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1.  Beta-escin has potent anti-allergic efficacy and reduces allergic airway inflammation 
BMC Immunology  2010;11:24.
Type I hypersensitivity is characterized by the overreaction of the immune system against otherwise innocuous substances. It manifests as allergic rhinitis, allergic conjunctivitis, allergic asthma or atopic dermatitis if mast cells are activated in the respective organs. In case of systemic mast cell activation, life-threatening anaphylaxis may occur. Currently, type I hypersensitivities are treated either with glucocorticoids, anti-histamines, or mast cell stabilizers. Although these drugs exert a strong anti-allergic effect, their long-term use may be problematic due to their side-effects.
In the course of a routine in vitro screening process, we identified beta-escin as a potentially anti-allergic compound. Here we tested beta-escin in two mouse models to confirm this anti-allergic effect in vivo. In a model of the early phase of allergic reactions, the murine passive cutaneous anaphylaxis model, beta-escin inhibited the effects of mast cell activation and degranulation in the skin and dose-dependently prevented the extravasation of fluids into the tissue. Beta-escin also significantly inhibited the late response after antigen challenge in a lung allergy model with ovalbumin-sensitized mice. Allergic airway inflammation was suppressed, which was exemplified by the reduction of leucocytes, eosinophils, IL-5 and IL-13 in the bronchoalveolar lavage fluid. Histopathological examinations further confirmed the reduced inflammation of the lung tissue. In both models, the inhibitory effect of beta-escin was comparable to the benchmark dexamethasone.
We demonstrated in two independent murine models of type I hypersensitivity that beta-escin has potent anti-allergic properties. These results and the excellent safety profile of beta-escin suggest a therapeutic potential of this compound for a novel treatment of allergic diseases.
PMCID: PMC2898835  PMID: 20487574
2.  Salicylate intolerance: a masquerader of multiple adverse drug reactions 
BMJ Case Reports  2009;2009:bcr02.2009.1602.
A female in her early 50s presented with a long-standing history of episodic urticaria and angioedema. She also reported urticarial reactions after ingestion of aspirin, prednisone and multiple antibiotics. These medications were all taken during upper respiratory tract infections. An elimination diet followed by a series of open challenges to food chemicals demonstrated an urticarial eruption following the ingestion of mints, which contain high levels of salicylates. A double-blinded placebo-controlled challenge to salicylate confirmed her sensitivity and explained her reaction to aspirin. The patient informed her treating physician of her copious ingestion of mints during upper respiratory tract infections. Drug hypersensitivity to antibiotics and prednisone was excluded on the basis of negative radioallergosorbent tests (RASTs) and/or absent skin-test responses and/or tolerance to oral challenges. This patient had a salicylate intolerance that caused her episodic urticaria and angioedema, and also masqueraded as a drug allergy due to the concurrent ingestion of mints.
PMCID: PMC3027804  PMID: 21918670
3.  A-Type GABA Receptor as a Central Target of TRPM8 Agonist Menthol 
PLoS ONE  2008;3(10):e3386.
Menthol is a widely-used cooling and flavoring agent derived from mint leaves. In the peripheral nervous system, menthol regulates sensory transduction by activating TRPM8 channels residing specifically in primary sensory neurons. Although behavioral studies have implicated menthol actions in the brain, no direct central target of menthol has been identified. Here we show that menthol reduces the excitation of rat hippocampal neurons in culture and suppresses the epileptic activity induced by pentylenetetrazole injection and electrical kindling in vivo. We found menthol not only enhanced the currents induced by low concentrations of GABA but also directly activated GABAA receptor (GABAAR) in hippocampal neurons in culture. Furthermore, in the CA1 region of rat hippocampal slices, menthol enhanced tonic GABAergic inhibition although phasic GABAergic inhibition was unaffected. Finally, the structure-effect relationship of menthol indicated that hydroxyl plays a critical role in menthol enhancement of tonic GABAAR. Our results thus reveal a novel cellular mechanism that may underlie the ambivalent perception and psychophysical effects of menthol and underscore the importance of tonic inhibition by GABAARs in regulating neuronal activity.
PMCID: PMC2560999  PMID: 18852885
4.  Comparison of Desensitizing Efficacy of an Iranian Dentifrice and a Commercially Available Dentifrice: A Randomized Double-Blinded Controlled Clinical Trial 
The aim of this randomized controlled clinical trial was to investigate the effect of a new Iranian toothpaste and a commercially available toothpaste containing desensitizing agent (5% potassium nitrate) on dentine hypersensitivity in a 24-week study.
