Aspirin use and post-operative bleeding from dental extractions.

Aspirin is a common, chronically administered preventive treatment for cardiovascular disease, but is often discontinued prior to invasive dental procedures because of concern for bleeding complications. We hypothesized that aspirin does not cause increased bleeding following a single tooth extraction. Thirty-six healthy persons requiring a tooth extraction were randomized to receive 325 mg/day aspirin or placebo for 4 days. Cutaneous bleeding time (BT) and platelet aggregation tests were obtained prior to extraction. The primary outcome measure, oral BT, and secondary bleeding outcomes were evaluated during and following extraction. No significant baseline differences, except for diastolic blood pressure, were found between groups. There were no differences in oral BT, cutaneous BT, secondary outcome measures, or compliance. Whole-blood aggregation results were significantly different between the aspirin and placebo groups. These findings suggest that there is no indication to discontinue aspirin for persons requiring single-tooth extraction.

The oral mucosa as a therapeutic target for xerostomia.

Autoimmune disorders, medical interventions, and aging are all known to be associated with salivary gland hypofunction, which results in the uncomfortable feeling of dry mouth (xerostomia) and significantly diminished oral health. The current therapeutic regimen includes increasing oral hydration using over-the-counter oral comfort agents and the use of systemic cholinergic drugs to stimulate salivary output. However, these approaches produce very transient relief or are associated with uncomfortable side-effects. Thus, new treatments that provide long-lasting relief from discomfort and improve oral health with minimal side-effects would benefit the therapy of this disease. The processes that mediate fluid loss from the oral cavity, such as the absorption of fluid from the oral mucosa, represent novel therapeutic targets for xerostomia. Preventing fluid absorption from the oral cavity is predicted to improve oral hydration and alleviate the clinical symptoms and discomfort associated with dry mouth. Furthermore, therapeutic strategies that prevent fluid absorption should complement current approaches that increase salivary output. This review discusses the current understanding of oral fluid balance and how these processes may be manipulated to provide relief for those suffering from dry mouth.

Reduction in MRSA environmental contamination with a portable HEPA-filtration unit.

There is renewed interest in the hospital environment as a potentially important factor for cross-infection with methicillin-resistant Staphylococcus aureus (MRSA) and other nosocomial pathogens. The aim of this study was to evaluate the effectiveness of a portable high-efficiency particulate air (HEPA)-filtration unit (IQAir Cleanroom H13, Incen AG, Goldach, Switzerland) at reducing MRSA environmental surface contamination within a clinical setting. The MRSA contamination rate on horizontal surfaces was assessed with agar settle plates in ward side-rooms of three patients who were heavy MRSA dispersers. Contamination rates were measured at different air filtration rates (60-235 m(3)/h) and compared with no air filtration using Poisson regression. Without air filtration, between 80% and 100% of settle plates were positive for MRSA, with the mean number of MRSA colony-forming units (cfu)/10-h exposure/plate ranging from 4.1 to 27.7. Air filtration at a rate of 140 m(3)/h (one patient) and 235 m(3)/h (two patients), resulted in a highly significant decrease in contamination rates compared with no air filtration (adjusted rate ratios 0.037, 0.099 and 0.248, respectively; P < 0.001 for each). A strong association was demonstrated between the rate of air filtration and the mean number of MRSA cfu/10-h exposure/plate (P for trend < 0.001). In conclusion, this portable HEPA-filtration unit can significantly reduce MRSA environmental contamination within patient isolation rooms, and this may prove to be a useful addition to existing MRSA infection control measures.

Randomized controlled trial of pilocarpine hydrochloride for the moderation of oral mucositis during autologous blood stem cell transplantation.

Pilocarpine hydrochloride has been reported to increase salivation and decrease oral mucositis in patients receiving head and neck radiotherapy, but there is only one report of its use in a cancer chemotherapy patient population. This prospective, double-blinded, randomized, placebo-controlled trial was undertaken to determine the efficacy of pilocarpine for the moderation of oral mucositis during autologous blood stem cell transplantation. Subjects were randomized to receive a 5 mg tablet of pilocarpine, or a placebo, during and following chemotherapy. Subjects were seen every other day and evaluated for gingival, oral, and oropharyngeal mucositis; nutrition; oral hygiene; eating; speaking; sleeping; pain at rest and/or with swallowing; and mouth dryness. We recorded the mean and highest scores and duration of problems, along with white blood cell counts and differentials, and the use of systemic narcotics for oral mucosal pain. We enrolled and randomized 36 subjects, and there were no statistically or clinically significant differences for the primary outcome of severity of mucositis and no clinically significant differences in any of the other outcome measures. Pilocarpine has no benefit for the moderation of the incidence, severity, or duration of mucositis in patients receiving autologous blood stem cell transplantation.

