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1.  Induced T Regulatory Cells Suppress Osteoclastogenesis and Bone Erosion in Collagen-induced Arthritis Better than Natural T Tegulatory Cells 
Annals of the rheumatic diseases  2012;71(9):1567-1572.
Osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA) and natural CD4+Foxp3+regulatory T cells (nTregs) can inhibit osteoclastogenesis. This study aims to determine whether TGF-β-induced CD4+Foxp3+regulatory T cells (iTregs) also suppress osteolastogenesis and bone erosion in collagen induced arthritis (CIA).
Osteoclasts were induced from bone-marrow CD11b+ cells with RANKL and macrophage colony-stimulating factor (M-CSF), and assessed with tartrate-resistant acid phosphatase (TRAP) staining. CD4+ iTregs were generated with TGF-β and added to cultures with different ratios with CD11b+ cells. Transwell and antibody blockade experiments were performed to define the mechanism of action. NF-kB activation was determined by western blot. 3×106 CD4+ iTregs, nTregs or control cells were adoptively transferred to DBA1/J mice on day 14 after immunization with CII/CFA. CIA onset and severity were monitored and bone erosion was examined by CT scan.
Both CD4+ Tregs almost completely suppressed osteoclastogenesis but only iTregs sustained the effect in the presence of IL-6 in vitro. CD4+ iTregs but not nTregs and control cells injected after immunization and before of onset of CIA significantly suppressed disease development. Of note, CT scan showed that the joints in CD4+ iTregs but not nTregs or control cells infused CIA had less bone erosion. Treatment with CD4+ iTregs but not other cells dramatically decreased the levels of NF-kB p65/p50 in osteoclasts in vitro and P65/50 and RANKL expression by synovial tissues in vivo.
Manipulation of CD4+ iTregs may have therapeutic effects on rheumatoid arthritis and other bone erosion related diseases.
PMCID: PMC4038329  PMID: 22764040
2.  Temporal Trends in the Utilization of Echocardiography in Ontario, 2001-2009 
JACC. Cardiovascular imaging  2013;6(4):515-522.
The purpose of this study was to examine utilization and growth in echocardiography among the general population of Ontario between 2001 and 2009. The age- and sex-adjusted rates of echocardiography grew from 39.1 per 1,000 persons in 2001 to 59.9 per 1,000 persons in 2009, for an annual rate of increase of 5.5%. Repeat echocardiograms increased at a rate of 10.6% per year and accounted for 25.3% of all procedures in 2009 as compared to 18.5% in 2002. While significant increases in echocardiography utilization were observed, opportunities may exist to improve the clinical utility of the echocardiograms performed in Ontario.
PMCID: PMC3915739  PMID: 23579013
echocardiography; resource utilization; cardiovascular imaging
3.  SAMe Treatment Prevents the Ethanol-Induced Epigenetic Alterations of Genes in the Toll-Like Receptor Pathway 
Prior studies showed that Toll-like receptor (TLR) signaling pathway genes were up regulated in the liver of rats fed ethanol, but not in rats fed ethanol plus S-adenosylmethionine (SAMe). These results were obtained using a PCR microplate array analysis for TLRs and associated proteins such as proinflammatory cytokines and chemokine mRNA levels. A large number of genes were up regulated by the ethanol diet, but not the ethanol plus SAMe diet. In the present study, using the same experimental rat livers, DNA methylation analysis was done by using an Epitect Methyl DNA Restriction Kit (Qiagen, 335451) (24 genes). The results of all the genes combined shows a highly significant increase in methylation in the ethanol-fed group of rats, but not in the dextrose-fed, SAMe-fed or ethanol plus SAMe-fed groups of rats. There was also an increase in DNA methylation in rats with high blood alcohol levels compared to a rat with a low blood alcohol level. The individual genes that were up regulated as indicated by the increased mRNA measured by qPCR correlated positively with the increased methylation of the DNA of the corresponding gene as follows: Cd14, Hspa1a, Irf1, Irak1, Irak2, Map3k7, Myd88, Pparα, Ripk2, Tollip and Traf6.