Materials and Methods:
Fifty healthy volunteers, who had at least two sensitive root surfaces, completed the study period. The participants were randomly given one of the two toothpastes; Iranian (antihypersensitive Pooneh) or commercially available (fresh mint Sensodyne) toothpaste. Visual analogue scales (VASs) indicating the intensity of tooth hypersensitivity responding to tactile, airblast and cold-water stimuli were examined at baseline and weeks 2, 4, 12 and 24.
Overall, VAS scores for tactile, airblast, and cold-water tests significantly reduced compared with the baseline in both groups (all P values <0.001).
However, there was no significant difference between the two groups regarding the measured parameters.
This study demonstrated that the Iranian dentifrice (antihypersensitive Pooneh) was as effective as the commercially available one (fresh mint Sensodyne) in reducing tooth hypersensitivity.
PMCID: PMC3875509  PMID: 24396354
Clinical Trial; Potassium Nitrate; Dentin Hypersensitivity; Toothpaste
5.  Persistence of increased mast cell numbers in tissues links dermatitis to enhanced airway disease in a mouse model of atopy† 
The development of chronic allergic dermatitis in early life has been associated with increased onset and severity of allergic asthma later in life. However, the mechanisms linking these two diseases are poorly understood. Here, we report that the development of oxazolone-induced chronic allergic dermatitis, in a mouse model, caused enhanced ovalbumin-induced allergic asthma after resolution of the former disease. Our findings show that oxazolone-induced dermatitis caused a marked increase in tissue mast cells, which persisted long after the resolution of this disease. Subsequent ovalbumin sensitization and airway challenge of mice that had recovered from dermatitis resulted in increased allergic airway hyperreactivity. The findings demonstrate that the accumulation of mast cells during dermatitis has the detrimental effect of increasing allergic airway hypersensitivity. Importantly, our findings also show that exposure to a given allergen can modify the immune response to an unrelated allergen.
PMCID: PMC3253240  PMID: 22180615
Allergy; Fc receptors; IgE; Mast cells/basophils; Skin; Rodent
6.  Flavored and Nonflavored Smokeless Tobacco Products: Rate, Pattern of Use, and Effects 
Nicotine & Tobacco Research  2012;15(1):88-92.
The initiation and maintenance of tobacco use are influenced by several factors, but of equal and often overlooked importance, until recently, is the palatability of the product. Because of the role that flavor may play in the initiation and maintenance of tobacco use, the Food and Drug Administration has decided to ban the use of flavorings, other than menthol, from cigarettes. To date, little attention has been paid to the impact of flavoring in smokeless tobacco (ST) products.
This study combined the data from 5 previously completed treatment or switching studies to examine the choice of brand flavor in the course of ST use, from initiation to regular use.
The analyses revealed that a majority of subjects’ first and current choice of product was flavored, specifically mint or wintergreen, and that a significant number of ST users switched to a flavored brand after already initiating ST use with a regular nonflavored product. In this population, however, flavored products did not appear to lead to greater dependence or increased exposure to nicotine or carcinogens.
More treatment seeking ST users began by using mint-flavored product and switched to and were current users of mint-flavored products. It is possible that mint products play a role in the initiation and maintenance of ST use.
PMCID: PMC3524058  PMID: 22529222
7.  Th-17/Tc-17 infiltration and associated cytokine gene expression in elicitation phase of allergic contact dermatitis 
The British journal of dermatology  2009;161(6):1301-1306.
Allergic contact dermatitis is a typical delayed-type hypersensitivity to sensitizing haptens mediated by T cells. Th1/Tc1 cells are currently considered to be the primary effectors in allergic contact dermatitis. There is little information concerning the role played in allergic contact dermatitis in humans by Th-17/Tc-17 cells, a recently defined subpopulation of effector T cells.
In the present report we attempted to characterize Th-17/Tc-17 cells in the infiltrates of the skin in elicitation phase of allergic contact dermatitis.
Th-17 as well as Th1/Th2 cytokine gene expression was examined by semi-quantitative real-time polymerase chain reaction in paired samples of positive patch test biopsies and normal skins from 11 patients allergic to 9 different allergens. The in situ characterization of IL-17-producing cells was carried out using anti-RORC and anti-T cell subset antibodies by double immunofluorescence.
Compared to normal paired skins, gene expression of transcription factor for human Th-17 cells, RORC, and Th-17-related cytokines IL-17A, IL-17F and IL-23, was significantly increased in positive patch test biopsies. The mRNA for IFN-γ and IL-4 was also increased. In the dermal infiltrates, about 20 % of the infiltrating cells were IL-17-producing cells as they expressed RORC, and such RORC expressing cells were detected in both CD4+ (~30%) and CD8+ (~20%) subsets.
