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1.  26 MIR-150 Suppresses Lung Inflammation in a Mouse Model of Experimental Asthma 
Background
Asthma is a complex disorder of the immune system caused by a combination of genetic predisposition with environmental exposures. The environmental factors play a predominant role in the etiology of asthma. It is hypothesized that epigenetic changes in miRNAs play a critical role in pathogenesis of asthma as an interface between genetic makeup and environmental exposures. (Wang, Jia-wang; Li, Kunyu; Hellermann, Gary; Lockey, Richard F.; Mohapatra, Subhra; and Mohapatra, Shyam. Regulating the Regulators: microRNA and Asthma. World Allergy Organization Journal. June 2011, Volume 4, Issue 6).
Methods
In the present study, we used miRNA array profiling in a mouse model of ovalbumin-induced asthma to identify differentially regulated miRNAs and characterized miR-150 in terms of cellular and humoral involvement and analysis of lung inflammation markers.
Results
We found that miR-150 was downregulated in CD4 T lymphocytes during asthmatic inflammation and Th1 and Th2 induction. Over-expression of miR-150 delivered by chitosan nanoparticles inhibited lung inflammation and decreased Th1 and Th2 cytokine levels. miR-150 suppressed Akt3, Cbl1 and Elk1 oncogenes, which are involved in inflammation and cytokine production. Transgenic mice overexpressing miR-150 are resistant to asthma induction, demonstrated by reduced AHR and cytokine inflammation production.
Conclusions
These results suggest that deregulation of miRNAs may be involved in the pathogenesis of asthma and miR-150 may suppress inflammation in asthma by inhibiting cytokine production by downregulating critical genes such as Akt, Elk1 and Cbl1. miR-150 may be an attractive candidate for asthma gene therapy.
doi:10.1097/01.WOX.0000411771.44473.bd
PMCID: PMC3513005
3.  Mir-206 Regulates Pulmonary Artery Smooth Muscle Cell Proliferation and Differentiation 
PLoS ONE  2012;7(10):e46808.
Pulmonary Arterial Hypertension (PAH) is a progressive devastating disease characterized by excessive proliferation of the Pulmonary Arterial Smooth Muscle Cells (PASMCs). Studies suggest that PAH and cancers share an apoptosis-resistant state featuring excessive cell proliferation. MicroRNA-206 (miR-206) is known to regulate proliferation and is implicated in various types of cancers. However, the role of miR-206 in PAH has not been studied. In this study, it is hypothesized that miR-206 could play a role in the proliferation of PASMCs. In the present study, the expression patterns of miR-206 were investigated in normal and hypertensive mouse PASMCs. The effects of miR-206 in modulating cell proliferation, apoptosis and smooth muscle cell markers in human pulmonary artery smooth muscle cells (hPASMCs) were investigated in vitro. miR-206 expression in mouse PASMCs was correlated with an increase in right ventricular systolic pressure. Reduction of miR-206 levels in hPASMCs causes increased proliferation and reduced apoptosis and these effects were reversed by the overexpression of miR-206. miR-206 over expression also increased the levels of smooth muscle cell differentiation markers α-smooth muscle actin and calponin implicating its importance in the differentiation of SMCs. miR-206 overexpression down regulated Notch-3 expression, which is key a factor in PAH development. These results suggest that miR-206 is a potential regulator of proliferation, apoptosis and differentiation of PASMCs, and that it could be used as a novel treatment strategy in PAH.
doi:10.1371/journal.pone.0046808
PMCID: PMC3468623  PMID: 23071643
4.  Multifunctional Magnetic Nanoparticles for Targeted Delivery 
Nanomedicine  2009;6(1):64-69.
A major problem associated with therapy is the inability to deliver pharmaceuticals to a specific site of the body without causing nonspecific toxicity. Development of magnetic nanoparticles and techniques for their safe transport and concentration in specific sites in the body would constitute a powerful tool for gene/drug therapy in vivo. Furthermore, drug delivery in vitro could improve further if the drugs were modified with antibodies, proteins or ligands. For in vivo experiments, magnetic nanoparticles were conjugated with plasmid DNA expressing GFP and then coated with chitosan. These particles were injected into mice through tail vein and directed to heart and kidney by means of external magnets of 25 gauss or 2kA –kA/m. These particles were concentrated in the lungs, heart, and kidney of mice and the expression of GFP in these sites were monitored. The expression of GFP in specific locations was visualized by whole-body fluorescent imaging and the concentration of these particles in the designated body locations was confirmed by transmission electron microscopy. In another model system, we used atrial natriuretic peptide (ANP) and Carcino Embryonic Antigen (CEA) antibodies coupled to the chitosan coated magnetic nanoparticles to target cells in vitro. The present work demonstrates that a simple external magnetic field is all that is necessary to target a drug to a specific site inside the body without the need to functionalize the nanoparticles. However, the option to use magnetic targeting with external magnets on functionalized nanoparticles could prove as a more efficient means of drug delivery.
