Oral ulceration in HIV infection: investigation and pathogenesis.

MacPhail LA, Greenspan JS.

UCSF Dept. of Stomatology 94143-0422, USA.

Abstract
Oral ulcerations associated with HIV infection include recurrent aphthous ulcers (RAU). Whereas RAU prevalence is

not increased, lesion severity is: among a group of HIV+ patients, 66% had the more severe herpetiform or major

RAU. This increased severity suggests that HIV disease-related changes in the immune system may exacerbate

RAU. In the peripheral blood of healthy subjects with RAU, CD4:CD8 cell ratios may be reversed and the proportion

of T cell receptor-gamma delta + cells increased. HIV disease-related immune system changes are characterized by

reversed CD4:CD8, lowered CD4 cell counts and an inverse correlation between CD4 cell counts and per cent

activated gamma delta lymphocytes. Adhesion molecules and cytokines involved in lymphocyte homing may be

important in RAU pathogenesis: ICAM-I and ELAM are strongly expressed, and TNF alpha production is increased in

peripheral blood lymphocytes of healthy patients with RAU. In patients with active HIV disease/AIDS, serum TNF

alpha levels are increased. Thalidomide, which inhibits TNF alpha production, is effective treatment for RAU. Some

RAU patients have vitamin B12 or folate deficiencies, levels of which are commonly low in HIV+/AIDS patients.

However, in a case control study of HIV+ patients, vitamin B12- or folate-deficiencies were not found to be significant

risk factors for RAU.

J Oral Pathol Med. 2009 Jan;38(1):120-5.

Oral ulcers in HIV-positive Peruvian patients: an immunohistochemical and in

situ hybridization study.

Delgado WA, Almeida OP, Vargas PA, León JE.

Department of Oral Pathology, Faculty of Stomatology, University Cayetano Heredia, Lima, Perú.

jorgeesquiche@yahoo.com.br

Abstract
BACKGROUND: This study describes the histopathological, immunohistochemical (IHC) and in situ hybridization

(ISH) data of 25 cases of oral ulcers in HIV-positive patients, with clinical and microscopical features similar to ulcers

not otherwise specified (NOS)/necrotizing ulcerative stomatitis (NUS). METHODS: Sex, age and clinical history were

obtained from the clinical records. Histological analysis for H&E, Gomori-Grocott and Ziehl-Neelsen stains, IHC
analysis to detect infectious agents and to characterize inflammatory cellular infiltrate, and ISH for cytomegalovirus

(CMV) and EBER1/2 were performed. RESULTS: Twenty-one patients were men and four were women (mean age of

34.6 years). The tongue was preferentially affected. Microscopically, the lesions showed extensive necrosis,

leukocytoclasia, vasculitis with luminal fibrin clots and an intense inflammatory cellular infiltrate predominated by

CD68(+) atypical large cells, normal-sized and crescent-shaped nuclei macrophages, interspersed by CD8(+) T

lymphocytes. Mast cells were also observed in all samples studied. CD4(+) T lymphocytes, CD20(+) B lymphocytes

and VS38c(+) plasma cells were practically absent. CMV and EBER1/2 were identified in scarce cells of 3 and 16 of

25 cases respectively. CONCLUSION: These results show that CD68(+) macrophages, followed by CD8(+) T

lymphocytes, were the predominant inflammatory cells, indicating they are relevant to the pathogenesis of the ulcers,

possibly reflecting an abnormal immune response in the oral mucosa. The clinicopathological and immunoprofile

features of the present cases are similar to NOS ulcers/NUS in HIV-positive patients.

P
MID: 19192057 [PubMed - indexed for MEDLINE

Detection of Helicobacter pylori in oral aphthous ulcers

C. Birek 1 R. Grandhi 1 K. McNeill 1 D. Singer 1 G. Ficarra 2 G. Bowden 1
1
Faculty of Dentistry, University of Manitoba, Canada 2 Institute of Stomatology, University of Florence, Italy
Correspondence to Catalena Birek, Department of Oral Biology, Faculty of Dentistry, University of Manitoba, 780 Bannatyne
Avenue, Winnipeg, Manitoba, Canada R3E 0W2
Copyright 1999 Munksgaard
KEYWORDS]

ABSTRACT
A causative role for Helicobacter pylori (H. pylori) in the pathogenesis of oral mucosal ulcerations has been suggested previously.
We have adopted the polymerase chain reaction (PCR) as a rapid and sensitive means to detect H. pylori in swabs of recurrent oral
aphthous ulcers and in samples of other oral sites. Of the oral aphthous ulcer samples, 32 (71.8%) were found to be positive, while
the saliva and plaque samples (most of them taken from the patients with aphthous ulcers) were consistently negative for H. pylori
DNA, as detected by the PCR assay. Only two of the swab samples from the tongue (collected at the time of concurrent, H. pylori-
positive oral aphthous ulcers) were found to be positive. The data suggest that H. pylori may be associated frequently with recurrent
oral aphthous ulcers, and are consistent with previous studies indicating that saliva and plaque are not likely sources of
contamination with this microorganism. There was no apparent correlation with HIV status (infection with human immunodeficiency
virus). The possible pathogenic significance of Helicobacter pylori in oral ulcerations is discussed.