This is the first demonstration of Th-17/Tc-17 cells in the elicitation phase of human allergic contact dermatitis, showing that they are a regular participant in the immunopathology of this common allergic reaction regardless of the nature of the triggering allergens.
PMCID: PMC3130797  PMID: 19785613
Allergic contact dermatitis; IL-17; Th-17 lymphocytes; patch test; RORC
8.  Langerhans cells protect from allergic contact dermatitis in mice by tolerizing CD8+ T cells and activating Foxp3+ regulatory T cells  
The Journal of Clinical Investigation  2012;122(5):1700-1711.
Allergic contact dermatitis is the most frequent occupational disease in industrialized countries. It is caused by CD8+ T cell–mediated contact hypersensitivity (CHS) reactions triggered at the site of contact by a variety of chemicals, also known as weak haptens, present in fragrances, dyes, metals, preservatives, and drugs. Despite the myriad of potentially allergenic substances that can penetrate the skin, sensitization is relatively rare and immune tolerance to the substance is often induced by as yet poorly understood mechanisms. Here we show, using the innocuous chemical 2,4-dinitrothiocyanobenzene (DNTB), that cutaneous immune tolerance in mice critically depends on epidermal Langerhans cells (LCs), which capture DNTB and migrate to lymph nodes for direct presentation to CD8+ T cells. Depletion and adoptive transfer experiments revealed that LCs conferred protection from development of CHS by a mechanism involving both anergy and deletion of allergen-specific CD8+ T cells and activation of a population of T cells identified as ICOS+CD4+Foxp3+ Tregs. Our findings highlight the critical role of LCs in tolerance induction in mice to the prototype innocuous hapten DNTB and suggest that strategies targeting LCs might be valuable for prevention of cutaneous allergy.
PMCID: PMC3336977  PMID: 22523067
9.  Therapeutic Efficacy and Immunological Response of CCL5 Antagonists in Models of Contact Skin Reaction 
PLoS ONE  2010;5(1):e8725.
Skin-infiltrating T-cells play a predominant role in allergic and inflammatory skin diseases such as atopic dermatitis, psoriasis and allergic contact dermatitis. These T-cells are attracted by several chemotactic factors including the chemokine CCL5/RANTES, a CC chemokine inducing both the migration and activation of specific leukocyte subsets. CCL5 has been found to be associated with various cell-mediated hypersensitive disorders such as psoriasis, atopic dermatitis and irritant contact dermatitis. We have used two antagonists, the first, Met-CCL5, a dual CCR1/CCR5 antagonist and the second, a variant in which GAG binding is abrogated, 44AANA47-CCL5, which acts as a dominant negative inhibitor of CCL5. The antagonists were tested in two models of contact skin reaction. The first, irritant contact dermatitis (ICD) is a pathological non-specific inflammatory skin condition arising from the release of pro-inflammatory cytokines by keratinocytes in response to haptens, usually chemicals. The second, contact hypersensitivity (CHS) is a T-cell dependent model, mimicking in part the T-cell-mediated skin diseases such as psoriasis. In both models, the CCL5 antagonists showed therapeutic efficacy by reducing swelling by 50% as well as the reduction of soluble mediators in homogenates derived from challenged ears. These results demonstrate that blocking the receptor or the ligand are both effective strategies to inhibit skin inflammation.
PMCID: PMC2806914  PMID: 20090949
10.  Modulation of Thermoreceptor TRPM8 by Cooling Compounds 
ACS Chemical Neuroscience  2012;3(4):248-267.
ThermoTRPs, a subset of the Transient Receptor Potential (TRP) family of cation channels, have been implicated in sensing temperature. TRPM8 and TRPA1 are both activated by cooling. TRPM8 is activated by innocuous cooling (<30 °C) and contributes to sensing unpleasant cold stimuli or mediating the effects of cold analgesia and is a receptor for menthol and icilin (mint-derived and synthetic cooling compounds, respectively). TRPA1 (Ankyrin family) is activated by noxious cold (<17 °C), icilin, and a variety of pungent compounds. Extensive amount of medicinal chemistry efforts have been published mainly in the form of patent literature on various classes of cooling compounds by various pharmaceutical companies; however, no prior comprehensive review has been published. When expressed in heterologous expression systems, such as Xenopus oocytes or mammalian cell lines, TRPM8 mediated currents are activated by a number of cooling compounds in addition to menthol and icilin. These include synthetic p-menthane carboxamides along with other class of compounds such as aliphatic/alicyclic alcohols/esters/amides, sulphones/sulphoxides/sulphonamides, heterocyclics, keto-enamines/lactams, and phosphine oxides. In the present review, the medicinal chemistry of various cooling compounds as activators of thermoTRPM8 channel will be discussed according to their chemical classes. The potential of these compounds to emerge as therapeutic agents is also discussed.