PMCID: PMC3562371  PMID: 23047067
TLR (Toll-like receptor); SAMe (S-adenosyl methionine); BAL/blood alcohol levels; 5-methylcytosine
4.  Divergent antiviral effects of bioflavonoids on the hepatitis C virus life cycle 
Virology  2012;433(2):346-355.
We have previously demonstrated that quercetin, a bioflavonoid, blocks hepatitis C virus (HCV) proliferation by inhibiting NS5A-driven internal ribosomal entry site (IRES)-mediated translation of the viral genome. Here, we investigate the mechanisms of antiviral activity of quercetin and six additional bioflavonoids. We demonstrate that catechin, naringenin, and quercetin possess significant antiviral activity, with no associated cytotoxicity. Infectious virion secretion was not significantly altered by these bioflavonoids. Catechin and naringenin demonstrated stronger inhibition of infectious virion assembly compared to quercetin. Quercetin markedly blocked viral translation whereas catechin and naringenin demonstrated mild activity. Similarly quercetin completely blocked NS5A-augmented IRES-mediated translation in an IRES reporter assay, whereas catechin and naringenin had only a mild effect. Moreover, quercetin differentially inhibited HSP70 induction compared to catechin and naringenin. Thus, the antiviral activity of these bioflavonoids is mediated through different mechanisms. Therefore combination of these bioflavonoids may act synergistically against HCV.
PMCID: PMC3478964  PMID: 22975673
HSP70; NS5A; IRES; HCV; Bioflavonoid
5.  Treatment Outcomes in Elderly with Advanced-Stage Non-small Cell Lung Cancer 
Lung  2013;191:645-654.
Lung cancer remains the top cause of cancer morbidity and mortality in the world. Although the identification of epidermal growth factor receptor (EGFR) gene mutations could predict efficacy of tyrosine kinase inhibitor (TKI), testing for predictive biomarkers are not always possible due to tissue availability. The overall therapeutic decision remains a clinical one for a significant proportion of elderly patients with advanced stage lung cancer but no known EGFR mutation status. The purpose of this study was to compare the outcome of drug treatment modalities in progression-free survival (PFS) and overall survival (OS) for elderly with advanced-stage non-small cell lung cancer (NSCLC) and to identify clinical parameters that could predict treatment outcome.
Clinical records of patients aged 70 years or older with advanced-stage NSCLC who have received treatment were reviewed. A group of gender- and histology-matched subjects younger than age 70 years were identified as controls.
Fifty-six elderly patients were included. The median age at diagnosis was 73 years; 60.7 % received only one line of treatment. Baseline performance status (PS) was the only predictor of improved PFS (p = 0.042) and OS (p = 0.002). There was no difference in survival between the upfront chemotherapy and the TKI groups
In elderly with advanced-stage NSCLC without known EGFR mutation status, use of EGFR–TKI and chemotherapy resulted in comparable survival benefits. Age was not predictive of worse treatment outcome. The baseline PS should be taken into consideration in the therapeutic decision in elderly with NSCLC where the EGFR mutation status is not known.
PMCID: PMC3837186  PMID: 23929397
Lung cancer; Elderly; Treatment; Outcome
6.  Current and emerging treatment options for Peyronie’s disease 
Peyronie’s disease (PD) is a condition of the penis, characterized by the presence of localized fibrotic plaque in the tunica albuginea. PD is not an uncommon disorder, with recent epidemiologic studies documenting a prevalence of 3–9% of adult men affected. The actual prevalence of PD may be even higher. It is often associated with penile pain, anatomical deformities in the erect penis, and difficulty with intromission. As the definitive pathophysiology of PD has not been completely elucidated, further basic research is required to make progress in the understanding of this enigmatic condition. Similarly, research on effective therapies is limited. Currently, nonsurgical treatments are used for those men who are in the acute stage of PD, whereas surgical options are reserved for men with established PD who cannot successfully penetrate. Intralesional treatments are growing in clinical popularity as a minimally invasive approach in the initial treatment of PD. A surgical approach should be considered when men with PD do not respond to conservative, medical, or minimally invasive therapies for approximately 1 year and cannot have satisfactory sexual intercourse. As scientific breakthroughs in the understanding of the mechanisms of this disease process evolve, novel treatments for the many men suffering with PD are anticipated.