Classification criteria for Sjögren's syndrome: a revised version of the European criteria proposed by the American-European Consensus Group.

Classification criteria for Sjögren's syndrome (SS) were developed and validated between 1989 and 1996 by the European Study Group on Classification Criteria for SS, and broadly accepted. These have been re-examined by consensus group members, who have introduced some modifications, more clearly defined the rules for classifying patients with primary or secondary SS, and provided more precise exclusion criteria.

Focal sialadenitis in patients with early synovitis.

OBJECTIVE: To investigate the frequency of sialadenitis on lip biopsy in patients with synovitis of recent onset (ES), and see how sialadenitis relates to clinical and laborator findings of ES. METHODS: Joint involvement, laboratory measures and biopsies of the minor salivary glands were evaluated in 10 ES patients. Diagnosis at a one-year follow-up exam was noted. RESULTS: Six ES patients (60%) had a positive lip biopsy (mononuclear cell focus score greater than 1). ES patients with a positive lip biopsy presented with oligoarthritis, while ES patients with a negative lip biopsy had a more polyarticular presentation. No differences in laboratory measures between patients with a positive and negative lip biopsy were present. Seven ES patients had a diagnosis of rheumatoid arthritis and three had undifferentiated arthritis at the end of one year. CONCLUSION: ES patients had a higher than expected frequency offocal sialadenitis.

Incidence of physician-diagnosed primary Sjögren syndrome in residents of Olmsted County, Minnesota.

OBJECTIVES: To estimate the incidence of physician-diagnosed primary Sjögren syndrome (SS) among residents of Olmsted County, Minnesota, in the setting of usual medical care and to determine how often objective criteria are available in the medical records of such patients. PATIENTS AND METHODS: We reviewed all medical records of residents in Olmsted County with physician-diagnosed SS from 1976 to 1992 to determine whether they had undergone objective tests for keratoconjunctivitis sicca, salivary dysfunction, or serologic abnormality. Confounding illnesses were excluded. To identify misclassified cases, all records from patients with xerostomia or keratoconjunctivitis sicca were also reviewed. The average annual SS incidence rates were calculated by considering the entire population to be at risk. RESULTS: Of 75 patients with onset of SS during the study period, 53 had primary SS. All patients were white, 51 (96.2%) were women, and the mean +/- SD age was 59+/-15.8 years. The age- and sex-adjusted annual incidence was 3.9 per 100,000 population (95% confidence interval, 2.8-4.9) for patients with primary SS. Eleven patients (20.8%) with physician-diagnosed SS had no documentation of objective eye, mouth, or laboratory abnormalities. Objective evaluations performed most frequently were laboratory and ocular tests and least often were investigations of xerostomia. CONCLUSIONS: The average annual incidence rate for physician-diagnosed primary SS in Olmsted County is about 4 cases per 100,000 population. These data probably underestimate the true incidence because they are based on usual medical care of patients with SS in a community setting, rather than on a case-detection survey. In the future, a true incidence may be possible with a higher index of suspicion, greater attention to objective tests, and increased awareness of new classification criteria for SS. For epidemiological studies based on existing data, application of current criteria may not be feasible, and consensus on criteria for such studies would be useful.

Use of orally administered anhydrous crystalline maltose for relief of dry mouth.

OBJECTIVES: To examine the safety and efficacy of anhydrous crystalline maltose (ACM) for treatment of dry mouth. DESIGN: ACM was delivered orally as a 200-mg lozenge given three times daily over a 12-week (study Alpha) or 24-week (study Omega) period to a total of 22 and 97 subjects, respectively. All participants had prominent complaints of persistent dry mouth associated with primary Sjögren's syndrome. Patients were examined every 4 weeks in study Alpha and every 6 weeks in study Omega. SETTINGS: Patients were seen in outpatient clinics at a total of 33 sites within the United States. OUTCOME MEASURES: Unstimulated whole saliva output, a measure of basal salivary gland function, was determined at each visit. Symptoms associated with oral and ocular dryness were assessed at the same time with the use of 100-mm visual analog scales. Safety was assessed by physical examination and laboratory studies. RESULTS: During these clinical trials, a majority of subjects demonstrated an increase in unstimulated whole saliva output and the treatment exhibited an excellent safety profile. The ACM treatment in study Omega led to significant improvement in several subjective measures of oral and ocular comfort. CONCLUSIONS: In these two studies, ACM lozenges administered three times daily for 12 or 24 weeks improved salivary output and decreased complaints of dry mouth and eyes. Side effects were minimal, and treatment was without significant adverse events. This safe and simple intervention may provide clinical benefit to individuals with distressing dry mouth symptoms.