Accepted for publication for publication December

Treatment Strategies for Recurrent Oral

Aphthous Ulcers
Robert W. Barrons
Authors and Disclosures
Posted: 01/01/2001; American Journal of Health-System Pharmacy. 2001;58(1) © 2001 American Society of
Health-System Pharmacists
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• Abstract and Introduction

• Clinical Features
• Classification
• Etiology
• Antimicrobial Mouthwashes
• Corticosteroids
• Amlexanox
• Levamisole
• Thalidomide
• Other Agents
• Treatment Selection
• Conclusion
• References

Abstract and Introduction

Abstract
The clinical features, etiology, and treatment of recurrent aphthous ulcers (RAU) are discussed.

Aphthous ulcers are among the most common oral lesions in the general population, with a frequency of up to
25% and three-month recurrence rates as high as 50%. The ulcers, which usually occur on the nonkeratinized
oral mucosa, can cause considerable pain and may interfere with eating, speaking, and swallowing. RAU is
classified as minor, major, and herpetiform on the basis of ulcer size and number. The cause of RAU is
idiopathic in most patients. The most likely precipitating factors are local trauma and stress. Other associated
factors include systemic diseases and nutritional deficiencies, food allergies, genetic predisposition, immune
disorders, the use of certain medications, and HIV infection. The primary goals of therapy for RAU are relief of
pain, reduction of ulcer duration, and restoration of normal oral function. Secondary goals include reduction in
the frequency and severity of recurrences and maintenance of remission. Topical medications, such as
antimicrobial mouth- washes and topical corticosteroids, can achieve the primary goals but have not been
shown to alter recurrence or remission rates. Systemic medications can be tried if topical therapy is ineffective.
Levamisole has shown variable efficacy in reducing ulcer frequency and duration in patients with minor RAU.
Oral corticosteroids should be reserved for severe cases of major RAU that do not respond to topical agents.
Thalidomide is effective but, because of its toxicity and cost, should be used only as an alternative to oral
corticosteroids.

RAU can be effectively managed with a variety of topical and systemic medications.

Introduction
Aphthous ulcers are among the most common oral lesions in the general population, with a frequency of 5-25%
and three-month recurrence rates as high as 50%.[1] Aphthous ulcers have been reported in 2-4% of HIV-
seropositive patients, although these patients suffer from larger and more frequent aphthae in advanced stages
of their disease.[2] Aphthous ulcers are often quite painful; may lead to difficulty in speaking, eating, and
swallowing; and may negatively affect patients' quality of life.[2,3] In patients with advanced HIV disease,
aphthous ulcers may exacerbate weight loss. While most aphthae are small and heal within 7-10 days, larger
 ulcers can persist for weeks or months. Consequently, therapy for the disease of recurrent aphthous ulcers
(RAU) should address both healing and the prevention of new ulcers.

This article reviews the clinical features and etiology of RAU in HIV-seropositive and HIV-seronegative persons;
the mechanisms of action, efficacy, and safety of medications used to treat RAU; and the recommended
therapeutic strategies. The studies that provided the basis for these recommendations were identified by a
MEDLINE search (1966 to present) of the English-language literature pertaining to aphthous ulcers and
aphthous stomatitis.

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• Abstract and Introduction

• Clinical Features
• Classification
• Etiology
• Antimicrobial Mouthwashes
• Corticosteroids
• Amlexanox
• Levamisole
• Thalidomide
• Other Agents
• Treatment Selection
• Conclusion
• References

Etiology

Trauma and Stress

The most likely factors precipitating aphthous ulcers are local trauma and stress. Injury to the oral mucosa may
result from accidental self-biting, dental procedures, toothbrush bristles, and sharp-edged foods (e.g., potato
chips). In a trial involving 128 patients, 16% claimed that a traumatic incident was associated with their RAU.[5]
Emotional and environmental stress may precede 60% of first-time aphthous ulcer cases and involve 21% of
recurrent episodes.[5] A frequency of RAU of 31-66% has been reported among medical and dental students,
compared with 10-20% in the general population.[5]
Systemic Diseases and Nutritional Deficiencies
Systemic diseases involving immune and nutritional deficiencies have been associated with aphthous ulcers.[5]
Oral ulcers have been reported in patients with cyclic neutropenia and agranulocytosis and are common in
patients with HIV disease. Nutritional deficiencies involving iron, folic acid, zinc, and vitamins B 1 , B 2 , B 6 ,
and B 12 are twice as common in patients with RAU as in healthy persons, occurring in up to 20% of patients.
RAU has been associated with gastrointestinal problems, including Crohn's disease, ulcerative colitis, and
celiac disease; whether the link is related to immunologic mechanisms or nutritional deficiencies resulting from
malabsorption is unknown.