PMCID: PMC3826933  PMID: 24400231
oral therapy; intralesional treatment; topical therapy; extracorporeal shockwave therapy; traction devices; plication; incision and grafting; penile prosthesis
7.  Polyclonal CD4+Foxp3+ Treg cells induce TGFβ-dependent tolerogenic dendritic cells that suppress the murine lupus-like syndrome 
Interplay between Foxp3+ regulatory T cells (Treg) and dendritic cells (DCs) maintains immunologic tolerance, but the effects of each cell on the other are not well understood. We report that polyclonal CD4+Foxp3+ Treg cells induced ex vivo with transforming growth factor beta (TGFβ) (iTreg) suppress a lupus-like chronic graft-versus-host disease by preventing the expansion of immunogenic DCs and inducing protective DCs that generate additional recipient CD4+Foxp3+ cells. The protective effects of the transferred iTreg cells required both interleukin (IL)-10 and TGFβ, but the tolerogenic effects of the iTreg on DCs, and the immunosuppressive effects of these DCs were exclusively TGFβ-dependent. The iTreg were unable to tolerize Tgfbr2-deficient DCs. These results support the essential role of DCs in ‘infectious tolerance’ and emphasize the central role of TGFβ in protective iTreg/DC interactions in vivo.
PMCID: PMC3523557  PMID: 22773728
regulatory T cells; dendritic cells; TGFβ; graft-versus-host disease
8.  Comparison of Cetirizine to Diphenhydramine in the Treatment of Acute Food Allergic Reactions 
PMCID: PMC3205335  PMID: 21945608
antihistamines; diphenhydramine; cetirizine; acute food allergic reactions; oral food challenges
9.  Correlation of specific IgE to shrimp with cockroach and dust mite exposure and sensitization in an inner city population 
Studies have demonstrated that IgE-binding cross-reactive epitopes between shrimp, cockroach and house dust mite tropomyosins can account for the presence of detectable IgE to shrimp in people who have cockroach and dust mite allergies.
We investigated the correlation between IgE-mediated sensitization to shrimp, cockroach, and dust mite in relation to allergen exposure in inner-city children.
Five hundred and four serum samples from the National Cooperative Inner City Asthma Study (NCICAS) were evaluated for specific IgE to shrimp and the results were compared to specific IgE to cockroach (Blattella germanica) and dust mite (Dermatophagoides farinae). Associations between IgE sensitization to these allergens and environmental exposures were determined.
There was a strong positive correlation between shrimp, cockroach, and dust mite IgE levels. High exposure to cockroach (Bla g) in the home, particularly in the bedroom and television room, was significantly correlated with higher shrimp and cockroach IgE levels. In contrast, high exposure to dust mite in the home was highly correlated with IgE to D.farinae, but not with shrimp IgE levels. There is a synergistic relationship between cockroach IgE and exposure in predicting shrimp IgE levels.
For children with evidence of IgE-mediated sensitization to cockroach and shrimp, having high exposure to cockroach in the home can contribute to higher shrimp IgE levels, which may not correlate with clinical reactivity. Further patient evaluations with clinical histories of shrimp exposure and reactions as well as oral food challenges would have to be performed to confirm these findings.
PMCID: PMC3185202  PMID: 21872304
cockroach; dust mite; shrimp; tropomyosin; cross-reactivity
10.  Adoptive Transfer of Induced-Treg Cells Effectively Attenuates Murine Airway Allergic Inflammation 
PLoS ONE  2012;7(7):e40314.