PMCID: PMC3369806  PMID: 22860192
Thermoreceptors; TRPM8; TRPA1; cooling compounds; menthol; icilin
11.  The effects of peppermint on exercise performance 
Enhancing athletic performance is a great desire among the athletes, coaches and researchers. Mint is one of the most famous natural herbs used for its analgesic, anti-inflammatory, antispasmodic, antioxidant, and vasoconstrictor effects. Even though inhaling mint aroma in athletes has been investigated, there were no significant effects on the exercise performance.
Twelve healthy male students every day consumed one 500 ml bottle of mineral water, containing 0.05 ml peppermint essential oil for ten days. Blood pressure, heart rate, and spirometry parameters including forced vital capacity (FVC), peak expiratory flow rate (PEF), and peak inspiratory flow (PIF) were determined one day before, and after the supplementation period. Participants underwent a treadmill-based exercise test with metabolic gas analysis and ventilation measurement using the Bruce protocol.
The FVC (4.57 ± 0.90 vs. 4.79 ± 0.84; p < 0.001), PEF (8.50 ± 0.94 vs. 8.87 ± 0.92; p < 0.01), and PIF (5.71 ± 1.16 vs. 6.58 ±1.08; p < 0.005) significantly changed after ten days of supplementation. Exercise performance evaluated by time to exhaustion (664.5 ± 114.2 vs. 830.2 ± 129.8 s), work (78.34 ±32.84 vs. 118.7 ± 47.38 KJ), and power (114.3 ± 24.24 vs. 139.4 ± 27.80 KW) significantly increased (p < 0.001). In addition, the results of respiratory gas analysis exhibited significant differences in VO2 (2.74 ± 0.40 vs. 3.03 ± 0.351 L/min; p < 0.001), and VCO2 (3.08 ± 0.47 vs. 3.73 ± 0.518 L/min; p < 0.001).
The results of the experiment support the effectiveness of peppermint essential oil on the exercise performance, gas analysis, spirometry parameters, blood pressure, and respiratory rate in the young male students. Relaxation of bronchial smooth muscles, increase in the ventilation and brain oxygen concentration, and decrease in the blood lactate level are the most plausible explanations.
PMCID: PMC3607906  PMID: 23517650
Peppermint essential oil; Exercise performance; Respiratory gas analysis; Spirometry
12.  Erythema Multiforme Following Application of Hair Dye 
Indian Journal of Dermatology  2012;57(3):230-232.
Erythema multiforme (EM) is an acute mucocutaneous hypersensitivity reaction with varying degrees of blistering and ulceration. Common causes of EM are herpes simplex virus infection, mycoplasma infection, drug hypersensitivity, vaccination and drug–virus interaction. EM induced by contact dermatitis is rare. Paraphenylene diamine, a common ingredient in many hair dyes, is well known to produce allergic contact dermatitis. We report a 35-year-old lady presenting with EM following severe contact dermatitis to hair dye. So far as we know, this is the first report from India describing EM following contact dermatitis.
PMCID: PMC3371533  PMID: 22707781
Contact dermatitis; erythema multiforme; hair dye
13.  Allergic hemiglossitis as a unique case of food allergy: a case report 
A unique case of topical food allergy is presented with unilateral swelling of the tongue with ulceration. Only one similar case has been reported in 1972.
Case presentation
76 years old female patient presented at the Emergency Department with a unilateral painful swelling and ulcerations of the tongue after eating mint chocolate. However the swelling did not compromised the airways the presentation was rather frightening for the patient. The allergic reaction responded to the parenteral steroid and oral chlorphenamine treatment and the three month follow up only revealed minimal scar formations.
Unilateral hemiglossitis is a rare form of allergic reactions which is usually self-limiting with full recovery of which takes an unusually long time.