doi:10.1016/j.nano.2009.04.002
PMCID: PMC3319306  PMID: 19446653
magnetic nanoparticles; gene therapy; iron oxide; localization; chitosan
6.  374 Effectiveness of an Educational Intensive Course on A/I Clinical and Diagnostic Procedures 
The World Allergy Organization Journal  2012;5(Suppl 2):S136-S137.
Background
The U.S.A. Accreditation Council for Graduate Medical Education (ACGME) requires that graduate medical education programs in A/I prepare specialists to provide expert medical care for patients with A/I disorders. The A/I intensive education course (boot camp) program was implemented at the University of South Florida (USF) to facilitate fellows' education of common clinical and diagnostic procedures conducted in the specialty. Educational methods included PowerPoint presentations and demonstration of clinical and diagnostic procedures by faculty and senior fellows and hands-on participation by the fellows-in-training. The topics covered included: anaphylaxis, spirometry, exhaled nitric oxide determination, routine and special skin testing, prescribing and administering immunotherapy, asthma education and inhaler technique, management of atopic dermatitis, food challenge, patch testing, antibiotic desensitization and challenge, principles of treatment with intravenous and subcutaneous gammaglobulin, and special immunology testing.
Methods
Six A/I fellows (four 1st and two 2nd year) participated in the boot camp on July 22, 2011. All completed a 49-item multiple-choice pre-test followed by the boot camp, after which same questions were administered as post-test. Scores were compared by paired t test.
Results
Six participants completed the study. The average number of correct answers increased from 26.3/49 to 39.0/49 with pre- and post-test mean scores of 53.8% and 79.6%, respectively (P = 0.009). There was a significant difference between 1st and 2nd year fellows in test results when comparing pre- and post-test scores (P ≤ 0.05).
Conclusions
An educational boot camp approach integrating theory and practice about A/I clinical and diagnostic procedures significantly increased the competency of A/I fellows at the beginning of their first and second year of training.
doi:10.1097/01.WOX.0000412137.89049.75
PMCID: PMC3512615
7.  382 An Unusual Reaction to Intravenous Iron Sucrose 
Background
Intravenous (IV) iron dextran, the original parenteral iron formulation, is associated with a high incidence of non-IgE mediated hypersensitivity. Newer formulations of IV iron therapies include low molecular weight iron sucrose (IS) and sodium ferric gluconate complex (SFGC) without dextran, reducing severe adverse reactions by 93%. A case of a rare reaction to IV IS associated with generalized skin pruritus and difficulty in breathing is reported.
Methods
A 62-year-old Caucasian male with multiple gastric surgeries, secondary to recurrent gastric ulcers and gastric outlet obstruction, presented with severe iron deficiency anemia (IDA) requiring IV iron therapy.
Results
Chronic malnutrition and malabsorption, associated with difficulty in tolerating oral and jejunostomy tube (J-tube) feedings, resulted in a two month 30 pound weight loss. Oral iron supplementation via a J-tube did not improve the IDA. Prior administrations of IV iron dextran resulted in flushing, generalized urticaria and angioedema associated with pruritus of the face and extremities within ten minutes of infusion.
The allergy/immunology service was consulted. Premedication with IV diphenhydramine, 50 mg, prednisone via J-tube, 32 mg, and IV ranitidine, 50 mg, was followed with slow administration of a test dose of IS, 25 mg, at 1.6 mg/min. Within 30 minutes of the IV IS infusion, symptoms of nausea, flushing, and generalized pruritus, and difficulty in breathing were noted. The infusion was stopped and treatment with IV methyprednisolone, 125 mg, resulted in resolution of the reaction over several hours. No eosinophilia or elevated liver transaminases occurred. Subsequently, the infusion was reattempted: pre-medications consisted of IV methylprednisolone, 60 mg, IV diphenhydramine, 50 mg, and IV ranitidine, 50 mg, 75 minutes prior to the infusion of IS, 275 mg, 1.5 mg/min. Treatment was tolerated without adverse effects.