Cytokine mRNA expression in the labial salivary glands of healthy volunteers.

OBJECTIVE: To examine the cytokine profile in minor salivary glands of healthy volunteers and examine differential cytokine production from acinar and ductal tissues. STUDY DESIGN: Acinar and ductal elements were isolated by a cell-specific micro-dissection technique from frozen 8 microns sections of minor salivary glands from healthy volunteers. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern hybridization using 32P-labeled cytokine gene-specific probes were utilized to detect cytokine mRNA. mRNA transcripts for the Th1 cytokines (IL-2, TNF-alpha, and IFN-gamma), Th2 cytokines (IL-4, IL-6, and IL-10), TGF-beta, actin, and CD3 delta were analyzed in acini, ducts and total tissue sections of minor salivary glands of six healthy controls. RESULTS: Actin, TGF beta and TNF alpha was present in 6/6 acinar, 6/6 ductal, and 6/6 total section samples. IFN gamma was present in 2/6 acinar, 3/6 ductal, and 6/6 total samples. IL-2 was found in 3/6 acinar, 3/6 ductal and 5/6 total sections. IL-6 was found in 1/6 acinar, 0/6 ductal, and 5/6 total sections. IL-10 was found in 3/6 acinar, 3/6 ductal, and 5/6 total sections. IL-4 was present in 0/6 acinar, 0/6 ductal and 1/6 total samples. CD3 delta was present in 6/6 acinar, 5/6 ductal and 6/6 total sections. CONCLUSIONS: These results demonstrate abundant expression of cytokines in healthy minor salivary glands. The production of these cytokines in healthy tissues demonstrates a likely role of supporting normal cellular function.

Clinical course of primary Sjögren's syndrome: salivary, oral, and serologic aspects.

OBJECTIVE: To assess changes in symptoms and signs, salivary function, serologic activity, and disease progression in primary Sjogren's syndrome (SS). METHODS: Treatment records on 80 patients seen in clinic and diagnosed with primary SS by defined criteria were reviewed. Forty-nine patients were evaluated at least twice a minimum of 5 years (mean 7 years) apart. Salivary flow rates from each of the major salivary glands and laboratory values were obtained. A structured interview with questions pertaining to signs and symptoms of primary SS was given and a physical examination was performed. An additional 26 patients completed a followup questionnaire by mail and their current medical records were obtained for review. For this group, the followup period was a mean of 10 years after their initial evaluation. Five patients were deceased. RESULTS: The patients seen twice showed relative stability in their salivary measurements and in their serologic values. The subjective sicca symptoms of oral and ocular dryness among the 75 surviving patients remained prominent. Very few individuals developed another connective tissue disease, therefore evolving into secondary SS. Among the 80 patients, 6 cases of B cell lymphoma were recognized during the followup period. CONCLUSION: Although it is not a benign condition, primary SS is a very slowly progressing disease without rapid deterioration in salivary function, systemic markers of disease activity, or dramatic changes in symptoms, with the exception of a high incidence of lymphoma.

Opening the flood gates: interferon-alpha treatment for Sjögren's syndrome.