Both nature and induced regulatory T (Treg) lymphocytes are potent regulators of autoimmune and allergic disorders. Defects in endogenous Treg cells have been reported in patients with allergic asthma, suggesting that disrupted Treg cell-mediated immunological regulation may play an important role in airway allergic inflammation. In order to determine whether adoptive transfer of induced Treg cells generated in vitro can be used as an effective therapeutic approach to suppress airway allergic inflammation, exogenously induced Treg cells were infused into ovalbumin-sensitized mice prior to or during intranasal ovalbumin challenge. The results showed that adoptive transfer of induced Treg cells prior to allergen challenge markedly reduced airway hyperresponsiveness, eosinophil recruitment, mucus hyper-production, airway remodeling, and IgE levels. This effect was associated with increase of Treg cells (CD4+FoxP3+) and decrease of dendritic cells in the draining lymph nodes, and with reduction of Th1, Th2, and Th17 cell response as compared to the controls. Moreover, adoptive transfer of induced Treg cells during allergen challenge also effectively attenuate airway inflammation and improve airway function, which are comparable to those by natural Treg cell infusion. Therefore, adoptive transfer of in vitro induced Treg cells may be a promising therapeutic approach to prevent and treat severe asthma.
PMCID: PMC3392250  PMID: 22792275
11.  Children in the New York Inner City Have High Rates of Food Allergy and IgE-Sensitization to Common Foods 
Short summary
IgE-mediated food sensitization and allergy are common in inner city children, even in the absence of reported clinical reactivity. Clinicians caring for this population should maintain a high index of suspicion for food allergy.
PMCID: PMC3129386  PMID: 21555148
food allergy; sensitization; inner city
12.  Food allergies and asthma 
Purpose of review
To consider the possible links between food allergy and asthma.
Recent findings
Food allergy and asthma coexist in many children, and recent studies demonstrate that having these co-morbid conditions increases the risk for morbidity. Children with food allergies and asthma are more likely to have near-fatal or fatal allergic reactions to food and more likely to have severe asthma.
Although a causal link has not been determined, increased awareness of the heightened risks of having both of these common childhood conditions, and good patient/parent education and management of both conditions, can lead to improved outcomes..
PMCID: PMC3155248  PMID: 21467928
food; allergy; asthma; prevalence
13.  Current understanding of egg allergy 
Egg is one of the most important allergens in childhood feeding, and egg allergy can pose quality of life concerns. A clear clinical history and the detection of egg white specific IgE will confirm the diagnosis of IgE-mediated reactions. Non-IgE-mediated symptoms such as in eosinophilic diseases of the gut might also be observed. Egg avoidance and education regarding the treatment of allergic reactions are the cornerstones of management of egg allergy. In this review, we discuss epidemiology, risk factors, diagnosis, treatment and natural history of egg allergy.
PMCID: PMC3069662  PMID: 21453811
Egg; allergy; food; children; hypersensitivity; IgE; ovomucoid; ovalbumin
14.  Food allergy 
Food allergies affect up to 6% of young children and 3%–4% of adults. They encompass a range of disorders that may be IgE and/or non-IgE mediated, including anaphylaxis, pollen food syndrome, food-protein–induced enterocolitis syndrome, food-induced proctocolitis, eosinophilic gastroenteropathies, and atopic dermatitis. Many complex host factors and properties of foods are involved in the development of food allergy. With recent advances in the understanding of how these factors interact, the development of several novel diagnostic and therapeutic strategies is underway and showing promise.
PMCID: PMC3049383  PMID: 21364287
15.  Clinical safety of FAHF-2, and inhibitory effect on basophils from patients with food allergy – extended phase I study 
Food allergy is a common and increasing health concern in westernized countries. No effective treatment is available and accidental ingestion can be life threatening. Food allergy herbal formula-2 (FAHF-2) blocks peanut anaphylaxis in a murine model of peanut-induced anaphylaxis. It was found to be safe, and well tolerated in an acute phase I study of food allergic patients.
To assess the safety of FAHF-2 in an extended phase I clinical trial and determine potential effects on peripheral blood basophils from food allergic patients.
