Transforming growth factor–β (TGFβ) is a multifunctional cytokine that plays diverse roles in physiologic processes as well as human disease, including cancer, heart disease, and fibrotic disorders. In the immune system, TGFβ regulates regulatory T cell (Treg) maturation and immune homeostasis. Although genetic manipulation of the TGFβ pathway modulates immune tolerance in mouse models, the contribution of this pathway to human allergic phenotypes is not well understood. We demonstrate that patients with Loeys-Dietz syndrome (LDS), an autosomal dominant disorder caused by mutations in the genes encoding receptor subunits for TGFβ, TGFBR1 and TGFBR2, are strongly predisposed to develop allergic disease, including asthma, food allergy, eczema, allergic rhinitis, and eosinophilic gastrointestinal disease. LDS patients exhibited elevated immunoglobulin E levels, eosinophil counts, and T helper 2 (TH2) cytokines in their plasma. They had an increased frequency of CD4+ T cells that expressed both Foxp3 and interleukin-13, but retained the ability to suppress effector T cell proliferation. TH2 cytokine–producing cells accumulated in cultures of naïve CD4+ T cells from LDS subjects, but not controls, after stimulation with TGFβ, suggesting that LDS mutations support TH2 skewing in naïve lymphocytes in a cell-autonomous manner. The monogenic nature of LDS demonstrates that altered TGFβ signaling can predispose to allergic phenotypes in humans and underscores a prominent role for TGFβ in directing immune responses to antigens present in the environment and foods. This paradigm may be relevant to nonsyndromic presentations of allergic disease and highlights the potential therapeutic benefit of strategies that inhibit TGFβ signaling.
There are presently no available therapeutic options for peanut-allergic patients.
To investigate the safety, efficacy, and immunologic effects of peanut sublingual immunotherapy (SLIT).
After a baseline oral food challenge (OFC) of up to 2g of peanut powder (~50% protein) (median successfully consumed dose [SCD] 46mg), 40 subjects, aged 12–37 (median 15) years, were randomized 1:1 across 5 sites to daily peanut or placebo SLIT. A 5g OFC was performed after 44 weeks followed by unblinding; placebo subjects then crossed over to higher dose peanut SLIT, followed by a subsequent crossover Week 44 5g OFC. Week 44 OFCs from both groups were compared to baseline OFCs; subjects successfully consuming 5g or at least 10-fold more peanut powder than the baseline OFC threshold were considered responders.
After 44 weeks of SLIT, 14/20 (70%) subjects receiving peanut SLIT were responders compared to 3/20 (15%) subjects receiving placebo (p<0.001). In peanut-SLIT responders, median SCD increased from 3.5mg to 496mg. After 68 weeks of SLIT, median SCD significantly increased to 996mg (compared to week 44, p=0.05). The median SCD at the Week 44 crossover OFC was significantly higher than baseline (603mg vs 71mg; p=0.02). 7/16 (44%) crossover subjects were responders; median SCD increased from 21mg to 496mg among responders. Of 10,855 peanut doses through Week 44 OFCs, 63.1% were symptom-free; excluding oral/pharyngeal symptoms, 95.2% were symptom-free.
Peanut SLIT safely induced a modest level of desensitization in a majority of subjects compared to placebo. Longer duration of therapy showed statistically significant increases in the SCD.
peanut allergy; sublingual immunotherapy; desensitization; food allergy
A novel robotic sensor is proposed to measure both the contact angle and the force acting between the tip of a surgical robot and soft tissue. The sensor is manufactured using a planar lithography process that generates microchannels that are subsequently filled with a conductive liquid. The planar geometry is then molded onto a hemispherical plastic scaffolding in a geometric configuration enabling estimation of the contact angle (angle between robot tip tangent and tissue surface normal) by the rotation of the sensor around its roll axis. Contact force can also be estimated by monitoring the changes in resistance in each microchannel. Bench top experimental results indicate that, on average, the sensor can estimate the angle of contact to within ±2° and the contact force to within ±5.3 g.
Background. The risk of developing childhood asthma
has been linked to the severity and etiology of viral respiratory illnesses in early
childhood. Since inner-city infants have unique environmental exposures, we hypothesized
that patterns of respiratory viral infections would also be distinct.