PMCID: PMC2291062  PMID: 18321388
14.  Metal Allergy and Systemic Contact Dermatitis: An Overview 
Contact dermatitis is produced by external skin exposure to an allergen, but sometimes a systemically administered allergen may reach the skin and remain concentrated there with the aid of the circulatory system, leading to the production of systemic contact dermatitis (SCD). Metals such as nickel, cobalt, chromium, and zinc are ubiquitous in our environment. Metal allergy may result in allergic contact dermatitis and also SCD. Systemic reactions, such as hand dermatitis or generalized eczematous reactions, can occur due to dietary nickel or cobalt ingestion. Zinc-containing dental fillings can induce oral lichen planus, palmoplantar pustulosis, and maculopapular rash. A diagnosis of sensitivity to metal is established by epicutaneous patch testing and oral metal challenge with metals such as nickel, cobalt, chromium, and zinc. In vitro tests, such as the lymphocyte stimulating test (LST), have some advantages over patch testing to diagnose allergic contact dermatitis. Additionally, the determination of the production of several cytokines by primary peripheral blood mononuclear cell cultures is a potentially promising in vitro method for the discrimination of metal allergies, including SCD, as compared with the LST.
PMCID: PMC3369403  PMID: 22693488
15.  Gastrokine 1 Expression in the Human Gastric Mucosa Is Closely Associated with the Degree of Gastritis and DNA Methylation 
Journal of Gastric Cancer  2013;13(4):232-241.
Gastrokine 1 plays an important role in gastric mucosal defense. Additionally, the Gastrokine 1-miR-185-DNMT1 axis has been shown to suppress gastric carcinogenesis through regulation of epigenetic alteration. Here, we investigated the effects of Gastrokine 1 on DNA methylation and gastritis.
Materials and Methods
Expression of Gastrokine 1, DNMT1, EZH2, and c-Myc proteins, and the presence of Helicobacter pylori CagA protein were determined in 55 non-neoplastic gastric mucosal tissue samples by western blot analysis. The CpG island methylation phenotype was also examined using six markers (p16, hMLH1, CDH1, MINT1, MINT2 and MINT31) by methylation-specific polymerase chain reaction. Histological gastritis was assessed according to the updated Sydney classification system.
Reduced Gastrokine 1 expression was found in 20 of the 55 (36.4%) gastric mucosal tissue samples and was closely associated with miR-185 expression. The Gastrokine 1 expression level was inversely correlated with that of DNMT1, EZH2, and c-Myc, and closely associated with the degree of gastritis. The H. pylori CagA protein was detected in 26 of the 55 (47.3%) gastric mucosal tissues and was positively associated with the expression of DNMT1, EZH2, and c-Myc. In addition, 30 (54.5%) and 23 (41.9%) of the gastric mucosal tissues could be classified as CpG island methylation phenotype-low and CpG island methylation phenotype-high, respectively. Reduced expression of Gastrokine 1 and miR-185, and increased expression of DNMT1, EZH2, and c-Myc were detected in the CpG island methylation phenotype-high gastric mucosa.
Gastrokine 1 has a crucial role in gastric inflammation and DNA methylation in gastric mucosa.
PMCID: PMC3915185  PMID: 24511419
Gastrokine 1; DNA methylation; microRNA-185; CagA protein; Gastric mucosa
16.  Allergic Urticaria: A Case Report of Rare Skin Allergy with a Common Mouthwash 
Chlorhexidine is a widely used antiseptic and disinfectant in medical and non-medical environments. Compared to its ubiquitous use, allergic contact dermatitis from chlorhexidine has rarely been reported and so its sensitization rate seems to be low. Chlorhexidine has been used for more than 50 years but it was only in the last two decades, that reports of immediate- type reactions to chlorhexidine were seen. Reactions ranging from localized urticaria to anaphylactic shock and hypersensitivity reactions, including delayed hypersensitivity reactions such as contact dermatitis, fixed drug eruptions, and photosensitivity reactions, began to appear more frequently. However the prevalence of contact urticaria and anaphylaxis due to chlorhexidine remains to be unknown. In this case report we have reported a case of urticaria due to oral use of chlorhexidine. The adverse reaction was confirmed by a skin prick test.
PMCID: PMC3555388  PMID: 23372227
Chlorhexidine; Allergic contact dermatitis; chlorhexidine Urticaria; delayed hypersensitivity; urticaria
17.  Dissection of antigenic and irritative effects of epicutaneously applied haptens in mice. Evidence that not the antigenic component but nonspecific proinflammatory effects of haptens determine the concentration-dependent elicitation of allergic contact dermatitis. 
Journal of Clinical Investigation  1996;98(5):1158-1164.
