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INTRODUCTION To establish the efficacy of bepotastine besilate ophthalmic solution (bepotastine) 1.5%, a dual acting histamine H1 receptor antagonist approved for treatment of ocular itching associated with allergic conjunctivitis, compared to placebo in relieving ocular itching and redness for subjects with active allergic rhinoconjunctivitis. METHODS A randomized, double-masked, placebo-controlled, confirmatory natural exposure study of bepotastine 1.5% and placebo was conducted during allergy season at 12 clinical sites throughout the U.S. Following a 7-day screening period, eligible subjects ≥12 years old were assigned in a 1:1 ratio to dosing OU b.i.d. either bepotastine 1.5% (n = 123) or placebo (n = 122). Subjects recorded instantaneous grades for their ocular symptoms prior to their next dose for 14 consecutive days. Clinically significant reduction in ocular sign or symptom grades between treatment groups required p ≤ 0.05 as determined by ANCOVA analysis. RESULTS Significant clinical effectiveness with bepotastine 1.5% was demonstrated over the 2-week treatment period in comparison to placebo in the intent-to-treat population for reducing mean instantaneous grades for both ocular itching (p = 0.007) and redness (p = 0.001). Investigator rating of efficacy over the 2-week treatment period across response categories was also superior for bepotastine 1.5% compared to placebo (p = 0.024). Only one subject discontinued participation in the study due to an adverse event. CONCLUSIONS These data support bepotastine 1.5% as an effective treatment for allergen-induced signs and symptoms in a clinical study designed to closely resemble the conditions under which patients with allergic rhinoconjunctivitis would require treatment.

Immunopathology is recognized as an important component of infectious disease manifestations, and corticosteroids have been used as an adjunct to antimicrobial therapy for a variety of conditions. Antiviral therapy of herpes labialis has been shown to result in only a small reduction in the time to healing and the duration of pain. To determine if topical application of a combination product containing 5% acyclovir and 1% hydrocortisone (ME-609) could provide benefit to herpes labialis patients, 380 immunocompetent adults with a history of herpes labialis were exposed to experimental UV radiation (UVR) to induce a recurrence. On day 2, just before the appearance of the majority of lesions (“delayed” lesions), subjects were randomized to receive active medication or vehicle control six times per day for 5 days. Overall, 120 of 380 patients developed delayed classical lesions, of whom 50 of 190 (26%) had been treated with ME-609 and 70 of 190 (37%) had received placebo (a reduction of 29% [ P = 0.02]). Healing time, measured as the time to normal skin, was reduced by treatment with ME-609 (9.0 days for treated patients versus 10.1 days for the controls [ P = 0.04]). There was a trend toward a reduction in the maximum lesion size in the ME-609 recipients compared to that in the controls (43 versus 60 mm 2 , respectively [ P = 0.07]). The treatment had no effect on lesion pain, but ME-609 treatment reduced the number of patients with moderate or severe tenderness. Compared to treatment with a placebo, treatment with the combination antiviral-immunomodulatory cream provided benefit to patients with experimental UVR-induced herpes labialis, reducing classical lesion incidence, healing time, lesion size, and lesion tenderness. ME-609 is a novel product that merits further evaluation as a treatment for cold sores.

The specific immune alterations associated with HSV recurrences are ill defined although it appears that alterations in cell-mediated immune mechanisms are more likely associated with recurrent disease than humoral immunity. Immunization with HSV glycoproteins B and D (gBgD) after primary HSV infection has reportedly reduced the frequency of recurrences but the mechanisms remain unidentified. We therefore evaluated the effects of immunization with cloned gBgD on selected cell-mediated immune responses and their relationship to recurrent disease by using the guinea pig model of genital HSV-2 infection. In two experiments, immunization with gBgD + CFA on days 21 and 42 after HSV-2 inoculation significantly decreased the number of subsequent recurrent lesion days observed whereas CFA alone had no effect. Immunization with gBgD + CFA increased the lymphoproliferative and in vitro IL-2 response to gBgD more than to whole HSV-2 Ag preparations. Peak responses were observed 2 wk after the second immunization. The HSV-specific cytolytic response was also persistently increased beginning 1 wk after the first immunization. Analysis including both untreated and gBgD-immunized animals revealed that recurrent lesion days were inversely correlated to the IL-2 response to whole HSV-2 Ag (p less than 0.0001), the IL-2 response to gBgD (p = 0.0004), and the HSV-specific cytolytic response (p = 0.005 and 0.003 in two experiments, respectively). When the untreated group was analyzed separately, only the IL-2 response to whole HSV-2 Ag correlated to recurrences (p = 0.007). HSV glycoprotein immunization may increase IL-2 or other cytokines secreted by HSV-sensitized T cells increasing critical immune responses, such as NK- or lymphokine-activated killer-mediated cytolysis, that could eliminate the reactivated virus before the development of clinically apparent lesions.