Conclusions
A rare systemic reaction to IV IS is reported. Pretreatment with methylprednisolone, diphenhydramine and ranitidine 75 minutes before IS infusion was successful.
doi:10.1097/01.WOX.0000412145.27167.07
PMCID: PMC3512674
8.  563 Measurement of Long-acting Natriuretic Peptide (Lanp) in Exacerbation of Asthma 
The World Allergy Organization Journal  2012;5(Suppl 2):S195-S196.
Background
Evidence exists that atrial natriuretic peptide (ANP) is a regulator of smooth muscle airway tone and is a potent bronchodilator and immune modulator in animals. Objective: Long-acting natriuretic peptide (LANP), encoded by the same gene and derived from the same pro-hormone as ANP, was measured in patients with acute asthma exacerbation pre- and post-treatment with systemic or inhaled glucocorticosteroids.
Methods
Measurement of LANP was obtained from plasma samples in 15 subjects with acute asthma exacerbation, by an enzyme immunoassay technique. A repeat measurement of LANP was obtained 5 to 7 and 10 to 14 days after initiation of treatment.
Results
No significant differences were found compared to baseline in plasma LANP level after treatment of the asthma exacerbation (P = 0.8904). The average LANP values were 2.12 higher in the oral glucocorticosteroid group versus the inhaled glucocorticosteroid group, (P = 0.0608). There was no significant difference in LANP levels between male and females (P = 0.5743), with antibiotic use (P = 0.9437), or with age (P = 0.6384).
Conclusions
Plasma LANP level did not differ before and after treatment for an asthma exacerbation. Measuring plasma LANP pro-hormone was not helpful in assessing treatment outcome of asthma exacerbation.
doi:10.1097/01.WOX.0000411678.65031.17
PMCID: PMC3512680
9.  114 A Highly Sensitive and Specific Universal Mirna Profiling Method 
Background
miRNAs can be used as robust biomarkers for diagnosis, staging, prognosis and the response to therapy in various diseases. Although a wide spectrum of miRNA detection techniques have been developed, none can accurately and sensitively perform genome-wide high-throughput miRNA profiling (Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, et al 2005. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 33:e179). This problem stems from that miRNAs are only ∼22 bases, and multiple species of nucleic acids that contain the mature miRNA sequences are present in the total RNA samples that are usually used for miRNA detection.
Methods
A novel RT-qPCR miRNA assay (UQmiR, universally quantitating miRNA) was developed to overcome the difficulty. This assay requires only one RT reaction and one universal set of multiple hydrolysis probes to detect all miRNAs, using one universal RT primer, a common reverse primer, and individual miRNA-specific forward primers. A computer program (MSPPD, miRNA-specific primer and probe designer) was developed for the assay.
Results
The UQmiR has the advantages, but not the disadvantages, of the 2 mostly used miRNA assays. It has the specificity of hydrolysis probe assay and the universal detection of SYBR Green assay. This assay is more sensitive and specific than the commercially available hydrolysis probe assay and SYBR Green assay. Using this method, we have successfully detected 91 out of 96 miRNAs in 0.8 mL of plasma for each miRNA.
Conclusions
This approach affords a highly specific, sensitive, economical and convenient system to profile the expression of all known miRNAs.
doi:10.1097/01.WOX.0000411859.83535.3d
PMCID: PMC3512736
10.  119 Enhancer of Zeste Homolog 2: A Pivotal Role in Pulmonary Artery Smooth Muscle Cell Proliferation 
Background
Pulmonary arterial hypertension (PAH) is a progressive and a devastating disease characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). The pathogenesis of PAH is not fully understood and treatment options are limited. Studies suggest that PAH and cancers share apoptosis resistant state featuring excessive cell proliferation. Proliferation of cancer cells is mediated by increased expression of Enhancer of Zeste Homolog 2 (EZH2), a mammalian histone methyltransferase that contributes to the epigenetic silencing of target genes. However, the role of EZH2 in PAH has not been studied. In this study, we hypothesized that EZH2 could play a role in PASMCs proliferation.
Methods
In the present study the effects of EZH2 overexpression on human PASMCs proliferation were tested. PASMCs were transfected with wild type EZH2 cDNA or GFP using the Lonza 4D nucleofector system. After transfection, cells were incubated for 48 hours at 37°C. PASMCs proliferation and cell cycle analysis were performed by flow cytometry; PASMCs apoptosis was determined using annexin V staining, and cell migration was tested by the wound healing assay. Expression levels of EZH2 were confirmed by real time PCR.
Results
The overexpression of EZH2 in PASMCs enhances proliferation, migration, and decreases the rate of apoptosis when compared to GFP transfected cells. There was a 3.5-fold increase in proliferation and a 1.5-fold increase in the percentage of cells in the G2/M phase in the EZH2 transfected cells while there was a significant decrease in the rate of apoptosis in the PASMCs.