Food allergies
Antibodies to cow's milk and wheat protein (celiac disease) have been demonstrated in patients with RAU.[6]
Strict elimination diets involving cow's milk or glutens (wheat, barley, and oats) have resulted in resolution of or
improvement in persistent aphthae in greater than 25% of patients.[6,7] However, many foods that are commonly
allergenic (e.g., strawberries, tomatoes, and nuts) have not been causally associated with RAU.[6]

Infection
A bacterial or viral cause of RAU has been suggested, but bacterial antibody titer association with RAU has
been inconclusive. Antibodies to herpes simplex virus and cytomegalovirus have not been consistently
demonstrated in the serum or lesional tissue of patients with RAU. The precipitation of RAU after viral
infections may result from the systemic and local immunosuppression associated with viral reactivation rather
than from the virus itself.[5,6]

Genetic predisposition
Some people have a well-established familial basis for RAU. However, evidence for a genetic predisposition is
not strong.[1] Patients with a family history of RAU may develop the disease earlier and more severely than
those with no family history.[5] Forty to fifty percent of first-degree relatives of patients with RAU may have the
condition.[5,6] RAU has been found more commonly in identical twins than in nonidentical twins. Elevations in
human leukocyte antigen markers have been observed in Israelis with RAU and in patients with Behçet's
syndrome.[5] However, what appears to be a familial association may reflect the effects of personality and
stressors in the domestic and work environments that collectively activate RAU.[1]

Immune disorders
RAU may be more common and more severe in patients with immune disorders, including cyclic neutropenia,
inflammatory bowel disease, Behçet's disease, and HIV disease.[8] Patients with RAU have evidence of
antibody-dependent cytotoxicity and elevated serum immunoglobulins.[1] Immunopathogenesis of RAU may
involve an imbalance in T-helper/inducer cells and T-suppressor/inducer cells.[8] Patients with severe RAU have
increased numbers of T-helper/inducer cells and fewer T-suppressor/inducer cells.[9] The presence of activated
T lymphocytes in the periphery of ulcers indicates that RAU may result from an activated cell-mediated
response.[10] Similarities in immunohistologic findings in HIV-seronegative and HIV-seropositive individuals with
RAU further confirm the hypothesis of a cell-mediated immunologic dysfunction involving primarily T
lymphocytes.[1,11] The antigen precipitating this reaction is unknown but may include many of the factors
discussed previously, including trauma, microorganisms, and food allergies.[10]

Drug induction
Antineoplastic medications cause ulcerative stomatitis in up to 37% of patients receiving therapy for acute or
chronic leukemia.[12] The likely mechanism is accelerated detachment of oral epithelial cells. Antineoplastic
drugs associated with stomatitis include methotrexate, daunorubicin, doxorubicin, and hydroxyurea. Predicting
which patients are most likely to manifest stomatitis is not possible. However, patients sensitive to one
stomatotoxic drug are often sensitive to others.[12] Burning and reddening of the oral mucosa occur within hours
of drug administration. The painful erosions and ulcerations involve both keratinized and nonkeratinized
epithelium. Chemotherapy-induced stomatitis should alert the clinician to the possibility of gastroenterocolitis,
 which often follows a parallel course.[12] Precautionary oral hygiene measures may avoid superimposed
infections.

Contact stomatitis with ulceration may occur after prolonged exposure to uncoated potassium chloride, aspirin,
and pancreatic enzyme preparations. Cases of "scalded mouth" have been reported with angiotensin-
converting- enzyme inhibitors, especially captopril.[13] Patients should be instructed to swallow the tablets as
quickly as possible. Stomatitis associated with systemic effects of medications is rare, and objective methods
for associating a drug with an event are lacking.

Other medications observed to cause stomatitis include antimicrobials, auranofin, barbiturates, didanosine,
foscarnet, griseofulvin, non-steroidal anti-inflammatory drugs, penicillamine, quinidine, and sulfonamides.[13]

HIV Disease
The frequency of aphthous ulcers is similar in persons seronegative and persons seropositive for HIV.
However, HIV-seropositive patients with CD4+ lymphocyte counts below 100 cells/mm 3 are more likely to
have major recurrent aphthae, which may lead to difficulty eating.[2] Therefore, early diagnosis and treatment
are important. The same causes of RAU in HIV-seronegative patients must be considered in HIV-seropositive
patients.[14] However, the presence of HIV infection may suggest other causes of oral ulcers -- neoplasms,
infections, and medications -- that should be excluded before the lesions are diagnosed as aphthous ulcers.[15]

Kaposi's sarcoma is the most common cause of oral tumors in AIDS patients, while tumors in non-Hodgkin's
lymphoma may be primarily located in the oral cavity. Herpes simplex virus reactivation and associated lesions
are frequent in HIV-infected individuals at any level of immunocompetence.[15] Oral ulcers attributable to
Histoplasma capsulatum and Crytococcus neoformans are uncommon but may occur in the setting of
disseminated disease. Candida albicans may cause oral ulcers in advanced stages of AIDS.[15] Oral and
esophageal ulcers are found in acute HIV infection, together with malaise, fever, myalgia, rash, acute myelitis,
and encephalitis.[15]