Patients in an open-label study received 3.3 grams (6 tablets) of FAHF-2 three times a day for 6 months. Vital signs, physical examinations, laboratory data, pulmonary function tests and electrocardiographic data were acquired at baseline and at 2 month intervals. During the course of the study, basophil activation and basophil and eosinophil numbers were evaluated using CCR3/ CD63 staining and flow cytometry.
Of eighteen patients enrolled, 14 completed the study. No significant drug-associated differences in laboratory parameters, pulmonary function studies, or electrocardiographic findings before and after treatment were found. There was a significant reduction (p<.010) in basophil CD63 expression in response to ex vivo stimulation at month 6. There was also a trend towards a reduction of eosinophil and basophil numbers after treatment.
FAHF-2 was safe, well-tolerated, and had an inhibitory effects on basophils in an extended phase I clinical study. A controlled phase II study is warranted.
Clinical Implications
FAHF-2 was safe, well-tolerated and inhibited basophils numbers and activation in a 6 month clinical trial for food allergic patients. FAHF-2 may provide a safe immunotherapeutic option for food allergic patients.
Capsule Summary
FAHF-2 was safe and well-tolerated in a six-month phase-I open label clinical trial for food allergy patients. Immunological beneficial effects of FAHF-2 were decreased basophil numbers and inhibition of activation.
PMCID: PMC3229682  PMID: 21794906
Food allergy; FAHF-2; Basophil activation
16.  Effect of marriage on duration of chest pain associated with acute myocardial infarction before seeking care 
Coronary artery disease is the most common cause of death in the Western world, and being married decreases the risk of death from cardiovascular causes. We aimed to determine whether marital status was a predictor of the duration of chest pain endured by patients with acute myocardial infarction before they sought care and whether the patient’s sex modified the effect.
We conducted a retrospective, population-based cohort analysis of patients with acute myocardial infarction admitted to 96 acute care hospitals in Ontario, Canada, from April 2004 to March 2005. We excluded patients who did not experience chest pain. Using multivariable regression analyses, we assessed marital status in relation to delayed presentation to hospital (more than six hours from onset of pain), both overall and stratified by sex. In patients who reported the exact duration of chest pain, we assessed the effect of marital status on the delay in seeking care.
Among 4403 eligible patients with acute myocardial infarction, the mean age was 67.3 (standard deviation 13.6) years, and 1486 (33.7%) were women. Almost half (2037 or 46.3%) presented to a hospital within two hours, and 3240 (73.6%) presented within six hours. Overall, 75.3% (2317/3079) of married patients, 67.9% (188/277) of single patients, 68.5% (189/276) of divorced patients and 70.8% (546/771) of widowed patients presented within six hours of the onset of chest pain. Being married was associated with lower odds of delayed presentation (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.30–0.71, p < 0.001) relative to being single. Among men, the OR was 0.35 (95% CI 0.21–0.59, p < 0.001), whereas among women the effect of marital status was not significant (OR 1.36, 95% CI 0.49–3.73, p = 0.55).
Among men experiencing acute myocardial infarction with chest pain, being married was associated with significantly earlier presentation for care, a benefit that was not observed for married women. Earlier presentation for medical care appears to be one reason for the observed lower risk of cardiovascular death among married men, relative to their single counterparts.
PMCID: PMC3176841  PMID: 21768255
17.  All-Trans Retinoic Acid Promotes TGF-β-Induced Tregs via Histone Modification but Not DNA Demethylation on Foxp3 Gene Locus 
PLoS ONE  2011;6(9):e24590.
It has been documented all-trans retinoic acid (atRA) promotes the development of TGF-β-induced CD4+Foxp3+ regulatory T cells (iTreg) that play a vital role in the prevention of autoimmune responses, however, molecular mechanisms involved remain elusive. Our objective, therefore, was to determine how atRA promotes the differentiation of iTregs.