The concept of using immunotherapy to treat recurrent herpesvirus infections dates back to the 1930s, although many of the initial studies were seriously flawed. Since the late-1980s, however, the use of the guinea pig model of genital herpes has allowed investigators to evaluate carefully several vaccine and immunomodulatory strategies for the control of recurrent herpesvirus infections. These investigations have clearly shown that both approaches can significantly decrease recurrence rates of genital herpes, and the most effective routes, adjuvants and treatment regimens have been identified. Similar strategies have also been shown to decrease herpes simplex virus (HSV)-1 recurrences in animal models of ocular infection. To date, only moderate success has been reported for human trials, although the optimum strategies that were identified in the animal models have not yet been evaluated.

Diisocyanates are among the most frequent causes of occupational asthma in industrialized countries. Early diagnosis of diisocyanate asthma followed by prompt termination of chemical exposure can prevent chronic morbidity due to persistent asthma. The accurate diagnosis of diisocyanate asthma requires a systematic approach that combines information obtained from the occupational history, immunologic tests and physiologic studies.The advantages, limitations and validity of various methods and diagnostic guidelines utilized in the evaluation of diisocyanate asthma are reviewed.Recommended methods for evaluation of diisocyanates asthma are similar to approaches for other causative agents. Serologic assays of specific IgE are specific but insensitive diagnostic markers of diisocyanate asthma. If possible, workers should be evaluated, while at work, in order to demonstrate work-related changes in lung function associated with diisocyanate exposures. Specific bronchoprovocation challenge testing with diisocyanates, is reserved for situations where the diagnosis cannot be confirmed at work. Such tests can be performed safely but should be conducted exclusively at specialized centers by experienced personnel.Published diagnostic guidelines for occupational asthma are directly applicable to the evaluation of diisocyanate asthma.

Mometasone furoate nasal spray (MFNS, NASONEX ), is a new synthetic corticosteroid with considerable efficacy in the treatment of seasonal and perennial rhinitis and less than 0.1% systemic absorption. This study was designed to evaluate the time of onset of action of MFNS. The subjects were evaluated over the course of 2 weeks during the spring allergy season.The effects of MFNS 200 microg given once daily for 2 weeks were evaluated in a randomized, multicenter, double-blind, placebo-controlled study in 201 patients with seasonal allergic rhinitis. Clinically significant onset of action was assessed prospectively by special patient diary cards kept during the first 3 days of treatment.By 12 h after initial dosage (the earliest evaluation), 28% of patients in the MFNS group experienced clinically significant relief, compared with 13% of those given placebo (P = 0.01). Median time to at least moderate symptom relief in patients who received MFNS was 35.9 h, compared with more than 72 h in patients given placebo (P0.01). By 72 h, 64% of the patients receiving MFNS experienced at least moderate relief, compared with 40% of those treated with placebo (P0.01). Both patient and physician ratings of symptom severity, response to treatment, and overall condition of rhinitis indicated significant (P0.01) superiority of MFNS over placebo. MFNS was well tolerated, with adverse events comparable to placebo.MFNS provided rapid onset of clinically significant symptom relief in patients with seasonal allergic rhinitis.

Intravaginal inoculation of mice with an attenuated strain of herpes simplex virus type 2 (HSV-2) resulted in vigorous HSV-specific immune responses that protected against subsequent challenge with fully virulent HSV-2 strains. Even in the presence of high titers of HSV-specific Ab, T cell-dependent mechanisms were required for protection of the vaginal mucosae of HSV-immune mice and could be detected by 24 h after intravaginal reinoculation. Depletion of specific T cell subsets from HSV-immune mice before HSV-2 reinoculation demonstrated that CD4+ T cells were primarily responsible for this protection. Similarly, optimal protection of the sensory ganglia against reinfection with HSV-2 was dependent on the presence of T cells. Infectious HSV-2 was not detected in the sensory ganglia or spinal cord of HSV-immune mice depleted of only CD4+ or CD8+ T cells, suggesting that the T cell-mediated protection could be provided by either subset. Similarly, neutralization of IFN-gamma during challenge of HSV-immune mice resulted in diminished protection of the vaginal mucosa, but not of the sensory ganglia. These results suggest that the ability to induce vigorous HSV-specific T cell responses is an important consideration in the design of vaccines to protect both the vaginal mucosa and sensory ganglia against HSV-2.