Accurate diagnosis of oral lesions in HIV-seropositive patients may require biopsy in combination with a clinical
examination and patient history. Lesions located on keratinized mucosa are probably not aphthous ulcers. Any
ulcer located on keratinized oral mucosa, major aphthous ulcer, or ulcer not responding to topical corticosteroid
treatment should be biopsied. Diagnostic protocols addressing the role of cultures, biopsies, and cytology
studies have been developed to help the clinician.[1

ams IG. Severe oral ulceration in patients with HIV infection: a case series. Oral Dis. 1997; 3(suppl 1):S194-6.
ulceration in HIV infection: investigation and pathogenesis. Oral Dis. 1997; 3(suppl 1):S190-3.
min Dermatol. 1994; 13(2):74-7.
phthous stomatitis. Dermatol Clin. 1996; 14:243-56.
thous ulcers: a review of diagnosis and treatment. J Am Dent Assoc. 1996; 127:1202-13.
aphthous stomatitis. Dig Dis Sci. 1981; 26:737-40.
omatitis: clinical characteristics and evidence for an immunopathogenesis. J Invest Dermatol. 1977; 69:499-509.
Alterations of T helper/inducer and T suppressor/inducer cells in patients with recurrent aphthous ulcers. Oral Surg Oral Med Oral

s of oral lichen planus and recurrent aphthous stomatitis. Semin Cutan Med Surg. 1997; 16(4):284-94.
erapies for major aphthous ulcer in AIDS patients. J Am Dent Assoc. 1992; 123:61-5.
MJ. Chemotherapy- induced oral mucositis in adult leukemia. Postgrad Med J. 1981; 69:103-12.
h disorders. Clin Exp Dermatol. 1995; 20:10-8.
nspan JS. Recurrent aphthous ulcers in association with HIV infection. Oral Surg Oral Med Oral Pathol. 1992; 73:283-8.
ed patients: an update on epidemiology and diagnosis. Oral Dis. 1997; 3(suppl 1):S183-9.
r CD et al. Effect of an antimicrobial mouthrinse on recurrent aphthous ulcerations. Oral Surg Oral Med Oral Pathol. 1991;

. Management of recurrent aphthous ulceration. A trial of chlorhexidine gel. Br Dent J. 1976; 141:118-20.
Hexitidine mouthrinse in the management of minor aphthous ulceration and as an adjunct to oral hygiene. Br Dent J. 1991;

luconate mouthwash in the management of minor aphthous ulceration. A double-blind, placebo controlled cross-over trial. Br

hip II. Effect of chlortetracycline mouthrinses on the healing of recurrent aphthous ulcers: a double- blind controlled trial. J Oral

of recurrent aphthous ulcers with Aureomycin mouth rinse or Zendium dentrifice. Acta Odontol Scand. 1985; 43:47-52.
e-blind trial of tetracycline in recurrent aphthous ulceration. J Oral Pathol. 1978; 7:376-82.
ssman AB et al. Betamethasone-17-benzoate in the treatment of recurrent aphthous ulcers. Oral Surg. 1978; 45:870-5.
Minor aphthous oral ulceration: a double-blind cross-over study of beclomethasone dipropionate aerosol spray. Scott Med J.

oric, and therapeutic features of aphthous stomatitis. Literature review and open clinical trial employing steroids. Oral Surg Oral

J. Topical triamcinolone acetonide in recurrent aphthous stomatitis. Lancet. 1968; 1:565-8.

et al. Use of steroids in treatment of aphthous ulceration. Br Med J. 1968; 2:147-9.
d clinical trial of the efficacy of topically applied fluocinonide in the treatment of recurrent aphthous ulceration. Br Dent J. 1983;

harmey MR et al. 5% Amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers. II. Pharmacokinetics and
al Surg Oral Med Oral Pathol Oral Radiol Endod. 1997; 83:221-8.
hanism of action of amoxanox (AA-673), an orally active antiallergic agent. Int Arch Allergy Appl Immunol. 1985; 78:43-50.
harmey MR et al. 5% Amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers. I. Clinical demonstration of
ion of pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1997; 83:222-30.
Immunomodulation by levamisole in patients with recurrent aphthous ulcers or oral lichen planus. J Oral Pathol Med. 1994;

e J et al. Levamisole in aphthous stomatitis: evaluation of three regimens. Br Med J. 1977; 1:671-4.
nd study of levamisole therapy in recurrent aphthous stomatitis. J Oral Pathol. 1978; 7:393-9.
al. Effect of levamisole on the incidence and prevalence of recurrent aphthous stomatitis. J Oral Pathol. 1978; 7:387-92.
mized, double- blind study of levamisole in recurrent aphthous stomatitis. J Oral Pathol. 1978; 7:414-7.
W et al. A randomized double-blind trial of levamisole in the therapy of recurrent aphthous stomatitis. Oral Surg Oral Med Oral

ble blind crossover trial of levamisole in recurrent aphthous ulceration. Lancet. 1976; 2:926-9.
D et al. Therapeutic evaluation of levamisole in recurrent aphthous stomatitis. J Oral Med. 1983; 38(4):161-3.
tzler J et al. Thalidomide for the treatment of oral aphthous ulcers in patients with human immunodeficiency virus infection.
ectious Diseases AIDS Clinical Trials Group. N Engl J Med. 1997; 336:1487-93.
l. Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-
98; 128:443-50.
 t al. Cross-over study of thalidomide vs. placebo in severe recurrent aphthous stomatitis. Arch Dermatol. 1990; 126:923-7.
pact in dermatology. Semin Cutan Med Surg. 1998; 17(4):231-42.
A et al. Thalidomide induces imbalances in T-lymphocyte subpopulations in the circulating blood of healthy males. Lepr Rev.

et al. Thalidomide selectively inhibits tumor necrosis factor production by stimulated human monocytes. J Exp Med. 1991;

. Elevated levels of interferon gamma, tumor necrosis factor alpha, interleukins 2, 4, and 5, but not interleukin 10, are present in
h Dermatol. 1998; 134:827-31.
quadio DJ et al. Super potent topical corticosteroid use associated with adrenal suppression: clinical considerations. J Am Acad
21.
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redbook. Montvale, NJ: Medical Economics; 1999.
son KE. Thalidomide neurotoxicity. Arch Dermatol. 1984; 120:338-41.
et al. Low dose thalidomide treatment of Behçet's syndrome. In: Wehchsler B, Godeau P, eds. Behçet's disease. Proceedings of
on Behçet's Disease. Paris: Excerpta Medica; 1993:649-53.
Guideline for the clinical use and dispensing of thalido-mide. Postgrad Med J. 1994; 70:901-4.