Methodology/Principal Findings
Addition of atRA to naïve CD4+CD25− cells stimulated with anti-CD3/CD28 antibodies in the presence of TGF-β not only increased Foxp3+ iTreg differentiation, but maintained Foxp3 expression through apoptosis inhibition. atRA/TGF-β-treated CD4+ cells developed complete anergy and displayed increased suppressive activity. Infusion of atRA/TGF-β-treated CD4+ cells resulted in the greater effects on suppressing symptoms and protecting the survival of chronic GVHD mice with typical lupus-like syndromes than did CD4+ cells treated with TGF-β alone. atRA did not significantly affect the phosphorylation levels of Smad2/3 and still promoted iTreg differentiation in CD4+ cells isolated from Smad3 KO and Smad2 conditional KO mice. Conversely, atRA markedly increased ERK1/2 activation, and blockade of ERK1/2 signaling completely abolished the enhanced effects of atRA on Foxp3 expression. Moreover, atRA significantly increased histone methylation and acetylation within the promoter and conserved non-coding DNA sequence (CNS) elements at the Foxp3 gene locus and the recruitment of phosphor-RNA polymerase II, while DNA methylation in the CNS3 was not significantly altered.
We have identified the cellular and molecular mechanism(s) by which atRA promotes the development and maintenance of iTregs. These results will help to enhance the quantity and quality of development of iTregs and may provide novel insights into clinical cell therapy for patients with autoimmune diseases and those needing organ transplantation.
PMCID: PMC3172235  PMID: 21931768
18.  BAFF Promotes Th17 Cells and Aggravates Experimental Autoimmune Encephalomyelitis 
PLoS ONE  2011;6(8):e23629.
BAFF, in addition to promoting B cell survival and differentiation, may affect T cells. The objective of this study was to determine the effect of BAFF on Th17 cell generation and its ramifications for the Th17 cell-driven disease, EAE.
Methodology/Principal Findings
Th17 cells were increased in BAFF-Tg B6 (B6.BTg) mice and decreased in B6.Baff−/− mice. Th17 cells in B6.Baff−/− mice bearing a BAFF Tg (B6.Baff−/−.BTg mice) were identical to those in B6.BTg mice, indicating that membrane BAFF is dispensable for Th17 cell generation as long as soluble BAFF is plentiful. In T + non-T cell criss-cross co-cultures, Th17 cell generation was greatest in cultures containing B6.BTg T cells and lowest in cultures containing B6.Baff−/− T cells, regardless of the source of non-T cells. In cultures containing only T cells, Th17 cell generation followed an identical pattern. CD4+ cell expression of CD126 (IL-6R α chain) was increased in B6.BTg mice and decreased in B6.Baff−/− mice, and activation of STAT3 following stimulation with IL-6 + TGF-β was also greatest in B6.BTg cells and lowest in B6.Baff−/− cells. EAE was clinically and pathologically most severe in B6.BTg mice and least severe in B6.Baff−/− mice and correlated with MOG35–55 peptide-induced Th17 cell responses.
Collectively, these findings document a contribution of BAFF to pathogenic Th17 cell responses and suggest that BAFF antagonism may be efficacious in Th17 cell-driven diseases.
PMCID: PMC3163640  PMID: 21897850
19.  Cutting Edge: All-Trans Retinoic Acid Sustains the Stability and Function of Natural Regulatory T Cells in an Inflammatory Milieu 
Recent studies have demonstrated that plasticity of naturally occurring CD4+Foxp3+ regulatory T cells (nTregs) may account for their inability to control chronic inflammation in established autoimmune diseases. All-trans retinoic acid (atRA), the active derivative of vitamin A, has been demonstrated to promote Foxp3+ Treg differentiation and suppress Th17 development. In this study, we report a vital role of atRA in sustaining the stability and functionality of nTregs in the presence of IL-6. We found that nTregs treated with atRA were resistant to Th17 and other Th cell conversion and maintained Foxp3 expression and suppressive activity in the presence of IL-6 in vitro. atRA decreased IL-6R expression and signaling by nTregs. Of interest, adoptive transfer of nTregs even from arthritic mice treated with atRA suppressed progression of established collagen-induced arthritis. We suggest that nTregs treated with atRA may represent a novel treatment strategy to control established chronic immune-mediated inflammatory diseases.