Methods. We compared the viral etiology of respiratory
illnesses in 2 groups: a cohort of 515 infants from 4 inner-city areas and a cohort of 285
infants from mainly suburban Madison, Wisconsin. Nasal secretions were sampled during
periods of respiratory illness and at 1 year of age and were analyzed for viral pathogens
by multiplex polymerase chain reaction.
Results. Overall, inner-city infants had lower rates
of viral detection. Considering specific viruses, sick urban infants had lower rates of
detectable rhinovirus or respiratory syncytial virus infection and higher rates of
adenovirus infection. Every urban site had a higher proportion of adenovirus-positive
samples associated with illnesses (10%–21%), compared with Madison
Conclusions. These findings provide evidence that
inner-city babies have different patterns of viral respiratory illnesses than babies who
grow up in a more suburban location. These findings raise important questions about the
etiology of virus-negative illnesses in urban infants and the possibility of long-term
consequences of early life infections with adenovirus in this population.
A recent study of peanut allergic subjects treated with omalizumab generated some results that were concordant with a study of cat allergics being treated with omalizumab. However, there were differences that provided additional insights into the nature of the cellular responses in allergic patients.
Determine the cause for failure to suppress the allergen-induced basophil response during treatment with omalizumab.
Peanut allergic patients were treated with omalizumab. Clinical, serological and cellular indices relevant to the response of the patient and their peripheral blood basophils (specific-to-total IgE ratio, cell surface FceRI expression, histamine release responses to anti-IgE Ab or peanut allergen) were obtained at 3 times.
Following treatment, approximately 60% of the subjects’ basophil responses to peanut allergen did not significantly decrease. In 40% of cases, the in vitro basophil response to peanut allergen increased 2–7 fold. The increases were associated with two primary factors, a high (>10%) specific-to-total IgE ratio and an increase in the intrinsic response of the basophil to IgE-mediated stimulation. The extent to which the basophil response to peanut allergen increased was inversely correlated with the improvement in the individual’s ability to tolerate ingestion of peanut.
The basophil response during treatment with omalizumab is a consequence of two competing factors, suppression of allergen-specific IgE on the cell surface vs. increased intrinsic sensitivity to IgE-mediated stimulation. In peanut allergy, the basophil response appears to mitigate against the ability of omalizumab to improve the patients’ tolerance of oral allergen.
basophil; anti-IgE; peanut; syk; IgE receptor
Orally administered, food-specific immunotherapy appears effective in desensitizing and potentially permanently tolerizing allergic individuals.
We sought to determine whether milk oral immunotherapy (OIT) is safe and efficacious in desensitizing children with cow’s milk allergy.
Twenty children were randomized to milk or placebo OIT (2:1 ratio). Dosing included 3 phases: the build-up day (initial dose, 0.4 mg of milk protein; final dose, 50 mg), daily doses with 8 weekly in-office dose increases to a maximum of 500 mg, and continued daily maintenance doses for 3 to 4 months. Double-blind, placebo-controlled food challenges; end-point titration skin prick tests; and milk protein serologic studies were performed before and after OIT.
Nineteen patients, 6 to 17 years of age, completed treatment: 12 in the active group and 7 in the placebo group. One dropped out because of persistent eczema during dose escalation. Baseline median milk IgE levels in the active (n = 13) versus placebo (n = 7) groups were 34.8 kUa/L (range, 4.86–314 kUa/L) versus 14.6 kUa/L (range, 0.93–133.4 kUa/L). The median milk threshold dose in both groups was 40 mg at the baseline challenge. After OIT, the median cumulative dose inducing a reaction in the active treatment group was 5140 mg (range 2540-8140 mg), whereas all patients in the placebo group reacted at 40 mg (P = .0003). Among 2437 active OIT doses versus 1193 placebo doses, there were 1107 (45.4%) versus 134 (11.2%) total reactions, with local symptoms being most common. Milk-specific IgE levels did not change significantly in either group. Milk IgG levels increased significantly in the active treatment group, with a predominant milk IgG4 level increase.
Milk OIT appears to be efficacious in the treatment of cow’s milk allergy. The side-effect profile appears acceptable but requires further study.
Cow’s milk; food allergy; IgE; prognosis; desensitization; tolerance; oral immunotherapy
Endocrine-disrupting compounds (EDCs) have immune-modulating effects. We were interested in determining their association with allergic sensitization.