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Oral Ulcers Produced by Mycophenolate Mofetil in Two Liver
Transplant Patients
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J. Naranjoa , J. Poniachikb, D. Ciscob,

J. Contrerasb, D. Oksenbergb, J.M. Valerab, J.C. Díazb, J. Rojasb, G. Cardemilb,
• Contact Information S. Menab, J. Castillob, G. Rencoretb, J. Godoyb, J. Escobarb, J. Rodríguezb, P. Leytonb,
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Abstract
Oral ulcers are a frequent problem in transplant medicine. It is important to
consider infectious etiologies, exacerbated by the immunosuppressive treatment,
 but other etiologies are also possible, like adverse drug reactions.
Mycophenolate mofetil (MMF) is an immunosuppressive medication that has
Bottom of Form been used in combination with calcineurin inhibitors and steroids. Reports of
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renal transplant patients with oral ulcers related to MMF have appeared lately
w w w .transplanta and herein we have described 2 cases in liver transplant patients. Their oral
ulcers resolved quickly after suspension of the medication. Our 2 cases in liver
/article/S0041-13 transplant patients represented a unique setting for this type of complication.
a Gastroenterology Department, Medicine Service, Clinical Hospital of the University of Chile,
Independencia, Santiago, Chile
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b Transplant Unit, Clinical Hospital of the University of Chile, Independencia, Santiago, Chile.

ADVERTISING INFORMATION Address reprint requests to J. Naranjo, Clinical Hospital of the University of Chile, Santos
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Ear Nose Throat J. 2007 Apr;86(4):232-3.

Tongue erosions and diet cola.

Jacob SE, Steele T.

Contact Dermatitis Clinic, Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University

of Miami, Florida, USA. sjacob@med.miami.edu

Abstract
We report the case of a 38-year-old woman who presented with a 10-year history of painful ulcerations on her

tongue. She reported that she drank large quantities of diet cola and some orange juice daily and that she used

cinnamon-flavored toothpaste and mouthwash nightly. Patch testing elicited positive reactions to balsam of Peru (a
 fragrance as well as a flavoring agent put in cola drinks that cross-reacts with orange juice) and cinnamic aldehyde.

She was diagnosed with allergic contact dermatitis. She was put on a restricted diet and a fragrance-free regimen,

and her condition resolved.

PMID: 17500397 [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances

Publication Types:
• Case Reports

MeSH Terms:
• Acrolein/adverse effects
• Acrolein/analogs & derivatives
• Adult
• Balsams/adverse effects
• Beverages/adverse effects
• Carbonated Beverages/adverse effects*
• Citrus sinensis/adverse effects
• Cross Reactions
• Dermatitis, Allergic Contact/diagnosis
• Dermatitis, Allergic Contact/etiology*
• Female
• Flavoring Agents/adverse effects*
• Glossitis/diagnosis
• Glossitis/etiology*
• Humans
• Oral Ulcer/diagnosis
• Oral Ulcer/etiology*
• Patch Tests
• Sweetening Agents/adverse effects*
• Toothpaste/adverse effects

Substances:
• Balsams
• Flavoring Agents
• Sweetening Agents
• Toothpaste
• cinnamic aldehyde
• Acrolein
• Peruvian balsam
 LinkOut - more resources

Full Text Sources:

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• ProQuest Information and Learning

Medical:
• Tongue Disorders - MedlinePlus Health Information

Molecular Biology Databases:

• ACROLEIN - HSDB
• CINNAMALDEHYDE - HSDB

Supplemental Content
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• Cross-reactions in patch testing and photopatch testing with ketoprofen, thiaprophenic acid, and cinnamic aldehyde. [Am J
Contact Dermat. 1996]
Cross-reactions in patch testing and photopatch testing with ketoprofen, thiaprophenic acid, and cinnamic aldehyde.
Pigatto P, Bigardi A, Legori A, Valsecchi R, Picardo M. Am J Contact Dermat. 1996 Dec; 7(4):220-3.

• Cross-reactions in patch testing with ketoprofen, fragrance mix and cinnamic derivatives. [Contact Dermatitis. 2006]
Cross-reactions in patch testing with ketoprofen, fragrance mix and cinnamic derivatives.
Girardin P, Vigan M, Humbert P, Aubin F. Contact Dermatitis. 2006 Aug; 55(2):126-8.

• A stomatitis due to artificial cinnamon-flavored chewing gum. [Arch Dermatol. 2005]

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Bousquet PJ, Guillot B, Guilhou JJ, Raison-Peyron N. Arch Dermatol. 2005 Nov; 141(11):1466-7.