National and international guidelines recommend the use of inhaled antiinflammatory medications in patients with all but the mildest forms of asthma. Twice daily dosing may increase compliance with therapy.We sought to evaluate the safety and efficacy of 400 microg twice daily triamcinolone acetonide (TAA) compared with placebo in adult patients with mild-to-moderate asthma who were poorly controlled by beta2-agonist therapy.We performed a multicenter, randomized, double-blind, placebo-controlled study, including a screening visit, a 7- to 21-day pretreatment baseline phase, and a 6-week double-blind treatment phase. Efficacy was measured by weekly spirometry and daily diary recordings of peak flow rates, asthma symptom scores, and albuterol use. Eligible patients used albuterol four or more times per day, had total asthma symptom scores of 15 or greater (possible total, 60) over 5 of 7 baseline days, and had FEV1 measurements of 60% of predicted value or greater.One hundred twenty-one patients were randomized to treatment. TAA was superior to placebo for all efficacy measures, with significant improvements in asthma symptoms, albuterol use, morning and evening peak flow rates, and forced vital capacity evident at Treatment Week 1. Significant improvements in other pulmonary function measurements were observed after 2 or more weeks. All efficacy variables improved progressively throughout the study.Twice daily TAA (400 microg) decreased asthma symptoms and improved lung function in patients with mild-to-moderate asthma compared with placebo. Therapeutic benefit was evident within 1 week and increased throughout treatment.

A study of occupational asthma among workers exposed to 4,4'-Diphenylmethane Diisocyanate (MDI).To demonstrate if serum concentrations of MDI-specific IgG or IgE are sensitive biological markers of disease or of MDI exposure.The study group consisted of nine MDI-exposed workers and nine nonexposed workers. Air sampling for MDI and polymethylene polyphenyl isocyanate, occupational and medical histories, respiratory physical exams, pre- and postshift spirometry, and self-administered peak expiratory flow rates were performed. Serum specific IgE and IgG antibodies to an MDI-human serum albumin (HSA) conjugate were assayed by the radioallergosorbent test and the enzyme-linked immunosorbent assay, respectively, and compared to nine nonexposed laboratory controls.No definitive cases of occupational asthma were documented. The mean level of MDI-specific IgG was significantly greater among exposed workers compared to nonexposed workers and laboratory controls (p = 0.04). Mean levels of TDI and HDI-specific IgG were also increased.This study demonstrates that serum concentrations of MDI-specific IgG appear to be a moderately sensitive biological marker of MDI exposure, but not an indicator of occupational asthma. Workers with IgG antibodies specific for one diisocyanate-HSA conjugate exhibit cross-reactivity to antigens prepared with other diisocyanates.

Sexually transmitted diseases (STDs) are associated with significant morbidities for adolescents. This study sought to determine the relationship of demographic characteristics, sexual history, and psychological characteristics to actual acquisition of STD. Adolescents were recruited from their source of primary care: 44 males and 88 females matched on age and race. A series of logistic regression analyses were used to determine which of the independent variables were significantly associated with self-reported STD occurrences. When age, race, and gender were pretested, older age and being female were found to be associated with more episodes. The final model consisted of older age, female gender, greater number of lifetime partners, perceived greater frequency of STDs among adolescents in general, less negative feelings about STD acquisition, and being less likely to believe your friends would think you were bad. The findings indicate that acquisition of an STD is related to the demographic characteristics of age and gender, as well as to the number of lifetime partners and attitudes about STD acquisition. This information can be used to develop intervention programs.

Multiple chemical sensitivity (MCS) has been defined as "an acquired disorder of recurrent symptoms, referable to multiple organ systems, occurring in response to chemically unrelated compounds at doses far below those established in the general population to cause harmful effects" [Cullen, State Art Rev. Occup. Med. 2, 655 (1987)]. The pathophysiologic basis for the MCS syndrome has not been clearly defined. However, allergic reactions to specific chemicals encountered in the environment are much better understood.