Conclusions
These findings suggest that EZH2 plays a role in the migration and proliferation of PASMCs .It also suggest that EZH2 could play a role in PAH development and serve as a potential target for new therapies for PAH.
doi:10.1097/01.WOX.0000411864.66502.14
PMCID: PMC3512741
11.  183 Incidence of Systemic Reactions (SRS) to Prick (P) and Intradermal (ID) Tests, Response to Immediate (“STAT”) Epinephrine IM (EPI IM) Dose versus BMI, Number of Delayed SRS, and WAO Systemic Reaction Grade 
The World Allergy Organization Journal  2012;5(Suppl 2):S77-S78.
Background
To determine the incidence of SRs to P and ID tests, the response to stat epi IM, number of delayed SRs, the dose of epi IM versus BMI and the World Allergy Organization (WAO) Grade (1-5) of the SRs.
Methods
SRs were compiled from 07/2010 to 06/2011 to P and ID tests for any combination of approximately 20 allergens (pollens, animal emanations, molds and Hymenoptera) in 1,332 subjects. Nurses administered stat epi IM (1:1000 v/v), 0.2 mg IM, into the arm or thigh for any signs or symptoms (SS) of a SR, including, but not limited to, itchy eyes, nose, pharynx, or palms; rhinorrhea, nasal congestion, sneezing; and generalized erythema, skin pruritus, or urticaria. SS (WAO Grade), total epi IM dose, and delayed SRs were recorded. Repeat doses of epi IM were given if SS persisted or worsened.
Results
31 (2%) had SRs: 24 (77%) female, 7 (23%) male; 5 (16%) pediatric, 26 (84%) adult. Of the 31 SRs, 26 (84%) had Grade 1, 5 (16%) Grade 2 and Grades 3 to 5. 13 (42%) experienced SS during P and 18 (58%) during ID or at the completion of P and ID. All received stat epi IM with any SS. 2 BMIs were not available. 28 SRs, with a mean BMI of 28.5 (overweight range 25.0–29.9) received one epi IM, 0.2 mg, and one BMI 20.4 (normal range 18.5–24.9) received 2 epi IM (total 0.3 mg). There were no underweight (less than 18.5) or obese (30.0 or greater) subjects.
Conclusions
31 (2%) had SRs to P and/or ID tests; 30 received one epi IM dose (0.2 mg) and one, 2 doses (0.3 mg total). There were no delayed SRs or relationship of epi IM dose to BMI and all but one were WAO Grade 1 reactions. Stat use of EPI IM may prevent more serious SRs and delayed reactions.
doi:10.1097/01.WOX.0000411940.43848.3c
PMCID: PMC3512750
12.  383 Urticaria and Arthralgias in a Nine-Year-Old with Recurrent Urinary Tract Infections 
Background
Serum sickness is a type III immune complex hypersensitivity reaction occurring after exposure to foreign antigens, most commonly medications. Symptoms typically begin 1 to 3 weeks after initial exposure to the offending agent and include fever, malaise, urticarial or morbilliform rashes and arthralgias which may progress to arthritis, nephritis, neuropathy or vasculitis. We report a case of drug-induced serum sickness in a patient who had previously tolerated trimethoprim/sulfamethoxasole (TMP/SMX) for treatment of recurrent urinary tract infections.
Methods
A 9 year-old female presented with a pruritic, erythematous rash that began 2 days after completing a 10 day course of TMP/SMX for a urinary tract infection. TMP/SMX had previously been prescribed to treat recurrent urinary tract infections without adverse side effects.
Results
Initially she developed a fever and a blotchy rash with patches of erythema which started on the torso and progressed to generalized urticaria over a 24 hour period. Associated symptoms included fatigue, lethargy, generalized myalgias and arthralgias with swelling limited to the left knee, ankles and fingers. No mucosal lesions, nausea, vomiting or diarrhea were present. Pertinent findings on physical examination included mild edema of the left knee without associated erythema or warmth and proximal and distal interphalangeal joints of the hands, wrists, knees and ankles absent of an effusion, but tender to palpation with full range-of-motion. Urticarial lesions with serpiginious borders and central clearing were noted on the trunk and extremities including the palms but not soles. Hyperpigmented areas at sites of previous urticarial lesions were present.
Prednisone, 10 mg 3 times daily, and cetirizine, 10 mg daily, was prescribed and within 24 to 48 hours, all symptoms improved. No further laboratory studies were obtained. Prednisone was tapered over a 2 week period and cetirizine was discontinued simultaneously without recurrence of symptoms. The patient was advised to avoid TMP/SMX indefinitely.