• Review Contact allergens in toothpastes and a review of their hypersensitivity. [Contact Dermatitis. 1995]
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Sainio EL, Kanerva L. Contact Dermatitis. 1995 Aug; 33(2):100-5.

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Bickers D, Calow P, Greim H, Hanifin JM, Rogers AE, Saurat JH, Sipes IG, Smith RL, Tagami H, RIFM expert panel. Food Chem Toxicol.
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, a,
Monique Michaud D.D.S., M.S.D., Assistant Professor , Gilles
Blanchette M.D., Assistant Professorb, a and Charles E. Tomich D.D.S.,
M.S.D., Professord, c
a
Faculté de médecine dentaire, Université de Montreál., Montreal, Canada
b
Faculté de Médecine, Université de Montreál, Montreal, Canada
c
Hôpital du Sacré-Coeur., Montreal, Canada
d
Indiana University School of Dentistry., Indianapolis, Ind., USA

Available online 29 March 2005.

Abstract

A case of unsuspected pulmonary tuberculosis was identified through the presence

of a 4-month-old oral ulcer. The implications for patients with undiagnosed,
untreated tuberculosis are discussed.

Article Outline
• References

Corresponding author. Reprint requests to: Dr. Monique Michaud Université de Montréal
Faculté de médecine dentaire Case postale 6209, Succursale A , Montréal, P. Québec, H3C
3T9, , Canada
 Oral Surgery, Oral Medicine, Oral Pathology
Volume 57, Issue 1, January 1984, Pages 63-67

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Copyright © 2010 Elsevier

Ir Med J. 2005 Oct;98(9):282.

Clopidogrel induced oral ulceration.

Adelola OA, Ullah I, Fenton JE.

PMID: 16300112 [PubMed - indexed for MEDLINE]

Publication Types, MeSH Terms, Substances

Publication Types:
• Case Reports
• Letter

MeSH Terms:
• Female
• Humans
• Middle Aged
• Oral Ulcer/chemically induced*
• Platelet Aggregation Inhibitors/adverse effects*
• Ticlopidine/adverse effects
• Ticlopidine/analogs & derivatives*

Substances:
• Platelet Aggregation Inhibitors
• Ticlopidine
• clopidogrel

LinkOut - more resources

Oral aphthous-like ulceration due to tiotropium

bromide

Vanja Vucicevic Boras, Neil Savage, Zuraiza Mohamad Zaini

Department of Oral medicine, School of Dental medicine, 200 Turbot

Street, University of Queensland, Brisbane, Australia

Correspondence

ABSTRACT

Unwanted side-effects of a drug therapy are well known to oral medicine

specialists and other colleagues. Usually they manifest itself as dry
mouth, taste disturbances, various allergic or toxic reactions on the lips
and/or in the oral cavity. However, the list of the drugs which might
induce unwanted reactions is everyday becoming longer as more and
more drugs are introduced on the market. Certain problems when
diagnosing and reporting unwanted side effects of the drugs exist as
only accurate method of diagnosis is repeated drug use in controlled
clinical setting where fatal consequences due to the anaphilactic shock
could be avoided. We report a side effect reaction to tiotropium bromide
(Spiriva®) cap used with HandiHaler manifesting itself as an oral
ulceration in a 65 yrs old male. On the third day of drug intake the
patient developed oral ulceration two times in a period of few months.
Other medications he has been using for several years. To our
knowledge this is a first report as an oral side-effect of this drug used for
treatment of chronic obstructive pulmonary disease (COPD).

Key words: Oral ulceration, side effect of drug, tiotropium bromide.

Introduction
Virtually every drug has the potential to cause adverse reactions on the
oral mucosa but some have greater ability to do so. So far, a wide range
of drugs have been recognized as potential inducers of unwanted
adverse reactions in the oral cavity. Smith and Burtner (1) reviewed
such reactions after administration of 200 most frequently prescribed
drugs and reported that the most freuquent ones were dry mouth
(80.5%), dysgeusia (47.5%) and stomatitis (33.9%). However, other
reactions to numerous drugs such as swellings, hypersalivation,
discoloration of saliva, white lesions, oral burns, fixed drugs eruptions,
mucositis, neoplasms, pemphigus and pemphigoid reactions and other
bullous disorders, mucosal pigmentation, lichenoid reactions, cheilitis,
neuropathies, and halitosis have been reported throughout the literature
(2).

Drug-related aphthous-like ulceration have been reported after the use

of beta blockers such as labetalol, captopril, nicorandil and non-steroidal
anti-inflammatory drugs (NSAID). Also such reactions have been
described after the use of mycophenolate or sirolimus, sodium lauryl
sulfate, protease inhibitors, tacrolimus and sulfonamides, though the
exact pathogenic mechanisms are unclear in all of these. A case control
study has now confirmed the association of oral ulceration with NSAIDs
and beta blockers, whereas all the other data are obtained from case
reports, small series and non-peer-reviewed reports (2). Recently, we
have reported a case report of a delayed contact sensitivity on the lips
and oral mucosa due to propolis (3).