Interferon (IFN)-alpha is the main IFN produced in response to viral infection. Low levels of IFNalpha can be detected in nasal secretions after exposure to viruses in vivo. Radioimmunoassay has shown that endogenous IFNalpha is low in children, reaches a peak in young adults, and gradually declines with aging. Importantly, this endogenous IFNalpha is significantly decreased in patients with Sjögren's syndrome (SS). IFNalpha has been tested as a therapeutic agent in patients with SS. Intramuscular human leucocyte IFNalpha increases saliva production significantly in patients with SS. Improvements have been noted in lacrimal function and in dryness symptoms. Since IFNalpha infrequently induces autoimmune phenomena and high dose IFNalpha treatment sometimes has a serious adverse event profile, treatment focus has shifted to use of low dose orally-administered IFNalpha. In a single-masked controlled trial, 60 patients with SS randomly received natural human IFNalpha 150IU 3 times a day in an oral lozenge formulation or sucralfate as control for 6 months. At study end, 15 (50%) of the 30 IFNalpha-treated patients had saliva production increases at least 100% above baseline. IFNalpha treatment was well tolerated and no patients withdrew. Labial minor salivary gland biopsies indicated significant decreases in lymphocytic infiltration accompanied by a significant increase in intact salivary gland tissue after 6 months of treatment. In another 12-week double-masked, randomised, placebo-controlled trial, stimulated saliva production in patients with SS receiving IFNalpha lozenges 150IU 3 times daily was significantly increased. This dosage was also suggestive of benefit for 5 of 7 subjective measures of oral and ocular comfort. The tolerability profile of these low dose oral IFNalpha lozenges is excellent; no serious adverse events have been recorded. Adverse effects were generally mild and there were no clinically significant changes in laboratory or clinical safety measures. Low oral doses of natural human IFNalpha thus appear to improve secretory function and relieve dryness in patients with SS without causing significant adverse events. Endogenous or orally administered IFNalpha may activate oropharyngeal lymphoid and epithelial cells and induce production of potent soluble factors which could mediate immunological reactivity. It has been suggested that IFNalpha/beta potentiates clonal expansion and survival of CD8 T cells. Stimulating effects have also been demonstrated on natural killer cell activity, which has been shown to be depressed in patients with SS. It is likely that some combination of these immunological effects results in anti-inflammatory activity and ameliorates signs and symptoms of SS.

Safety and efficacy of adenovirus-mediated transfer of the human aquaporin-1 cDNA to irradiated parotid glands of non-human primates.

This study evaluated the safety and efficacy of a single administration of a recombinant adenovirus encoding human aquaporin-1 (AdhAQP1) to the parotid glands of adult rhesus monkeys. In anticipation of possible clinical use of this virus to correct irradiation damage to salivary glands, AdhAQP1 was administered (at either 2 x 10(9) or 1 x 10(8) plaque-forming units/gland) intraductally to irradiated glands and to their contralateral nonirradiated glands. Radiation (single dose, 10 Gy) significantly reduced salivary flow in exposed glands. Virus administration resulted in gene transfer to irradiated and nonirradiated glands and was without untoward local (salivary) or systemic (sera chemistry, complete blood count) effects in all animals. However, the effect of AdhAQP1 administration varied and did not result in a consistent positive effect on salivary flow rates for all animals under these experimental conditions. We conclude that a single adenoviral-mediated gene transfer to primate salivary glands is well-tolerated, although its functional utility in enhancing fluid secretion from irradiated parotid glands is inconsistent.

Sex differences in primary Sjögren's syndrome.

OBJECTIVE: To examine the clinical and serologic characteristics of 14 men compared to 28 women with primary Sjögren's syndrome (SS) and contrast these findings with studies evaluating sex differences in primary SS. METHODS: Patient information was collected from patients seen at the National Institutes of Health Salivary Gland Dysfunction Clinic from 1987 to 1998. A total of 14 male patients were diagnosed with primary SS during this period. The control group consisted of 28 female patients matched according to focus score of the labial minor salivary gland biopsy. RESULTS: Women had significantly higher antinuclear antibody titers and erythrocyte sedimentation rate than men. A significant sex difference was also noted in extraglandular manifestations, with more women reporting fatigue compared to men (68 vs 21%, respectively). CONCLUSION: This study indicates that women may have more positive serological findings than men and a higher prevalence of fatigue. No sex differences could be established with other extraglandular manifestations of SS.

Salivary gland cytokine expression in NOD and normal BALB/c mice.