Conclusions
Medications are the most common cause of serum sickness with TMP/SMX being frequently implicated. Immune complex reactions generally occur a few weeks after initial exposure to a medication; however, drug -induced serum sickness should still be considered in cases to which an agent may have been previously tolerated.
doi:10.1097/01.WOX.0000412146.04297.1b
PMCID: PMC3512873
13.  591 A Case of Idiopathic Recurrent Isolated Orbital Angioedema with Exophthalmos 
Background
Idiopathic angioedema is a term applied to recurrent episodes of angioedema of unknown etiology. The following is a case report of idiopathic recurrent isolated orbital angioedema with exophthalmos which responds to prolonged courses of oral corticosteroids.
Methods
A 67 year old Caucasian female with aspirin exacerbated respiratory disease (AERD) sought treatment for an acute, progressive painless left eye swelling with exophthalmos without visual deficits or urticaria. High dose corticosteroids were initiated followed by a low maintenance dose. The swelling subsided after one year of corticosteroid therapy.
Ten years later, orbital swelling with exophthalmos returned in the same eye. No medications, such as aspirin1 or non steroidal anti-inflammatory drugs,2 were associated with the swelling. A CT of the orbits revealed an isolated proptosis with swelling of the medial and inferior rectus muscles and mild hypertrophy and swelling of the left lacrimal gland. A complete history and physical examination were negative. The family history likewise was negative.
Results
High-dose systemic glucocorticoid therapy was initiated. Symptoms resolved after 1 month of tapered corticosteroid therapy, however, swelling reoccurred in the orbit within one week. Low dose maintenance corticosteroids were reinitiated with resolution of the orbital swelling. Work-up for acquired C1 esterase deficiency is negative.
Conclusions
An atypical case of recurrent idiopathic isolated orbital angioedema with exophthalmos in a patient with AERD and no triggering factor, systemic findings and a negative evaluation is presented.
doi:10.1097/01.WOX.0000411706.35430.68
PMCID: PMC3512896
14.  115 Caspase-4 Plays a Role in the Activation of the Cryopyrin/NLRP3 Inflammasome 
Background
The inflammasome is a multi-protein complex which regulates the activation of caspase-1. This activation results in the cleavage and secretion of the IL-1β super family cytokines, IL-1β, IL-18, and IL-33. NLR family-pyrin domain containing- 3 (NLRP3) is a nucleotide binding domain-leucine rich repeat (NLR) family protein responsible for sensitization and oligomerization of the NLRP3 inflammasome complex. Although various damage and pathogen associated patterns have been implicated as stimuli, the exact mechanism of activation has yet to be elucidated. Capase-5, an inflammatory caspase with similar homology to caspase-1, is a key molecule activation of the NLRP1 inflammasome. Caspase-4, an evolutionary duplicate in humans to murine caspase 12 along with caspase 5, is important in IL-1β processing; its involvement with the NLRP3 inflammasome is unknown. We therefore investigated whether caspase-4 plays a role in the activation of the NLRP3 inflammasome.
Methods
Inflammasomes in THP-1 macrophages were activated using Nigericin (10 μg/mL), a bacterial pore causing toxin and NLRP3 inflammasome activator, in the presence or absence of various concentrations (0.1 μM, 1 μM, and 10 μM) of caspase-4 inhibitor, Z-YVAD-FMK. We analyzed the inflammasome activation, caspase-1 cleavage, and IL-1β release by western blot and ELISA analysis.
Results
Our results indicate that inhibition of caspase-4 leads to a dose dependant decrease in IL-1β secretion. In addition, our results show that caspase-4 contributes to IL-1β and caspase-1 cleavage, both of which are hall marks of inflammasome activation.
Conclusions
These findings suggest that caspase-4 is important to the activation of the NLRP3 inflammasome. In modulating the inflammasome, caspase-4 appears to be a druggable target for treatment of chronic inflammatory pulmonary conditions such as allergy and asthma.
doi:10.1097/01.WOX.0000411860.83535.b0
PMCID: PMC3512947
15.  25 Role of Myeloid Derived Suppressor Cells in Asthma 
Background
We know that a heterogeneous group of myeloid cells termed myeloid derived suppressor cells (MDSC) accumulate in almost all pathological conditions, which elicit an inflammatory signal. The exact role played by these cells in asthma is not known. In this study we investigated the function and role of these cells in asthma.