Case report

The patient, 65 years old was reviewed on the annual appointment for
long-standing oral lichen planus at the Department of Oral medicine,
University of Queensland. At the time his lesions of oral lichen planus
were barely visible and only discrete whitish lines were seen on the
lateral left side of the tongue. However, during the examination, he
reported development of the ulceration in the vestibular mucosa in the
region 41 and 42 which started after he took the third cap (by use of
HandiHaler) of tiotropium bromide for his COPD symptoms. At the closer
inspection the ulceration has now been in healing phase (Figure 1).
Additionally patient reported that last time he was using tiotropium
bromide also after 3 days of therapy, the ulceration developed. Given
the clear relationship between appearence of the lesion and the
administration of tiotropium bromide the patient was advised to stop
taking it. The lesion resolved after ten days. Detailed medical history
revealed that he suffered heart attack before 18 years and he had blood
transfusion eleven years ago. From time to time he has lower back pain.
Apart from that he has been using the same medications throughout
many years such as diltiazem hydrochloride (Cardizem®; 240 mg/day),
isosorbide dinitrate (Isordil®; 5mg/6x a day), candesartan cilexetil
(Atacand®; 8mg/day), perindopril erbumine (Coversyl® plus; 4/1.25 a
day), aspirin (Astrix®; 100 mg/day), biperiden hydrochloride (Akineton®;
2mg/day). To date, 3 months from our patients last review no such
lesions developed and patient stopped taking tiotropium bromide. A
 biopsy was not taken because there was a clear relationship between the
drug use and oral lesion.

Oral nicorandil-induced lesions are not Top of Form

aphthous ulcers quicksearch journal 1600-0714

S. Boulinguez , A. Sommet , C. Bédane , R. Viraben ,
1,2 3 1 2

J. M. Bonnetblanc 1
1
Department of Dermatology, University Hospital Dupuytren, issn Journal of Oral Pa blah
Limoges, 2 Department of Dermatology, University Hospital
La Grave, Toulouse, and 3 Department of Epidemiology and
Health economy and Community Health, School of Medicine, 118487901
Toulouse, France
Correspondence to
S. Boulinguez SEARCH IN THIS TITLE
Service de dermatologie,
CHU Dupuytren, Journal of Oral Pathology & Medicine
2, Avenue Martin Luther-King, Enter words or phrases
87042 Limoges Cedex,
France
Tel.: +33 5 550 5 64 31
Telecopy: +33 5 550 5 64 47
e-mail: serge@boulinguez.com.fr All Fields
Copyright © Blackwell Munksgaard 2003
KEYWORDS Select a Field
nicorandil • oral cancer • aphthous ulcer

ABSTRACT

Abstract
Objectives: (i) To accurately define these lesions
determining whether oral nicorandil-induced lesions are
Bottom of Form
aphthous ulcers; (ii) To determine clinical characteristics of
oral nicorandil-induced lesions.
Top of Form
Materials and methods: Two slide conferences citation blah 1600-0714
were held. A total of 60 dermatologists assigned diagnosis
and clinical criteria to 11 photographs of oral nicorandil-
induced lesions. Two slides were randomly selected and
duplicated to be used as control. The panel of slides included SEARCH BY CITATION
independent lesions and photographs of different lesions of
the same patient. Statistical analysis used χ2-test, estimation Vol:
of the percentage interobserver agreement, and kappa-
values.

Results: The diagnosis of non-aphthous ulcer (71.8%)

was significantly held in comparison with the diagnosis of oral Issue:
aphthous ulcer (28.2%; P < 0.001). To differentiate aphthous
ulcer from non-aphthous ulcer, physicians significantly used
three clinical criteria. The diagnosis of non-aphthous ulcer
were significantly associated with the absence of yellow-
based ulceration (P < 0.001), with the linear shape Page:
(P = 0.006) and the absence of inflammatory halo
(P = 0.003).

Conclusion: Oral nicorandil-induced lesions are not

aphthous ulcers. We propose that at this stage of our
knowledge, oral nicorandil-induced ulcer is the most suitable
terminology.
Bottom of Form
Accepted for publication December 17, 2002 Top of Form

DIGITAL OBJECT IDENTIFIER (DOI) 1

10.1034/j.1600-0714.2003.00166.x About DOI
 Bottom of Form
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Alimentary Pharmacology & Therapeutics

Volume 21 Issue 4, Pages 295 - 306
Published Online: 8 Feb 2005
Journal compilation © 2010 Blackwell Publishing Ltd

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Abstract | References | Full Text: HTML, PDF (Size: 572K) | Related Articles | Citation Tracking

Review article: oral ulcers and its relevance to systemic disorders

S. R. Porter* & J. C. Leao†
*Oral Medicine, Division of Maxillofacial Diagnostic, Medical and Surgical Sciences, Eastman Dental Institute for Oral Health Care
Sciences, UCL, University of London, London, UK ; †Departamento de Clinica e Odontologia Preventiva, Disciplina de
Estomatologia, Universidade Federal de Pernambuco, Brazil
Correspondence to Prof. S. R. Porter, Oral Medicine, Division of Maxillofacial Diagnostic, Medical and Surgical Sciences, Eastman
Dental Institute for Oral Health Care Sciences, UCL, University of London, 256 Gray's Inn Road, London WC1X 8LD, UK.
E-mail: sporter@eastman.ucl.ac.uk
Copyright 2005 Blackwell Publishing Ltd

Summary

Oral ulceration is a common problem, and is sometimes a marker of gastroenterological disease. Patients with signs or symptoms of
oral ulcers are sometimes referred to gastroenterology clinics, however, in most instances the ulcers does not reflect gastrointestinal
disease. Indeed, a spectrum of disorders other than those of the gut can give rise to oral mucosal ulcers ranging from minor local
trauma to significant local disease such as malignancy or systemic illness. This present article reviews aspects of the aetiology,
diagnosis and management of common ulcerative disorders of the oral mucosa.