To determine the association between EDCs and allergic sensitization and if this relationship depended on the antimicrobial properties of the EDCs and/or gender.
Data were obtained from the 2005–2006 National Health and Nutrition Examination Survey in which urinary bisphenol A, triclosan, benzophenone-3, and propyl, methyl, butyl and ethyl paraben, and specific IgE were available on 860 children. Aeroallergen and food sensitization were defined as having at least one positive (≥0.35 kU/L) specific IgE to an aeroallergen or a food. Logistic regression was used to determine the association of EDCs and sensitization. Analyses were adjusted for urinary creatinine, age, ethnicity, and poverty index ratio.
The odds of aeroallergen sensitization significantly increased with the level of the antimicrobial EDCs triclosan and propyl and butyl paraben (p≤0.04). The odds of food sensitization significantly increased with the level of urinary triclosan among male subjects (odds ratio for 3rd versus 1st tertile 3.9, p=0.02 for trend). There was a significant interaction between gender and triclosan, with males being more likely to be food sensitized with exposure (p=0.03). Similar associations were not identified for the non-antimicrobial EDCs bisphenol A and benzophenone-3 (p>0.2).
As a group, EDCs are not associated with allergen sensitization. However, levels of the antimicrobial EDCs triclosan and parabens were significantly associated with allergic sensitization. The potential role of antimicrobial EDCs in allergic disease warrants further study as they are commonly used in Western society.
Triclosan; paraben; benzophenone; bisphenol A; endocrine disrupting compound; aeroallergen; sensitization; food; allergy
Bla g allergens are major targets of IgE responses associated with cockroach allergies. However, little is known about corresponding T cell responses, despite their potential involvement in immunopathology and the clinical efficacy of Specific ImmunoTherapy (SIT). Bioinformatic predictions of the capacity of Bla g 1, 2, 4, 5, 6, and 7 peptides to bind HLA DR, DP and DQ molecules, and PBMC responses from 30 allergic donors, identified 25 T cell epitopes. Five immunodominant epitopes accounted for over half of the response. Bla g 5, the most dominant allergen, accounted for 65% of the response, and Bla g 6 accounted for 20%. Bla g 5 induced both IL-5 and IFN-γ responses, while Bla g 6 induced mostly IL-5 and, conversely, Bla g 2 induced only IFN-γ. Thus, responses to allergens within a source are independently regulated, suggesting a critical role for the allergen itself, and not extraneous stimulation from other allergens or co-presented immunomodulators. In comparing antibody with T cell responses for several donor/allergen combinations we detected IgE titers in the absence of detectable T cell responses, suggesting that unlinked T-B help might support development of IgE responses. Finally, SIT resulted in IL-5 down-modulation, which was not associated with development of IFN-γ or IL-10 responses to any of the Bla g derived peptides. In summary, the characteristics of T cell responses to Bla g allergens appear uncorrelated with IgE responses. Monitoring these responses may therefore yield important information relevant to understanding cockroach allergies and their treatment.
To examine circumstances of allergic reactions to foods in a cohort of preschool-aged children.
We conducted a prospective, 5-site observational study of 512 infants aged 3 to 15 months with documented or likely allergy to milk or egg, and collected data prospectively examining allergic reactions.
Over a median follow-up of 36 months (range: 0–48.4), the annualized reaction rate was 0.81 per year (367/512 subjects reporting 1171 reactions [95% confidence interval: 0.76–0.85]). Overall, 269/512 (52.5%) reported >1 reaction. The majority of reactions (71.2%) were triggered by milk (495 [42.3%]), egg (246 [21.0%]), and peanut (93 [7.9%]), with accidental exposures attributed to unintentional ingestion, label-reading errors, and cross-contact. Foods were provided by persons other than parents in 50.6% of reactions. Of 834 reactions to milk, egg, or peanut, 93 (11.2%) were attributed to purposeful exposures to these avoided foods. A higher number of food allergies (P < .0001) and higher food-specific immunoglobulin E (P < .0001) were associated with reactions. Of the 11.4% of reactions (n = 134) that were severe, 29.9% were treated with epinephrine. Factors resulting in undertreatment included lack of recognition of severity, epinephrine being unavailable, and fears about epinephrine administration.