Methods
Accumulation of MDSC and other subsets of myeloid cells were analyzed from peripheral blood mononuclear cells from patients with non-severe asthma (FEV1) >60) and severe asthma (FEV1 <60) by multicolor-flowcytometry and compared to healthy controls. Allergic mouse models were used to determine the role of microRNA-142 (miR-142) in regulation and expansion of MDSC.
Results
There is a significant increase in the proportion of MDSC in severe versus non-severe asthmatics and controls, corresponding to a decrease in myeloid dendritic cells. Allergic mice had significant increased levels of MDSC expansion which were associated with increased levels of IL-6 and downregulation of miR-142. miR-142 overexpression induced MDSC differentiation.
Conclusions
An accumulation of MDSC is associated with severe asthma in humans and mice. In an allergic mouse model, IL-6 levels increase. miR-142 may play an important role in regulation and differentiation of MDSC, leading to altered immunity.
doi:10.1097/01.WOX.0000411770.14047.89
PMCID: PMC3512949
16.  575 Photoaging Attenuates Skin Test Response to Histamine More Than Natural Aging 
Background
Clinical experience suggests that skin test reactivity is often decreased in photo-exposed skin versus sun-protected skin in older individuals. The current study was designed to address whether photoaging or natural aging of skin causes a greater diminution in skin test reponse.
Methods
Prick-puncture skin tests to histamine were performed on sun-exposed and sun-protected areas in younger (n = 61, age 20–50) and older (n = 63, age 60–87) adult volunteers who were recruited for skin prick testing because of suspect allergic rhinitis and/or allergic asthma. The skin was scored for photoaging by physical examination and coloration was measured by a colorimeter.
Results
There was no observed difference in wheal and flare response to histamine when patients were stratified by age alone. However, photoaging was significantly correlated with decreased skin reactivity to histamine on the upper back (a sun-exposed area) as compared to the lower back (a sun-protected area). In patients with the most severely sun-damaged skin, there was a trend toward decreased skin reactivity in all areas.
Conclusions
Skin test reactivity to histamine is negatively correlated to the degree of photoaging and is independent of patients' chronological age. This result has clinical implications for patients with significant photoaging, suggesting that care should be taken to perform skin testing on anatomic sites in sun-protected areas. In patients with severe photoaging, allergen-specific IgE testing should be considered to avoid possible false-negative interpretation of skin-prick testing.
doi:10.1097/01.WOX.0000411690.82064.d7
PMCID: PMC3513004
17.  35 Body Mass Index (BMI) and Immediate (“STAT”) Dose of Epinephrine im (EPI IM) Needed to Treat Subcutaneous Allergen Immunotherapy (SCIT) Systemic Reactions (SRS) 
Background
The purposes of this study are to document the number of SRs to SCIT, the relationship between BMI versus the severity of SRs [World Allergy Organization (WAO) Grade 1 to 5 reactions], and the possible relationship between BMI and the total amount of epi IM needed to treat the SRs.
Methods
This is a retrospective study of SRs to optimal dose SCIT with any combination of approximately 20 allergens (pollens, animal emanations, molds, and Hymenoptera) in 840 subjects representing 13,812 encounters over 12 months (June 2010–May 2011). Nurses administered stat epi IM (1:1000 v/v), 0.2 mg, immediately into the arm or thigh for any systemic signs or symptoms (SS) of a SR, including, but not limited to, itchy eyes, nose, pharynx, palms; rhinorrhea, nasal congestion, sneezing; and generalized erythema, pruritus, or urticaria. Repeat doses of epi IM were administered as necessary.
Results
32 subjects (3.8%) each had one SR: 21 (66%) Grade 1, 10 (31%) Grade 2, 1 (3%) Grade 3, and Grades 4 or 5. BMIs were missing in 3 subjects. Fifteen of 29 were in the normal weight range (BMI 18.5–24.9), 9 Grade 1 (mean epi IM, 0.27 mg) and 6 Grade 2 (mean epi IM, 0.3 mg). Mean epi IM was 0.28 mg. Eight of 29 subjects were overweight (BMI 25–29.9), 7 Grade 1 (mean epi IM, 0.23 mg), and 1 Grade 3 (mean epi IM, 0.3 mg). Mean epi IM was 0.24 mg. Six of 29 were obese (BMI >30), 4 Grade 1 (mean epi IM, 0.3 mg) and 2 Grade 2 (mean epi IM, 0.2 mg). Mean epi IM was 0.27 mg.