Allergic contact dermatitis differs from most other immune reactions by its strict dose dependence during the elicitation phase. Moreover, almost all known contact allergens can also induce dose-dependent irritative dermatitis and in general only elicit allergic contact dermatitis in sensitized individuals when applied within a narrow dose range. Therefore, we hypothesized that elicitation of contact hypersensitivity (CHS) may require two signals, antigen-specific effector cell activation and a non-antigen-specific proinflammatory signal, both of which are provided by application of a sufficient dose of hapten. To dissociate these putative two signals, oxazolone-sensitized mice were ear challenged with a dose of the specific hapten which was too low to elicit CHS. At the same time, an unrelated hapten was applied in a conventional concentration to the same skin site. Whereas neither treatment alone elicited a significant CHS response, application of both compounds together resulted in a strong CHS response that was indistinguishable from that elicited by the full dose of the specific hapten. Upon coadministration of the irrelevant hapten, allergic contact dermatitis could be elicited even when the dose of the specific hapten was further reduced by a factor of 10(3). In contrast, a dose reduction of the irrelevant hapten by a factor of two resulted in the loss of the CRS response. These data indicate that non-antigen-specific effects of epicutaneously applied haptens significantly contribute to the elicitation of CHS responses and that the capacity of the hapten to evoke this proinflammatory stimulus rather than its antigenicity is responsible for the strict concentration dependence.
PMCID: PMC507538  PMID: 8787679
18.  Diet and Dermatitis: Food Triggers 
Given increasing awareness of the link between diet and health, many patients are concerned that dietary factors may trigger dermatitis. Research has found that dietary factors can indeed exacerbate atopic dermatitis or cause dermatitis due to systemic contact dermatitis. In atopic dermatitis, dietary factors are more likely to cause an exacerbation among infants or children with moderate-to-severe atopic dermatitis relative to other populations. Foods may trigger rapid, immunoglobulin E-mediated hypersensitivity reactions or may lead to late eczematous reactions. While immediate reactions occur within minutes to hours of food exposure, late eczematous reactions may occur anywhere from hours to two days later. Screening methods, such as food allergen-specific serum immunoglobulin E tests or skin prick tests, can identify sensitization to specific foods, but a diagnosis of food allergy requires specific signs and symptoms that occur reproducibly upon food exposure. Many patients who are sensitized will not develop clinical findings upon food exposure; therefore, these tests may result in false-positive tests for food allergy. This is why the gold standard for diagnosis remains the double-blind, placebo-controlled food challenge. In another condition, systemic contact dermatitis, ingestion of a specific food can actually cause dermatitis. Systemic contact dermatitis is a distinct T-cell mediated immunological reaction in which dietary exposure to specific allergens results in dermatitis. Balsam of Peru and nickel are well-known causes of systemic contact dermatitis, and reports have implicated multiple other allergens. This review seeks to increase awareness of important food allergens, elucidate their relationship with atopic dermatitis and systemic contact dermatitis, and review available diagnostic and treatment strategies.
PMCID: PMC3970830
19.  The health effects of menthol cigarettes as compared to non-menthol cigarettes 
Tobacco Induced Diseases  2011;9(Suppl 1):S7.
Since the 1920s, menthol has been added to cigarettes and used as a characterizing flavor. The health effects of cigarette smoking are well documented, however the health effects of menthol cigarettes as compared to non-menthol cigarettes is less well studied. This review discusses menthol’s effects on 1) biomarkers of tobacco smoke exposure, 2) toxicity and cellular effects, 3) lung function and respiration, 4) pulmonary and/or vascular function, 5) allergic reactions and inflammation, and 6) tobacco-related diseases. It is concluded that menthol is a biologically active compound that has effects by itself and in conjunction with nicotine, however much of the data on the other areas of interest are inconclusive and firm conclusions cannot be drawn.
PMCID: PMC3102906  PMID: 21624153
20.  Gum Arabic as a Cause of Occupational Allergy 
Journal of Allergy  2011;2011:841508.
Background. Gum arabic is a potential sensitizer in food industry. Methods. We examined 11 candy factory workers referred to examinations due to respiratory and skin symptoms paying attention to exposure and sensitization to gum arabic. Skin tests, pulmonary function tests, and respiratory provocation tests were carried out as indicated by the symptoms and findings. Results. Occupational asthma, caused by gum arabic was diagnosed in 4/11 candy factory workers and two of them had also occupational contact urticaria and one had occupational rhinitis. One of them had oral symptoms associated with ingestion of products containing gum arabic. Conclusions. Airborne exposure to gum arabic may cause sensitization leading to allergic rhinitis, asthma, and urticaria.