Previous clinical studies have demonstrated that injectable gold salts and the oral gold compound, auranofin, possess significant steroid-sparing effects in the treatment of asthma.The objectives of this investigation were to determine whether auranofin could reduce oral corticosteroid requirements and to evaluate the safety of auranofin in the treatment of chronic corticosteroid-dependent asthma.Patients with asthma were eligible if they required at least 10 mg of prednisone per day for control and prevention of asthma exacerbations. Two hundred seventy-nine patients with chronic corticosteroid-dependent asthma (requiringor = 10 mg/day) were randomized to receive auranofin, 3 mg twice daily, or placebo during an 8-month clinical trial, which was divided into three phases including: a 4-week baseline period (phase I), a 6-month double-blind treatment and steroid reduction period (phase II), and a 4-week posttreatment observation period during which steroid and auranofin doses or placebo doses were maintained at levels achieved by the end of phase II (phase III). The primary efficacy variable was "therapeutic success" or reduction of daily corticosteroid use by 50% or more.The proportion of patients in the auranofin group achieving therapeutic success (41%) was significantly higher than that in the placebo group (27%) (p = 0.01). This effect was greatest in patients requiring 10 to 19 mg of oral prednisone per day at baseline (p0.001). In all treated patients, including those who did and did not complete the trial, significant reduction (or = 50% of baseline) in oral corticosteroid dosage was achieved in the auranofin group (60%) compared with the placebo group (32%) (p0.001). There were no significant differences between treatment groups in symptoms, concomitant medication use, or lung function. Mean serum total IgE levels decreased significantly from baseline in the auranofin group (-44.63 IU/ml) compared with the placebo group (p = 0.001). Gastrointestinal and cutaneous adverse events were greater in the auranofin group.Auranofin demonstrated a steroid-sparing effect without concomitant worsening of symptoms or lung function and appeared to be more effective in patients dependent on 10 to 19 mg of prednisone per day. Therefore this study has demonstrated that auranofin is useful as a steroid-sparing agent in the treatment of chronic corticosteroid-dependent asthma.

Thirty-six employees who produced industrial enzymes from selected strains of bacteria and fungi were evaluated by epicutaneous threshold testing and enzyme-linked immunosorbent assays (ELISA) for specific IgE and IgG antibodies. The workers complained of 'asthma- and flu-like' symptoms, which generally lessened away from work. The enzymes evaluated were: alpha-amylase (1,4-alpha-d-glucan glucanohydrolase) from Bacillus licheniformis (alpha ABl), B. subtilis formation 1 (alpha A1Bs) and B. subtilis formation 2 (alpha A2Bs); purified alpha-amylase from B. licheniformis (C alpha ABl) and A. oryzae (C alpha AAo); alkaline protease from B. licheniformis (APBl) and purified alkaline protease (CAPBl); amyloglucosidase (1,4-alpha-d-glucan glucohydrolase) from A. niger (AGAn) and purified amyloglucosidase (CAGAn). Statistically significant increases (P0.05) in the proportion of workers having positive skin tests to CAPBl, AGAn and CAGAn were found. Significantly elevated (P0.05) mean specific IgE results were observed for C alpha AAo CAGAn and AGAn, and elevated (P0.05) mean specific IgGs were observed for C alpha AAo, CAGAn, AGAn, alpha A1Bs, alpha AB1 and alpha A2Bs. These results indicate that occupational exposure to some industrial enzymes can cause immediate-onset cutaneous hypersensitivity reactions, pulmonary function deficits and significantly elevated specific antibody levels. Our results are equivocal as to whether work-related respiratory and cutaneous hypersensitivity reactions are antibody mediated, as there was no statistically significant association between these reactions and specific IgE or IgG levels.