Conclusions
SRs occurred in 3.8% of SCIT subjects. No significant association was found between BMI and the WAO Grade severity (P = 0.13 by Fisher's exact test) and BMI and total epi IM dose given (P = 0.82 by Kruskal-Wallis test). BMI should not influence risk assessment of SCIT or IM epi administered for SR.
doi:10.1097/01.WOX.0000411780.59720.8a
PMCID: PMC3513112
18.  85 Clinical Efficacy of Recombinant Human C1 Inhibitor in Patients with Acute Hereditary Angioedema Attacks 
Background
Recombinant human C1 Inhibitor (rhC1INH) has been approved in Europe for the treatment of acute hereditary angioedema attacks. The efficacy of rhC1INH was demonstrated in 2 randomized-controlled trials. Open-label extension studies, where patients could be treated for subsequent HAE attacks, demonstrated continued efficacy for repeated rhC1INH treatments.
Objective
To review the integrated efficacy data of rhC1INH for treatment of acute HAE attacks.
Methods
Efficacy was assessed using patient-reported HAE-specific visual analog scales. The primary endpoint was time to onset of relief of symptoms (VAS decrease ≥20 mm), and the secondary efficacy endpoint was time to minimal symptoms (VAS <20 mm at all locations). Other endpoints included clinical response (relief achieved within 4 hours) and relapse (recurrence of symptoms within 24 hours following initial improvement). Subgroup analyses by attack location were also performed.
Results
The dataset included 141 HAE patients treated for 403 attacks. Median times to the onset of symptom relief for attacks treated with 100 U/kg, 50 U/kg and 2100 U rhC1INH were 66, 60, and 61 minutes, respectively, compared to 495 minutes in the placebo-treated group. Median times for time to minimal symptoms were 266, 240 and 241 minutes for the 100 U/kg, 50 U/kg, and 2100 U rhC1INH-treated attacks respectively compared to 1210 minutes for the placebo-treated attacks. High clinical response rates were observed for the rhC1INH-treated groups (93, 96 and 88% for the 100 U/kg, 50U/kg, and 2100 U respectively) compared to the placebo group (41%). None of the rhC1INH-treated attacks relapsed. Subgroup analysis by attack location showed that abdominal attacks had the fastest median time to onset of symptom relief (50, 36 and 60 minutes for 100 U/kg, 50 U/kg and 2100 U doses respectively), followed by oro-facial-pharyngeal-laryngeal attacks (70, 65 and 120 minutes), and peripheral attacks (75, 84 and 121 minutes). No drug-related serious adverse events or hypersensitivity reactions were observed.
Conclusions
RhC1INH has demonstrated efficacy for the treatment of repeated HAE attacks for all doses tested (100 U/kg, 50 U/kg and 2100 U). Controlled studies did not show additional benefit with doses greater than 50 U/kg. RhC1INH was generally safe and well tolerated.
doi:10.1097/01.WOX.0000411830.69753.fb
PMCID: PMC3513148
19.  Regulating the Regulators: microRNA and Asthma 
One obstacle to developing an effective therapeutic strategy to treat or prevent asthma is that the fundamental causes of asthma are not totally understood. Asthma is thought to be a chronic TH2 immune-mediated inflammatory disease. Epigenetic changes are recognized to play a role in the initiation and maintenance of a TH2 response. MicroRNAs (miRNAs) are key epigenetic regulators of gene expression, and their expression is highly regulated, therefore, deregulation of miRNAs may play an important role in the pathogenesis of asthma. Profiling circulating miRNA might provide the highest specificity and sensitivity to diagnose asthma; similarly, correcting potential defects in the miRNA regulation network may lead to new therapeutic modalities to treat this disease.
doi:10.1186/1939-4551-4-6-94
PMCID: PMC3651079  PMID: 23282474
microRNA; circulating; epigenetics; asthma; biomarkers
20.  Oral curcumin supplementation in patients with atopic asthma 
Allergy & Rhinology  2011;2(2):e51-e53.
