy
Peanut OIT has shown promise as a potential treatment for food allergy. However, there remain numerous unanswered questions surrounding this investigational treatment, including the risks of OIT compared to avoidance, dosing regimen issues, patient selection, post-desensitization strategy, allocation of clinical resources, and reimbursement. Further studies are needed to address these outstanding issues in order to determine if this type of therapy is appropriate for clinical use.
peanut allergy; oral immunotherapy; desensitization
Immune features of infants with food allergy have not been delineated.
To explore basic mechanisms responsible for food allergy and identify biomarkers, e.g. prick skin tests (PST), food-specific IgE, and mononuclear cell responses in a cohort of infants with likely milk/egg allergy at increased risk of developing peanut allergy.
Infants aged 3–15 months were enrolled with a positive PST to milk or egg and either a corresponding convincing clinical history of allergy to milk or egg, or with moderate to severe atopic dermatitis (AD). Infants with known peanut allergy were excluded.
Overall, 512 infants (67% males) were studied with 308 (60%) having a history of a clinical reaction. Skin tests and/or detectable food-specific IgE revealed sensitization as follows: milk-78%, egg-89% and peanut-69%. PST and food-specific IgE levels were discrepant for peanut: 15% IgE ≥ 0.35 kUA/L/PST- versus 8% PST+/IgE < 0.35, p = 0.001. Mononuclear cell allergen stimulation screening for CD25, CISH, FOXP3, GATA3, IL-10, IL-4, IFN-gamma and TBET expression using casein, egg white and peanut revealed that only allergen-induced IL-4 expression was significantly increased in those with clinical allergy to milk (compared to non-allergic) and in those sensitized to peanut, despite the absence of an increase in GATA-3 mRNA expression.
Infants with likely milk/egg allergy are at considerably high risk of having elevated peanut-specific IgE (potential allergy). Peanut-specific serum IgE was a more sensitive indicator of sensitization than PST. Allergen-specific IL-4 expression may be a marker of allergic risk. Absence of an increase in GATA-3 mRNA expression suggests that allergen-specific IL-4 may not be of T cell origin.
food allergy; sensitization; atopy
AIM: To examine trends in and correlates of liver disease and viral hepatitis in an human immunodeficiency virus (HIV)-infected cohort.
METHODS: The multi-site adult/adolescent spectrum of HIV-related diseases (ASD) followed 29 490 HIV-infected individuals receiving medical care in 11 U.S. metropolitan areas for an average of 2.4 years, and a total of 69 487 person-years, between 1998 and 2004. ASD collected data on the presentation, treatment, and outcomes of HIV, including liver disease, hepatitis screening, and hepatitis diagnoses.
RESULTS: Incident liver disease, chronic hepatitis B virus (HBV), and hepatitis C virus (HCV) were diagnosed in 0.9, 1.8, and 4.7 per 100 person-years. HBV and HCV screening increased from fewer than 20% to over 60% during this period of observation (P < 0.001). Deaths occurred in 57% of those diagnosed with liver disease relative to 15% overall (P < 0.001). Overall 10% of deaths occurred among individuals with a diagnosis of liver disease. Despite care guidelines promoting screening and vaccination for HBV and screening for HCV, screening and vaccination were not universally conducted or, if conducted, not documented.
CONCLUSION: Due to high rates of incident liver disease, viral hepatitis screening, vaccination, and treatment among HIV-infected individuals should be a priority.
Human immunodeficiency virus; Hepatitis B; Hepatitis C; Liver disease
In several human cancers, ErbB2 over-expression facilitates the formation of constitutively active homodimers resistant to internalization which results in progressive signal amplification from the receptor, conducive to cell survival, proliferation, or metastasis. Here we report on studies of the influence of ErbB2 over-expression on localization and signaling in polarized Caco-2 and MDCK cells, two established models to study molecular trafficking. In these cells, ErbB2 is not over-expressed and shares basolateral localization with ErbB3. Over-expression of ErbB2 by transient transfection resulted in partial separation of the receptors by relocalization of ErbB2, but not ErbB3, to the apical surface, as shown by biotinylation of the apical or basolateral surfaces. These results were confirmed by immunofluorescence and confocal microscopy. Polarity controls indicated that the relocalization of ErbB2 is not the result of depolarization of the cells. Biotinylation and confocal microscopy also showed that apical, but not basolateral ErbB2 is activated at tyrosine 1139. This phosphotyrosine binds adaptor protein Grb2, as confirmed by immunoprecipitation. However, we found that it does not initiate the canonical Grb2-Ras-Raf-Erk pathway. Instead, our data supports the activation of a survival pathway via Bcl-2. The effects of ErbB2 over-expression were abrogated by the humanized anti-ErbB2 monoclonal antibody Herceptin added only from the apical side. The ability of apical ErbB2 to initiate an altered downstream cascade suggests that subcellular localization of the receptor plays an important role in regulating ErbB2 signaling in polarized epithelia.