Accepted for publication 9 November 2004

DIGITAL OBJECT IDENTIFIER (DOI)

•
T. Lehner

This article has been cited by other articles in PMC.

515 517 518 519 520 521 522 523 524

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 Thi
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American Journal of Health-System Pharmacy, Vol icl
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Copyright © 2001 by American Society of Health- Ale
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Immunoglobulin estimation of blood and
saliva in human recurrent oral ulceration

References and further reading may be available for this article. To view references and further
reading you must purchase this article.

T. Lehnera
a
Department of Oral Medicine and Pathology, Guy's Hospital Medical School, London, S.E.1., England

Available online 8 March 2004.

Abstract
Immunoglobulin estimations by an immunochemical method were performed in serum and
saliva of 120 subjects; 70 patients with recurrent oral ulceration, 20 with lichen planus and 30
normal controls. Raised levels of serum IgA and IgG were found in patients with recurrent oral
ulcers, as compared with normal controls, but the 5 per cent level of significance was reached
only in patients, with major aphthous ulcers. In lichen planus, however, serum IgG concentration
was significantly depressed, although IgA was slightly raised. Salivary IgA concentration
showed little variation between the controls and patients and depressed IgA clearance was found
only in herpetiform ulceration. Although IgG was not detectable by this method in parotid saliva,
it was found in almost all samples of whole saliva. Serum IgM was normal in all groups of
patients and IgM was not detected in any of the samples of saliva. Recurrent oral ulceration is
not associated with immunoglobulin deficiency in serum or saliva. The raised serum IgG and
IgA levels are consistent with those found in some autoimmune disorders. Immunoglobulin
transport into saliva is discussed.
Résumé
Des analyses d'immunoglobulines, par une méthode immunochimique, sont réalisées dans le
sérum et la salive de 120 sujets, dont 70 patients présentent des ulcérations récidivantes, 20 des
lichens plans et 30 sont des sujets normaux. Des quantités plus élevées d'IgA et d'IgG sériques
sont notées chez des malades présentant des ulcères buccaux récidivants, mais la proportion
significative de 5 pour cent n'est observée que chez des patients atteints d'aphtes buccaux
importants. Dans les cas de lichen plan, cependant, la concentration en IgG est significativement
plus basse, alors que l'IgA est légèrement élevée. La concentration en IgA salivaire varie peu
entre les sujets normaux et les malades. Une clearance diminuée en IgA n'est notée que dans les
cas d'ulcérations herpétiformes. Bien que l'IgG no peut être mise en évidence dans la salive
parotidienne, on la retrouve dans presque tous les échantillons de salive mixte. L'IgM sérique est
normale dans tous les groupes et l'IgM n'est détectable dans aucun des prélèvements salivaires.
Les ulcérations buccales récidivantes ne sont pas en rapport avec une déficience en
immunoglobuline sérique ou salivaire. Les proportions élevées d'IgG et d'IgA sériques sont
conformes à celles retrouvées dans certaines maladies auto-immunitaires. Le passage
d'immunoglobuline dans la salive est discuté.

Zusammenfassung
Mit Hilfe immunochemischer Methoden wurden Immunglobuline in Serum und Speichel von
120 Personen bestimmt. 70 Patienten hatten rezidivierende Ulzerationen an der
Mundschleimhaut, 20 Lichen ruber planus, 30 Patienten dienten als normale Kontrollen. Erhöhte
Serumwerte für IgA und IgG wurden bei Patienten mit rezidivierenden Ulzerationen im
Vergleich zu den normalen Kontrollen gefunden, jedoch wurde die 5 prozent-Signifikanzgrenze
lediglich bei Patienten mit gröβeren aphthösen Ulcera erreicht. Bei Lichen ruber planus war
dagegen das Serum-IgG signifikant erniedrigt und das IgA leicht erhöht. Die IgA-Konzentration
im Speichel, zeigte wenig Abweichungen zwischen Kontrollen und Patienten. Eine verminderte
IgA-Clearance wurde nur bei der herpetiformen Ulzeration gefunden. Obwohl IgG mit Hilfe
dieser Methode im Parotisspeichel nicht feststellbar war, wurde es in fast allen
Vollspeichelproben gefunden. Bei allen Patientengruppen war des Serum-IgM normal, es lieβ
sich in keiner der Speichelproben nachweisen. Rezidivierende Mundelzerationen hängen nicht
mit einem Immunglobulinmangel im Serum oder Speichel zusammen. Die erhöhten Serum-IgG-
und IgA-Spiegel entsprechen dem bei einigen Autoimmunkrankheiten gefundenen. Der
Immunglobulintransport in den Speichel wird diskutiert.
 Thi
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Archives of Oral Biology icl
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Volume 14, Issue 4, April 1969, Pages 351-364, IN3
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