Oral curcumin is recognized to have anti-inflammatory properties and has been used by ancient traditional medicine for centuries to treat a variety of diseases. In vitro studies have confirmed the ability of curcumin to inhibit allergic inflammatory cytokine responses from lymphocytes; however, there are no in vivo studies of curcumin to treat inflammation associated with allergic asthma. This study was designed to determine the effect of oral curcumin supplementation on patients with stable, persistent, atopic asthma. Adult patients with stable, persistent asthma with evidence of allergic sensitization were randomized to receive 1000 mg of curcumin twice daily or placebo. Subjects were followed for 6 months and performed monthly spirometry (pre- and postbronchodilator); Asthma Control Test (ACT) scoring; and measurements for fractional excretion of nitric oxide (NO), serum eosinophil count, leukocyte count, total IgE, specific IgE to Dermatophagoides pteronyssinus (Der p) and Dermatophagoides farinae (Der f), use of rescue albuterol, and dose of inhaled corticosteroid. Nine patients were randomized into the treatment arm and six were randomized into the placebo group. No differential response was seen in the treatment and placebo groups regarding the primary end point, postbronchodilator forced expiratory volume in 1 second (FEV1). Similarly, all secondary end point evaluations were not significantly different. Despite in vitro evidence that curcumin has anti-inflammatory properties and can inhibit allergic cytokine responses from lymphocytes in vitro, curcumin, 1000-mg, twice daily supplementation did not significantly affect postbronchodilator FEV1, ACT scores, use of rescue bronchodilator, dose of inhaled corticosteroid, exhaled NO, serum IgE, total white blood cell count specific IgE to Der p or Der f, and blood eosinophils in patients with persistent atopic asthma.
doi:10.2500/ar.2011.2.0016
PMCID: PMC3390116  PMID: 22852117
Allergy; asthma; curcumin; herbal
21.  Interleukin-13 Signaling and Its Role in Asthma 
Asthma affects nearly 300 million people worldwide. The majority respond to inhaled corticosteroid treatment with or without beta-adrenergic agonists. However, a subset of 5 to 10% with severe asthma do not respond optimally to these medications. Different phenotypes of asthma may explain why current therapies show limited benefits in subgroups of patients. Interleukin-13 is implicated as a central regulator in IgE synthesis, mucus hypersecretion, airway hyperresponsiveness, and fibrosis. Promising research suggests that the interleukin-13 pathway may be an important target in the treatment of the different asthma phenotypes.
doi:10.1097/WOX.0b013e31821188e0
PMCID: PMC3651056  PMID: 23283176
interleukin-13; asthma; airway hyper-reactivity; fibrosis; single nucleotide polymorphism
24.  Epinephrine: The Drug of Choice for Anaphylaxis--A Statement of the World Allergy Organization 
The World Allergy Organization Journal  2008;1(Suppl 2):S18-S26.
Anaphylaxis is an acute and potentially lethal multisystem allergic reaction. Most consensus guidelines for the past 30 years have held that epinephrine is the drug of choice and the first drug that should be administered in acute anaphylaxis. Some state that properly administered epinephrine has no absolute contraindication in this clinical setting. A committee of anaphylaxis experts assembled by the World Allergy Organization has examined the evidence from the medical literature concerning the appropriate use of epinephrine for anaphylaxis. The committee strongly believes that epinephrine is currently underused and often dosed suboptimally to treat anaphylaxis, is underprescribed for potential future self-administration, that most of the reasons proposed to withhold its clinical use are flawed, and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate intramuscular doses.
doi:10.1097/1939-4551-1-S2-S18
PMCID: PMC3666145  PMID: 23282530
anaphylaxis; epinephrine; management; prevention
25.  Aspirin-Exacerbated Asthma 
This review focuses on aspirin-exacerbated asthma (AEA). The review includes historical perspective of aspirin, prevalence, pathogenesis, clinical features and treatment of AEA. The pathogenesis of AEA involves the cyclooxygenase and lipooxygenase pathway. Aspirin affects both of these pathways by inhibiting the enzyme cycooxygenase-1 (COX-1). Inhibition of COX-1 leads to a decrease in prostaglandin E2 (PGE2). The decrease in PGE2 results in an increase in cysteinyl leukotrienes by the lipooxygenase pathway involving the enzyme 5-lipooxygenase (5-LO). Leukotriene C4 (LTC4) synthase is the enzyme responsible for the production of leukotriene C4, the chief cysteinyl leukotriene responsible for AEA. There have been familial occurences of AEA. An allele of the LTC4 synthase gene in AEA is known as allele C. Allele C has a higher frequency in AEA. Clinical presentation includes a history of asthma after ingestion of aspirin, nasal congestion, watery rhinorrhea and nasal polyposis. Treatment includes leukotriene receptor antagonists, leukotriene inhibitors, aspirin desinsitaztion and surgery. AEA is the most well-defined phenotype of asthma. Although AEA affects adults and children with physician-diagnosed asthma, in some cases there is no history of asthma and AEA often goes unrecognized and underdiagnosed.
doi:10.1186/1710-1492-4-2-75
PMCID: PMC2868885  PMID: 20525128
aspirin desensitization; aspirin exacerbated asthma; aspirin exacerbated respiratory disease; aspirin sensitive asthma; cysteinyl leukotriene; leukotriene; leukotriene C4; leukotriene C4 synthase

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