The morbidity and mortality of neonatal herpes simplex virus infection remains unacceptably high despite antiviral therapy. A better understanding of factors that might contribute to this poor outcome is needed but has been hindered by a lack of a good animal model. The recently described guinea pig model of neonatal HSV-2 infection was used to explore the effect of age and route of inoculation on the outcome of infection. After intranasal inoculation the onset, extent, and severity of the primary disease, as well as the number of recurrent lesion days, varied inversely with age. The route of inoculation also affected the outcome. Newborn animals were inoculated either intradermally on the scalp or by the intranasal, oral or corneal route. Animals inoculated on the scalp had the best outcome with no deaths or evidence of neurologic disease while the intranasal route produced the most severe disease, 88% mortality. Neurologic disease was common after oral (41%) and corneal (56%) inoculation but resolved spontaneously whereas following intranasal (39%) inoculation all animals with neurologic disease died. Recurrent disease manifest by cutaneous lesions was observed in all survivors of each group but also differed by the route of inoculation. The guinea pig model of neonatal HSV-2 disease appears to mimic human disease. The studies presented here show that the outcome of infection is influenced by the age and route of inoculation.

Rotavirus is a leading cause of morbidity and mortality from dehydrating gastroenteritis in infants and young children worldwide. Virtually every child is infected by age 4 years, justifying universal childhood immunization when a safe and effective vaccine is available. We report the results of a multicenter, placebo-controlled field trial in the United States of monovalent serotype 1 and tetravalent (TV) rhesus-human reassortant rotavirus vaccines (RRVs).In this randomized, double-blind trial, 1278 healthy infants ages 5 to 25 weeks received three oral doses of RRV serotype 1, RRV-TV, or a placebo at approximately 2, 4, and 6 months of age. Vaccines contained 4 x 10(5) plaque-forming units of virus. Gastroenteritis episodes were monitored, and severity was graded throughout one rotavirus season. Two stool specimens per episode were tested for rotavirus.The incidence of reactions did not differ among treatment groups during the 5-day, postvaccination safety surveillance period for any of the three doses. Both vaccines significantly reduced the incidence of rotavirus gastroenteritis. Vaccination was most protective against serious rotavirus illness; RRV-TV prevented 49% of rotavirus episodes, 80% of very severe episodes, and 100% of dehydrating rotavirus illness. Reduction of rotavirus disease by RRV-TV resulted in significantly fewer total episodes of gastroenteritis of all causes and an 82% reduction in all cases of dehydrating diarrhea.RRV-TV is highly protective against very severe, dehydrating rotavirus gastroenteritis.

Six auto parts manufacturing workers were referred for evaluation of a 6-week history of work-related dyspnea, cough, and fatigue. Two workers also reported fever and weight loss. All six worked in a machining area where a waterbased metalworking fluid was used and recirculated under high pressure, thereby creating an aerosol. Chest radiographs revealed pulmonary interstitial infiltrates in four workers. Lung function tests showed that four workers had decreased diffusing capacity. After removal from the work area, all workers recovered. The metalworking fluid was cultured for bacteria and fungi. Isolates from broth cultures were sonicated to obtain antigen extracts. Serum precipitins to one or more of the microbial isolates were identified in all six workers but not in eight of nine nonexposed control subjects. The most frequent precipitin response (six of six workers) was against antigens of Pseudomonas fluorescens, which was cultured from the metalworking fluid. In all workers, precipitins to at least one other cultured organism were detected; these included Aspergillus niger, Staphylococcus capitas, an acid-fast Rhodococcus sp, and Bacillus pumilus. This represents the first report of hypersensitivity pneumonitis associated with industrial exposure to aerosolized metalworking fluid. Observed precipitin responses to a variety of microbial contaminants in metalworking fluid strongly suggest a causative role for microbial antigens in the induction and elicitation of this manifestation of hypersensitivity pneumonitis.

In a large placebo-controlled efficacy trial of the rhesus tetravalent (RRV-TV) and serotype 1 monovalent (RRV-S1) rotavirus vaccines in multiple sites throughout the United States, protection against rotavirus disease over a 2-year period was found to be 57 and 40%, respectively (Bernstein et al., J. Am. Med. Assoc., 1995, 273, 1191-1196). Sera collected from a subset of subjects during this trial were used to determine possible correlations between rotavirus antibody responses after vaccination and protection. Between 82% (RRV-S1) and 92% (RRV-TV) of the vaccinees seroconverted by at least one of the six antibody assays performed (i.e. rotavirus IgA and neutralizing antibody to RRV and serotype 1-4 human rotaviruses). Rises in neutralizing antibody were due primarily to RRV. The seroconversion rate was only 18-22% to each of the four human rotavirus serotypes following RRV-TV vaccination and was only 43% to serotype 1 human rotavirus after RRV-S1 administration. Furthermore, no correlate of immunity against rotavirus infection or disease was identifiable based on seroconversion to any of the antibodies measured. Likewise, no consistent relationship was found between the titers of any of these six antibodies following vaccination and protection against rotavirus, thus suggesting that serum antibody titers will not be useful markers of protection with these reassortant RRV vaccines. In addition, vaccinated subjects did not develop higher titers of neutralizing antibody to human rotaviruses following a subsequent natural rotavirus illness, a further indication that only weak immune responses to human rotaviruses were stimulated by vaccination with the RRV reassortants.(ABSTRACT TRUNCATED AT 250 WORDS)