The autoimmune diabetes-prone nonobese diabetic (NOD) mouse develops a chronic lymphocytic infiltration of endocrine and exocrine glands. The objectives of this study were to characterize the salivary immune infiltration and cytokine expression of NOD mice and compare these findings to those of normal BALB/c mice. A decline in salivary flow rates in NOD mice began between 8 and 12 weeks of age. At this same time lymphocytic foci are detectable in the salivary glands. Lymphocytic infiltration in the salivary glands of NOD mice increased with age and simultaneously salivary function declined. No lymphocytic infiltration was seen in BALB/c salivary tissues. Messenger RNA expression of several inflammatory cytokines, including interleukin-1beta (IL-1beta), IL-2, IL-10, interferon-gamma, and tumor necrosis factor-alpha was detected in the submandibular glands of both NOD and BALB/c mice by the reverse transcription polymerase chain reaction. IL-4 synthesis was also present in some tissues. Immunohistochemical analysis demonstrated the intense expression of inflammatory cytokines within lymphocytic infiltrates and epithelial cells of all NOD mice. Minimal expression of the same cytokines was detected only occasionally in BALB/c tissues stained in parallel. These results demonstrate cytokine expression in the salivary glands of normal mice and suggest that the overexpression of these inflammatory cytokines is likely involved in the development and progression of the organ-localized autoimmunity in the salivary glands of NOD mice.

Treatment of primary Sjögren's syndrome with low-dose natural human interferon-alpha administered by the oral mucosal route: a phase II clinical trial. IFN Protocol Study Group.

The purpose of this investigation was to examine the safety and efficacy of four dosages of natural human interferon-alpha (nHuIFN-alpha) delivered over a 12-week period orally in lozenges (150 IU and 450 IU, once [QD] or three times [TID] daily) compared to placebo in subjects with primary Sjögren's syndrome. This randomized, double-blinded clinical trial demonstrated that nHuIFN-alpha at a dose of 150 IU administered TID by oral lozenge significantly improved stimulated whole saliva output compared to placebo after 12 weeks of treatment. The 150 IU TID dose also was suggestive of benefit for 5 of 7 subjective measures of oral and ocular comfort. IFN lozenges demonstrated a good safety profile, with no serious adverse events found in any treatment group. There were no significant differences between the placebo and the four doses of IFN for adverse events by total number, organ system, severity, dropouts, and number judged to be related to treatment. In conclusion, these results demonstrated that the use of 150 IU IFN lozenges TID for 12 weeks in subjects with primary Sjögren's syndrome improved salivary output and decreased complaints of xerostomia without causing significant adverse medical events.

Re-engineering the functions of a terminally differentiated epithelial cell in vivo.

Because of their easy access, and important role in oral homeostasis, mammalian salivary glands provide a unique site for addressing key issues and problems in tissue engineering. This manuscript reviews studies by us in three major directions involving re-engineering functions of salivary epithelial cells. Using adenoviral-mediated gene transfer in vivo, we show approaches to i) repair damaged, hypofunctional glands and ii) redesign secretory functions to include endocrine as well as exocrine pathways. The third series of studies show our general approach to develop an artificial salivary gland for clinical situations in which all glandular tissue has been lost.

Ion transport and signalling in human labial glands.

Recent reports characterizing the physiological properties of normal human labial acini are reviewed with particular emphasis on mechanisms related to fluid secretion. In contrast to the salivary glands of several experimental animals, human labial acinar cells do not appear to have a1-adrenergic receptors, substance P peptidergic receptors, or significant levels of Cl-/HCO3- exchange. Nor do they appear to secrete HCO3- in response to Ca2+ mobilizing stimuli. The data presently available indicates that fluid secretion by these glands is mainly under muscarinic control and is due to acinar Cl- secretion driven by a basolateral Na+ -K+ -2Cl- cotansporter.

Cytokine expression in human labial minor salivary gland epithelial cells in health and disease.

Microdissection of biopsy material from labial minor salivary glands followed by RT-PCR demonstrates extensive production of cytokines IL-2, 1L-6, IL-10, TNF-alpha, TGF-beta, and IFN-gamma in both normal glands and in glands affected by Sjögren's syndrome. Continuation of these studies should expand our knowledge of normal salivary gland function and the pathogenesis of Sjögren's syndrome.

Long-term salivary effects of single-dose head and neck irradiation in the rat.

The effect of a single dose of X-irradiation (either 2.5, 5, 7.5, 10 or 15 Gy) to the head and neck region on parotid and submandibular gland function in rats was evaluated for up to 1 year. No animal receiving 15 Gy survived the entire study. Animals receiving > or = 7.5 Gy showed significantly less increase in body weight over time. Average wet weights of both gland types were reduced with as little as 2.5 Gy. Pilocarpine-stimulated parotid salivary flow was diminished significantly at 12 months for each radiation-dose group. Significant salivary flow reductions from submandibular glands were seen at > or = 7.5 Gy at this same time-point. These results show that a single radiation exposure of as low as 2.5 Gy to the head and neck region of rats can cause significant long-term alterations in salivary gland function.