PMCID: PMC3124965  PMID: 21747872
21.  The Role of the Left Inferior Frontal Gyrus in Implicit Semantic Competition and Selection: An Event-Related fMRI Study 
Brain research  2008;1229:167-178.
Recent research suggests that the left inferior frontal gyrus (LIFG) plays a role in selecting semantic information from among competing alternatives. A key question remains as to whether the LIFG is engaged by the selection of semantic information only or by increased semantic competition in and of itself, especially when such competition is implicit in nature. Ambiguous words presented in a lexical context provide a means of examining whether the LIFG is recruited under conditions when contextual cues constrain selection to only the meaning appropriate to the context (e.g., coin-mint-money) or under conditions of increased competition when contextual cues do not allow for the resolution to a particular meaning (e.g., candy-mint-money). In this event-related fMRI study, an implicit task was used in which subjects made lexical (i.e., word/nonword) decisions on the third stimulus of auditorily-presented triplets in conditions where the lexical context either promoted resolution toward a particular ambiguous word meaning or enhanced the competition among ambiguous word meanings. LIFG activation was observed when the context allowed for the resolution of competition and hence the selection of one meaning (e.g., coin-mint-money) but failed to emerge when competition between the meanings of an ambiguous word was unresolved by the context (e.g., candy-mint-money). In the latter case, there was a pattern of reduced activation in frontal, temporal and parietal areas. These findings demonstrate that selection or resolution of competition as opposed to increased semantic competition alone engages the LIFG. Moreover, they extend previous work in showing that the LIFG is recruited even in cases where the selection of meaning takes place implicitly.
PMCID: PMC2566953  PMID: 18656462
fMRI; left inferior frontal gyrus; left superior temporal gyrus; semantic ambiguity; semantic competition; semantic selection
22.  Influence of the Chungkookjang on histamine-induced wheal and flare skin response: a randomized, double-blind, placebo controlled trial 
Allergic disease is a consequence of exposure to normally innocuous substances that elicit the activation of mast cells. Mast-cell-mediated allergic response is involved in many diseases such as anaphylaxis, urticaria, allergic rhinitis, asthma and allergic dermatitis. The development of food products for the prevention of allergic disease is an important subject in human health. The chungkookjang (CKJ) has been reported to exhibit antiallergic inflammatory activity. Therefore, the aim of the study is to examine the effects of the CKJ to reduce histamine-induced wheal and flare skin responses.
A randomized, double-blind, placebo-controlled study in 60 healthy subjects will be carried out. Sixty volunteers (aged 20-80) who gave a written consent before entering the study will be randomized in two groups of thirty subjects each. The skin prick test with histamine solution of 10 mg/ml will be performed on the ventral forearm, 10 cm from the elbow. The subjects will be instructed to take 35 g per day of either the CKJ pills or a placebo pills for a period of 3 months. Diameters of wheal and flare will be assessing 15 minutes after performing the above-mentioned skin prick test. The primary outcome is change in wheal and flare responses. Secondary outcomes will be include change in serum histamine, immunoglobulin E, cytokines (interferon-gamma, interleukin-4, -10, and tumor necrosis factor-alpha), and eosinophil cationic protein.
This study will show the potential anti-inflammatory properties of the CKJ in their skin activity when histamine is the challenging agent as occurs in the clinical situation. And the present protocol will confirm the efficacy and safety of the CKJ for allergy symptoms, suggesting more basic knowledge to conduct further randomized controlled trials (RCT). If this study will be successfully performed, the CKJ will be an alternative dietary supplemental remedy for allergy patients.
Trial Registration
PMCID: PMC3295693  PMID: 22136279
23.  Hypersensitivity manifestations to the fruit mango 
Asia Pacific Allergy  2011;1(1):43-49.
The objectives of this study are 1) To review the published data and document the current knowledge on allergic manifestations to the fruit mango 2) To highlight the two distinct clinical presentations of hypersensitivity reactions caused by mango 3) To discuss the role of cross-reactivity 4) To increase awareness of potentially life threatening complications that can be caused by allergy to mango. An extensive search of the literature was performed in Medline/PubMed with the key terms "mango", "anaphylaxis", "contact dermatitis", "cross-reactivity", "food hypersensitivity", "oral allergy syndrome" and "urticaria". The bibliographies of all papers thus located were searched for further relevant articles. A total of 17 reports describing 22 patients were documented, including ten patients with immediate hypersensitivity reaction and twelve patients with delayed hypersensitivity reaction to mango. Ten of these patients (four with immediate reaction; six with delayed reaction) were from geographical areas cultivating mango, whereas twelve patients (six with immediate reaction; six with delayed reaction) were from the countries where large scale mango cultivation does not occur. The clinical features, pathogenesis and diagnostic modalities of both these presentations are highlighted. The fruit mango can cause immediate and delayed hypersensitivity reactions, as also "oral allergy syndrome". Although rare, it can even result in a life threatening event. Reactions may even occur in individuals without prior exposure to mango, owing to cross reactivity. It is imperative to recognize such a phenomenon early so as to avoid potentially severe clinical reactions in susceptible patients.