Rapid venom immunotherapy regimens have been developed to provide safe protection to individuals who have experienced Hymenoptera anaphylaxis by administering greater than 50 micrograms of venom over two to three hours on treatment day 1. A rapid venom immunotherapy protocol which consisted of administration of a cumulative dose of 58.55 micrograms of each venom on treatment day 1 followed by an accelerated build-up over 3 weeks to a final maintenance dose of 100 micrograms per venom was developed by our group in 1984.We report our 10-year cumulative experience with this rapid venom immunotherapy regimen.Seventy-seven venom-allergic patients received a cumulative dose of 58.55 micrograms per venom on treatment day 1 in an ambulatory care setting. Rapid venom immunotherapy was assessed for safety. A cost analysis was performed to compare rapid venom immunotherapy to a modified rush immunotherapy regimen.Four patients (5.2%), experienced mild systemic reactions consisting of diffuse urticaria on day 1. Treatment was otherwise well tolerated. Resting events occurred in 21 patients, a mean number of 12 months (range: 3 days to 48 months) after treatment, without systemic reactions.This experience confirms that rapid venom immunotherapy is safe to administer in an ambulatory setting and should be considered especially for patients during the stinging insect season when rapid protection is required.

Imiquimod, an immunomodulator with no direct in vitro antiviral activity, has in vivo anti-herpesvirus activity by inducing interferon and enhancing other only partially defined immune responses. Imiquimod treatment of primary genital herpes simplex virus (HSV) infection in guinea pigs reduces the level of genital disease by 90%. We further investigated its utility as suppressive therapy of recurrent disease in animals that had recently recovered from primary genital HSV-2 disease. Imiquimod administered intravaginally once per day for 5 days reduced the number of recurrences only during treatment, while a 21-day regimen reduced the number of recurrences for 8 weeks. For the entire 10 weeks of observation, overall numbers of recurrences were reduced 67% by the 21-day imiquimod treatment (P < 0.0001). Latent HSV in ganglia was not affected by either regimen. Increased circulating alpha interferon activity was observed during therapy with both regimens. Interferon levels rapidly returned to baseline with cessation of treatment. Posttreatment, 5-day imiquimod treatment did not provide clinical benefit or enhancement of cell-mediated or cytokine responses. Twenty-one-day imiquimod treatment reduced both the number of clinical recurrences and levels of HSV antibody for 5 to 6 weeks posttreatment compared with the placebo. Additionally, 21-day imiquimod treatment enhanced HSV antigen-specific interleukin 2 production and proliferative responses by mononuclear cells (P < 0.001) for 4 weeks after treatment. Twenty-one-day imiquimod therapy suppressed recurrent HSV genital disease during and for weeks after therapy, enhanced memory-dependent cytokine and T-cell responses, and reduced the level of antibody responses.

The quaternary amine, benzalkonium chloride, has been associated with cutaneous and mucosal delayed hypersensitivity reactions and with paradoxical bronchoconstriction after use of aerosolized asthma medications. Until now, quaternary amines have not been reported to cause occupational asthma. We describe a case of occupational asthma caused by prolonged exposure to a cleaning solution containing benzalkonium chloride in the workplace. Single-blind, placebo-controlled, open-room challenges were performed to determine the specific agent responsible for the patient's symptoms. Pulmonary function and epicutaneous challenge tests were also performed. The patient had positive responses to challenges with a liquid toilet bowl cleaner containing benzalkonium chloride but was unreactive to other agents tested. Removal from the workplace resulted in complete resolution of symptoms. The exact mechanisms responsible for occupational asthma induced by quaternary amines remain unknown; however, this case emphasizes the importance of recognizing reactive chemicals as possible causes.