There was a high frequency of reactions caused by accidental and nonaccidental exposures. Undertreatment of severe reactions with epinephrine was a substantial problem. Areas for improved education include the need for constant vigilance, accurate label reading, avoidance of nonaccidental exposure, prevention of cross-contamination, appropriate epinephrine administration, and education of all caretakers.
food allergy; IgE-mediated allergic reaction; epinephrine
Season of birth has been reported as a risk factor for food allergy, but the mechanisms by which it acts are unknown.
Two populations were studied; 5862 children from the National Health and Nutrition Examination Survey (NHANES) III, 1514 well-characterized food allergic children from the Johns Hopkins Pediatric Allergy Clinic (JHPAC). Food allergy was defined as self report of an acute reaction to a food (NHANES), or as milk, egg and peanut allergy. Logistic regression compared fall or non-fall birth between (1) food allergic and non-allergic subjects in NHANES, adjusted for ethnicity, age, income and sex, and (2) JHPAC subjects and the general Maryland population. For NHANES, stratification by ethnicity and for JHPAC, eczema, was examined.
Fall birth was more common among food allergic subjects in both NHANES (OR: 1.91, 95%CI: 1.31–2.77) and JHPAC/Maryland (OR: 1.31, 95%CI: 1.18–1.47). Ethnicity interacted with season (OR 2.34, 95%CI 1.43–3.82 for Caucasians, OR 1.19, 95%CI 0.77–1.86 for non-Caucasians, p=0.04 for interaction), as did eczema (OR 1.47, 95%CI 1.29–1.67 with eczema, OR 1.00, 95%CI 0.80–1.23 without eczema, p=0.002 for interaction).
Fall birth is associated with increased risk of food allergy, and this risk is greatest among those most likely to have seasonal variation in vitamin D during infancy (Caucasians) and those at risk for skin barrier dysfunction (subjects with a history of eczema), suggesting that vitamin D and the skin barrier may be implicated in seasonal associations with food allergy.
food allergy; season of birth; eczema; vitamin D
The objective of this study was to determine the frequency of complications in median and paramedian mandibulotomies. In addition, the interdental space in the median and paramedian region was calculated.
Tertiary care center.
A retrospective chart review was performed for all cases where a mandibulotomy was performed from 2002 to 2010. 117 charts (61 paramedian and 56 median) were identified. We included data on complications, which fell in the following 2 categories: plate and dental complications. For our second objective, we evaluated 40 different patients with base of tongue or tonsillar cancer treated with intensity modulated radiation therapy (IMRT). The interdental space between the lateral incisors and the canines was electronically calculated on the digital Panorex images.
Main outcome measures
Dental and plate complications were evaluated. We also assessed interdental space.
Patient characteristics were not significantly different. The median group had significantly more dental complications (p=0.0375, RD=0.19 and 95% CI (0.0139-0.3661)). The paramedian group had significantly more plate complications (p=0.0375, RD=0.082 and 95% CI (0.0131-0.1508). The distance between the central incisors was significantly less than the distance between the lateral incisors and canines both at the crestal and apical levels (p=0.0086 and p<0.001).
There are significantly more dental complications in the median approach. There were significantly more plate complications in the paramedian group. In addition, there is significantly less space in the between the median region as compared to the paramedian region. This is the first study that documents the advantage of the paramedian approach for dental complications.
Mandibulotomy; Complications; Median; Paramedian; Dental; Medial
Social support has been shown to influence health outcomes in later life. In this study, we focus on social engagement as an umbrella construct that covers select social behaviors in a lifespan sample that included oldest-old adults, a segment of the adult population for whom very little data currently exist. We examined relationships among social engagement, positive health behaviors, and physical health to provide new evidence that addresses gaps in the extant literature concerning social engagement and healthy aging in very old adults. Participants were younger (21–59 years), older (60–89 years), and oldest-old (90–97 years) adults (N = 364) in the Louisiana Healthy Aging Study (LHAS). Linear regression analyses indicated that age, gender, and hours spent outside of the house were significantly associated with self-reported health. The number of clubs and hours outside of home were more important factors in the analyses of objective health status than positive health behaviors, after considering age group and education level. These data strongly suggest that social engagement remains an important determinant of physical health into very late adulthood. The discussion focuses on practical applications of these results including social support interventions to maintain or improve late life health.
Social engagement; social relations; positive health behaviors; physical health; healthy aging
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