PMCID: PMC3206236  PMID: 22053296
Allergy; Anaphylaxis; Contact dermatitis; Cross-reactivity; Mango; Oral allergy syndrome; Urticaria
A variety of cell-mediated hypersensitivity reactions in experimental animals include a prominent infiltrate of basophilic leukocytes. This form of reactivity has been designated cutaneous basophil hypersensitivity and is favored when sensitization to several types of antigen is accomplished without the use of complete Freund's adjuvant. A similar type of hypersensitivity response was sought in man using morphologic techniques which permit identification of basophilic leukocytes. Eight individuals with allergic contact dermatitis to a variety of allergens were studied and six of these developed typical contact reactions with erythema, edema, and epidermal vesicles. The microscopic findings in 3-day biopsies from these individuals differed significantly from classic descriptions of tuberculin hypersensitivity and showed, in addition to mononuclear cells and the characteristic epidermal changes, a substantial infiltrate of basophilic leukocytes and evidence of altered vascular permeability with vascular compaction, dermal edema, and fibrin deposition. Serial biopsies from one individual permitted analysis of the microscopic pathology as it unfolded at successive intervals after patch test. The initial lesion consisted of perivascular accumulations of lymphocytes; this was followed by an influx of basophils and, subsequently, of eosinophils. These findings associate contact allergy in man with the parallel reactions of cutaneous basophil hypersensitivity in animals and provide further evidence for the heterogeneity of the cellular immune response. The data are consistent with the hypothesis that interaction between sensitized lymphocytes and antigen, at a local test site, is responsible for the attraction of basophils. They also directly implicate the clotting system in delayed-type reactions and suggest the possibility of a synergistic relationship between cellular immunity and reactions mediated by basophil-bound, homocytotrophic antibody.
PMCID: PMC2180522  PMID: 5060290
25.  A case of anaphylaxis to peppermint 
Anaphylaxis, a form of IgE mediated hypersensitivity, arises when mast cells and possibly basophils are provoked to secrete mediators with potent vasoactive and smooth muscle contractile activities that evoke a systemic response. We report a case of IgE mediated anaphylaxis to peppermint (Mentha piperita) in a male shortly after sucking on a candy.
Case presentation
A 69 year old male developed sudden onset of lip and tongue swelling, throat tightness and shortness of breath within five minutes of sucking on a peppermint candy. He denied lightheadedness, weakness, nausea, vomiting, or urticaria. He took 25 mg of diphenhydramine, but his symptoms progressed to onset of cough, wheeze and difficulty with talking and swallowing. He was rushed to the nearest emergency department, where he was treated with intramuscular epinephrine, antihistamines and steroids. On history, he reported recent onset of mouth itchiness and mild tongue and lip swelling after using Colgate peppermint toothpaste. He denied previous history of asthma, allergic rhinitis, food or drug allergies. His past medical history was remarkable for hypercholesterolemia, gastroesophageal reflux and gout. He was on simvastatin, omeprazole, aspirin, and was carrying a self-injectable epinephrine device. He moved to current residence three years ago and cultivated mint plants in his backyard. He admitted to develop nasal congestion, cough and wheeze when gardening. Physical examination was unremarkable apart from slightly swollen pale inferior turbinates. Skin prick test (SPT) was strongly positive to a slurry of peppermint candy and fresh peppermint leaf, with appropriate controls. Same tests performed on five healthy volunteers yielded negative results. Skin testing to common inhalants including molds and main allergenic foods was positive to dust mites. Strict avoidance of mint containing items was advised. Upon reassessment, he had removed mint plants from his garden which led to resolution of symptoms when gardening.
IgE mediated anaphylaxis to peppermint is rare. This case demonstrates a systemic reaction to a commonly consumed item, incapable of triggering anaphylaxis in the far majority of the population, yet causing a severe episode for our patient.
PMCID: PMC3912937  PMID: 24472564
Anaphylaxis; Peppermint; Menthol; IgE mediated

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