PMCID: PMC3098624  PMID: 20679534
20.  Role of SMAD and Non-SMAD Signals in the Development of Th17 and Regulatory T Cells 
Whereas TGF-β is essential for the development of peripherally induced Foxp3+ regulatory T cells (iTreg cells) and Th17 cells, the intracellular signaling mechanism by which TGF-β regulates development of both cell subsets is less understood. In this study, we report that neither Smad2 nor Smad3 gene deficiency abrogates TGF-β–dependent iTreg induction by a deacetylase inhibitor trichostatin A in vivo, although the loss of the Smad2 or Smad3 gene partially reduces iTreg induction in vitro. Similarly, SMAD2 and SMAD3 have a redundant role in development of Th17 in vitro and in experimental autoimmune encephalomyelitis. In addition, ERK and/or JNK pathways were shown to be involved in regulating iTreg cells, whereas the p38 pathway predominately modulated Th17 and experimental autoimmune encephalomyelitis induction. Therefore, selective targeting of these intracellular TGF-β signaling pathways during iTreg and Th17 cell development might lead to the development of therapies in treating autoimmune and other chronic inflammatory diseases.
PMCID: PMC3087811  PMID: 20304828
21.  Comparison of the SERT-selective [18F]FPBM and VMAT2-selective [18F]AV-133 radiotracers in a rat model of Parkinson’s Disease 
Nuclear medicine and biology  2010;37(4):479-486.
The utility of [18F]FPBM (2-(2′-((dimethylamino)methyl)-4′-(3-[18F]-fluoropropoxy)phenylthio)benzenamine), a selective serotonin transporter (SERT) tracer, and [18F]AV-133 ((+)-2-Hydroxy-3-isobutyl-9-(3-fluoropropoxy)-10-methoxy-1,2,3,4,6,7-hexahydro-11bH-benzo[a]quinolizine), a selective vesicular monoamine transporter 2 (VMAT2) tracer, were tested in the 6-hydroxydopamine (6-OHDA) unilateral lesioned rat model.
PET imaging of three 6-OHDA unilateral lesioned male Sprague Dawley rats (rats #1-3) were performed with [18F]FPBM and [18F]AV-133 to examine whether changes in SERT and VMAT2 binding, respectively, could be detected in the brain. The brains of the three rats were then removed and examined by in vitro autoradiography with [18F]FPBM and the dopamine transporter ligand, [125I]IPT, for confirmation.
PET image analysis showed varying levels of SERT binding reduction (rat #1 = −11%, rat #2 = −4%, rat #3 = −43%; n = 2) and a clear and definitive loss of VMAT2 binding (rat #1 = −87%, rat #2 = −72%, and rat #3 = −91%; n = 1) in the left striatum when compared to the right (non-lesioned side) striatum. The results from PET imaging were corroborated with quantitative in vitro autoradiography. Rats treated with a selective serotonin toxin (PCA, p-chloroamphetamine) showed a significant reduction of uptake in the cortex and hypothalamus regions of the brain.
The preliminary data suggest that [18F]FPBM and [18F]AV-133 may be useful for the examination of serotonergic and dopaminergic neuron integrity, respectively, in the living brain.
PMCID: PMC2909692  PMID: 20447560
brain imaging; radioligand; SERT; VMAT2; Parkinson’s Disease
22.  Management of the Patient with Multiple Food Allergies 
Food allergies affect 6% of children and 3% to 4% of adults in the United States. Although several studies have examined the prevalence of food allergy, little information is available regarding the prevalence of multiple food allergies. Estimates of prevalence of people allergic to multiple foods is difficult to ascertain because those with allergy to one food may avoid additional foods for concerns related to cross-reactivity, positive tests, or prior reactions, or they may be reluctant to introduce foods known to be common allergens. Diagnosis relies on an accurate history and selective IgE testing. It is important to understand the limitations of the available tests and the role of cross-reactivity between allergens. Allergen avoidance and readily accessible emergency medications are the cornerstones of management. In addition, a multidisciplinary approach to management of individuals with multiple food allergies may be needed, as avoidance of several food groups can have nutritional, developmental, and psychosocial consequences.