Determination of protective efficacy after natural rotavirus infection is important as a basis for evaluating rotavirus vaccines. Therefore, placebo recipients in a large 2-year rotavirus vaccine trial conducted across the United States were followed to determine the protection afforded by natural rotavirus infection. Serotype 1 rotaviruses predominated (93% year 1, 66% year 2), but isolates of all four major human rotavirus serotypes circulated during both years. Of the 45 placebo recipients with documented rotavirus illnesses in year 1, 1 developed rotavirus disease in year 2 compared with 29 of the other 235 placebo recipients (P = .03). Serologic data were available for 171 placebo recipients, and 37 of 140 without rotavirus illnesses in year 1 had evidence of asymptomatic rotavirus infection. None of these 37 experienced rotavirus disease in year 2 compared with 22 of the remaining 103 (P.001). Overall efficacy after natural rotavirus infection was 93% (95% confidence interval, 50%-99%).

Localized vaginal inflammation after contact with seminal plasma has been previously described but without a clear understanding of the underlying immunopathogenesis. The purpose of this report is to describe three women who presented with localized postcoital vaginal reactions that were successfully treated with rapid immunotherapy using human seminal plasma proteins.One atopic and two nonatopic women with histories of immediate onset of localized postcoital vaginal symptoms and immediate skin test reactions to human seminal plasma were treated with rapid immunotherapy using their spouse's purified seminal plasma protein fractions. One of the women had decreased cutaneous reactivity post-therapy and detectable circulating specific immunoglobulin (Ig) G and IgE antibodies to her spouse's fractionated seminal plasma proteins. Increased IgG, IgE, and IgA antibodies were found in these patients' sera to whole seminal plasma of a normal male control and to fractionated proteins of different men, indicating that one or more homologous seminal plasma proteins may be responsible for these reactions. Their localized vaginal symptoms resolved completely after rapid immunotherapy treatment. Two of the women have remained symptom-free, whereas the third woman had recurrent localized vaginal symptoms after failing to maintain frequent sexual intercourse after treatment.Rapid immunotherapy immediately alleviated vaginal reactions to seminal plasma in all patients. These cases indicate that the pathogenesis of some localized vaginal inflammatory reactions may involve IgE-mediated or other immune responses to human seminal plasma proteins.

A patient with severe acquired angioneurotic edema had essentially no C1- inhibitor activity in his serum and nearly died of cardiopulmonary arrest during an acute episode of facial, oral, and pharyngeal edema. This patient had an antibody directed against C1- inhibitor and C1- inhibitor-anti-C1- inhibitor complexes in his serum. The antibody required a normal residue (Arg) in the reactive center of the inhibitor for its optimal interaction with the inhibitor. Plasmapheresis with 5% human serum albumin replacement relieved him of his antibody load and the edema; additional treatment with pulsed cyclophosphamide has provided a sustained remission. The 5% albumin solution that was used contained functional C1- inhibitor; other lots that were tested contained only traces or none. No underlying disease has yet been identified. During this acute episode of edema, the C1- inhibitor in the patient's plasma was a 92 kd component, and on recovery, a 105 kd component reappeared. C1- inhibitor isolated from the patient's plasma, which was obtained before pheresis, was mainly in lower molecular weight forms (56 kd and 45 kd). The antibody in the patient's serum appeared to render C1- inhibitor susceptible to proteolysis, for when purified antibody was added to normal serum, a cleaved form of C1- inhibitor was generated.

Context National disease burden of rotavirus disease requiring hospitalization in the US has been estimated by an epidemiologic case definition (ECD) that combines nonspecific diagnosis codes with age and seasonal patterns of rotavirus illness and that has unknown sensitivity and specificity. Objective To compare estimates of rotavirus disease requiring hospitalization using the ECD compared with active case finding (ACF = acute gastroenteritis with RV detection). Design/Methods Age-eligible children were enrolled 5 days a week over 2 years at three pediatric hospitals if acute ( Patients Of 73,087 hospitalizations, 14,951 age-eligible patients were screened. Of these, 3,109 had eligible symptoms, 2,254 (72%) were enrolled, and 1,951 (87%) had a stool tested. Results Of 1,598 patients with acute gastroenteritis, 208 (13%) met the ECD and 447 (115% more) the ACF. Other children (13% more) with rotavirus illness detected by stool excretion included some with short-stay hospitalizations, F only, or younger age (15-30 d). From the 19% seroresponse rate in 89 serum pairs, 221-296 (106-142% more) rotavirus hospitalizations occurred from children testing rotavirus negative. Rotavirus-positive cases not ECD eligible (n = 94) were younger, less likely to have diarrhea or vomiting, less likely to have acute gastroenteritis attributed to be the cause of hospitalization, and more likely to be given generic diagnoses for "febrile illness " or "viral infection " (each comparison with p Conclusions The epidemiologic case definition did not detect 71-74% of the rotavirus hospitalizations in this multicenter, active surveillance study.