POLARITY; EPITHELIA; CARCINOMAS; COLON; ErbB; RAS; Bcl-2
Assessment of the predictive ability of the Mini-Mental Status Exam (MMSE) domains (orientation to time, orientation to place, registration, attention& calculation, recall, language, and visual construction) for falls in Mexican-American elders tested the hypothesis that low MMSE domain scores are related to an increased number of falls.
Data was obtained from the 1998–99 re-survey (Wave 3) Hispanic Established Populations for the Epidemiologic Study of the Elderly (H -EPESE), a population based study of older Mexican Americans residing in the southwestern United States.
Retrospective Case Control Study- 926 subjects at Wave 3 age 77 and older, were examined. MMSE scores were utilized to predict falls two years later. Measurements included Socio-demographic characteristics, MMSE scores, Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), and fall rates.
Main Outcome Measures
Relationships between MMSE domain scores and falls
Of the 681 subjects examined two years later, 35.7% experienced at least one fall. Subjects with errors on orientation to place (OR = 2.01) and visual construction (OR = 1.9) were most likely to fall.
Poor scores on MMSE domains are most predictive of falls in Mexican - Americans elders include: orientation to place and visual construction. Further evaluation for confusion level and visual ability in elders presenting with dysfunction on these domains may lead to a reduction of falls in this ethnic group.
Cognition; Frailty; Mexican American Aged
BACKGROUND & AIMS
To identify the prevalence and characteristics of gall bladder disease (GBD) that has been self-reported in Mexican American Elders.
A prospective survey of a regional probability sample of self identified Mexican Americans aged 65 and over. The Hispanic Established Population for the Epidemiologic Studies of the Elderly (H-EPESE), a probability sample of non-institutionalized, Mexican Americans, aged 65 and over, residing in Southwestern states of Texas, New Mexico, Colorado, Arizona, and California.
In 1993–1994 (Wave 1), 3,050 Mexican Americans, aged 65 and over, were selected at baseline as a weighted probability sample. In 1995–1996 (Wave 2), 2,895 remained. Sample weights were used to extrapolate to the estimated 498,176 older Mexican Americans residing in the Southwest United States. Self-reported GBD was collected via in home interviews.
The prevalence of self-reported GBD in Mexican American elders was found to be 18.8% with an average age of 75.05 years. The findings indicate that older Mexican Americans have an increased rate of gallbladder disease if they are female, have history of arthritis or hypertension and have more acculturation to the United States. However, the rate decreases when they score poorly on the Mini Mental State Exam. One major limitation was reliance on self report, as gallbladder disease and other co-morbid illnesses may be under, or over estimated.
Age is not protective in the prevalence of GBD in elder Mexican Americans. Persistent underlying genetics and dietary habits most likely attribute to this consistent high percentage, even in the elderly.
Electronic Medical Records (EMRs) are increasingly used in modern health care. As a result, systematically applying usability principles becomes increasingly vital in creating systems that provide health care professionals with satisfying, efficient, and effective user experiences, as opposed to frustrating interfaces that are difficult to learn, hard to use, and error prone. This study demonstrates how the TURF framework  can be used to evaluate the usability of an EMR module and subsequently redesign its interface with dramatically improved usability in a unified, systematic, and principled way. This study also shows how heuristic evaluations can be utilized to complement the TURF framework.
UFuRT; TURF; Interface Design; Usability; Meaningful Use; Electronic Medical Record (EMR)
The national prevalence and patterns of food allergy (FA) in the United States (US) are not well understood.
We developed nationally representative estimates of the prevalence of and demographic risk factors for FA, and investigated associations of FA with asthma, hay fever, and eczema.
8,203 participants in the National Health and Nutrition Examination Survey (NHANES) 2005–2006 had food-specific serum IgE measured to peanut, cow's milk, egg white, and shrimp. Food-specific IgE and age-based criteria were used to define Likely FA (LFA), Possible FA (PFA), and Unlikely FA (UFA), and to develop estimates of clinical FA. Self-reported data were used to evaluate demographic risk factors and associations with asthma and related conditions.
In the US, the estimated prevalence of clinical FA was 2.5% (peanut 1.3%, milk 0.4%, egg 0.2%, shrimp 1.0%, not mutually exclusive). Risk of PFA/LFA was increased in non-Hispanic blacks (odds ratio (OR) 3.06; 95% confidence interval (CI) 2.14-4.36), males (1.87; 1.32-2.66), and children (2.04; 1.42-2.93). Study participants with doctor-diagnosed asthma (vs. no asthma) exhibited increased risk of all measures of food sensitization. Moreover, in those with LFA, the adjusted OR for current asthma (3.8; 1.5-10.7) and an emergency room (ER) visit for asthma in the past year (6.9; 2.4-19.7) were both notably increased.
Population-based serologic data on 4 foods indicate an estimated 2.5% of the US population has FA, and increased risk was found for blacks, males, and children. Additionally, FA could be an under-recognized risk factor for problematic asthma.
asthma; eczema; egg; food allergy; food sensitization; food-specific serum IgE; peanut; hay fever; milk; prevalence; risk; shrimp