PMCID: PMC3071637  PMID: 20431971
Multiple food allergy; IgE; Sensitization; Cross-reactivity; Diagnosis; Allergy management
23.  Correlation of IgE/IgG4 milk epitopes and affinity of milk-specific IgE antibodies with different phenotypes of clinical milk allergy 
Results from large-scale epitope mapping using peptide microarray have been shown to correlate with clinical features of milk allergy.
We sought to assess IgE and IgG4 epitope diversity and IgE affinity in different clinical phenotypes of milk allergy and identify informative epitopes that may be predictive of clinical outcomes of milk allergy.
Forty-one subjects were recruited from a larger study on the effects of ingesting heat-denatured milk proteins in milk-allergic individuals. Using food challenges, subjects were characterized as clinically reactive to all forms of milk (n = 17), tolerant to heated milk (HM) products (n = 16), or outgrown their milk allergy (n = 8). Eleven non-milk allergic, healthy volunteers served as controls. Peptide microarray was performed using the previously published protocol.
Milk allergic subjects had increased epitope diversity as compared to those who outgrew their allergy. HM tolerant subjects had IgE binding patterns similar to those who had outgrown their allergy, but IgG4 binding patterns that were more similar to the allergic group. Binding to higher numbers of IgE peptides was associated with more severe allergic reactions during challenge. There was no association between IgG4 peptides and clinical features of milk allergy. Using a competitive peptide microarray assay, allergic patients demonstrated a combination of high and low affinity IgE binding whereas HM tolerant subjects and those who had outgrown their milk allergy had primarily low affinity binding.
Greater IgE epitope diversity and higher affinity as determined by peptide microarray were associated with clinical phenotypes and severity of milk allergy.
PMCID: PMC2841053  PMID: 20226304
Milk allergy; Peptide microarray; IgE pitope; IgE affinity; IgG4 epitope
24.  Safety, tolerability, and immunologic effects of a food allergy herbal formula in food allergic individuals: a randomized, double-blinded, placebo-controlled, dose escalation, phase 1 study 
Food allergy is a common and serious health problem. A new herbal product, called food allergy herbal formula 2 (FAHF-2), has been demonstrated to have a high safety profile and potent long-term efficacy in a murine model of peanut-induced anaphylaxis.
To evaluate the safety and tolerability of FAHF-2 in patients with food allergy.
In this randomized, double-blinded, placebo-controlled, dose escalation, phase 1 trial, patients received 1 of 3 doses of FAHF-2 or placebo: 2.2 g (4 tablets), 3.3 g (6 tablets), or 6.6 g (12 tablets) 3 times a day for 7 days. Four active and 2 placebo patients were treated at each dose level. Vital signs, physical examination results, laboratory data, pulmonary function test results, and electrocardiogram data were monitored. Immunomodulatory studies were also performed.
Nineteen food allergic participants were included in the study. Two patients (1 in the FAHF-2 group and 1 in the placebo group) reported mild gastrointestinal symptoms. One patient withdrew from the study because of an allergic reaction that was unlikely related to the study medication. No significant differences were found in vital signs, physical examination results, laboratory data, pulmonary function test results, and electrocardiogram data obtained before and after treatment visits. Significantly decreased interleukin (IL) 5 levels were found in the active treatment group after 7 days. In vitro studies of peripheral blood mononuclear cells cultured with FAHF-2 also demonstrated a significant decrease in IL-5 and an increase in culture supernatant interferon γ and IL-10 levels.
FAHF-2 appeared to be safe and well tolerated in patients with food allergy.
PMCID: PMC3026589  PMID: 20642207
25.  Correction: Characterization of Protective Human CD4+CD25+ FOXP3+ Regulatory T Cells Generated with IL-2, TGF-β and Retinoic Acid 
PLoS ONE  2011;6(1):10.1371/annotation/8f29ac57-8219-4ffd-84c9-5e6bf6dcd017.
PMCID: PMC3021482

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