R837 is an immune modulator with no in vitro activity against herpes simplex virus (HSV). We evaluated topical R837 as therapy for genital HSV type 2 infection using the guinea pig model of this disease. Furthermore, we investigated the effect of R837 therapy on acute and latent neural HSV infections. Therapy initiated 12 h after viral inoculation and given twice a day significantly reduced the acute neural infection so that HSV was recovered from only 1 of 64 neural tissue specimens obtained from R837 recipients compared with 43 of 56 specimens obtained from placebo recipients (P less than 0.0001). R837 initiated 36 h after HSV inoculation and given once a day also significantly reduced the total mean lesion score of the acute disease from 14.1 +/- 4.3 to 2.6 +/- 5.3 (P less than 0.0001) and shortened the period of vaginal HSV shedding from 6.9 +/- 1.7 to 3.2 +/- 1.4 days (P less than 0.001). R837-treated animals also developed fewer HSV recurrences than did controls (2.0 +/- 1.7 versus 5.1 +/- 1.7; P less than 0.0002). Latent HSV was detected in 23 of 24 dorsal root ganglia explant cultures from placebo recipients but in only 2 of 30 cultures from R837-treated animals, and HSV in these 2 cultures was detectable only with the addition of a demethylating agent. Topical R837 exhibited in vivo anti-HSV activity, reducing both acute and latent neural infections as well as acute and recurrent genital disease.

Acute serum samples from patients with nonprimary first-episode genital herpes were evaluated for the presence of type-specific antibody to herpes simplex virus type 1 and type 2. A standard microneutralization assay and western blot analysis, which identified the response to individual polypeptides of type 1 and type 2 herpes, were performed in both unadsorbed serum samples and serum samples adsorbed with either type 1 or type 2 antigens to remove cross-reacting antibodies. Of 24 serum samples examined, seven were found to contain only type 1 antibodies, 11 had type 2 antibodies alone, and six serum samples had both type 1 and type 2 antibodies. It is believed that a majority of the 17 patients whose acute serum samples already contained type 2 antibody were experiencing their first clinically apparent recurrence of a previous asymptomatic type 2 infection. Physicians should, therefore, acknowledge that patients with first-episode nonprimary herpes 2 infection may not have had a recent sexual contact with a herpes simplex virus-infected partner.

Clinical reactions and hemagglutinating-inhibiting (HAI) antibody responses to recent whole-virus and split-product influenza vaccines were studied in 168 children and young adults. The subjects initially received a monovalent vaccine, followed one month later by a trivalent preparation. The reactogenicity of whole-virus and split-product vaccines with an equivalent hemagglutinin content was similar except in the youngest age (6 to 36 months) group in which the whole-virus preparation was more reactogenic. The whole-virus vaccines were more immunogenic, especially in subjects who were previously unprimed (preimmunization HAI antibody titer, less than 5). In these subjects, the geometric mean titers of HAI antibody wee significantly higher after vaccination with whole-virus vaccines than the split-product vaccines. Specific IgM antibody was found more frequently after vaccination with whole-virus vaccines (34%) than after split-product vaccines (11%).

Twenty workers exposed to trimellitic anhydride (TMA) powder an phthalic anhydride (PA) fumes concurrently were evaluated by questionnaire and serum antibody studies. The study group was divided into high-an low-exposure groups on the basis of job descriptions and intensity of daily exposure. The questionnaire, which was designed to identify symptoms compatible with TMA-associated rhinitis, asthma, late respiratory systemic syndrome, and irritant responses, was administered to 18 of 20 workers. Total antibody binding was determined by the ammonium sulfate assay, and specific IgG and IgE binding was measured with an enzyme-linked immunosorbent assay (ELISA) to both PA-human serum albumin (PA-HSA) and TMA-human serum albumin (TM-HSA) conjugates. Specific IgE to TM-HSA was measured with the polystyrene-tube radioimmunoassay (PTRIA). The questionnaire identified nonirritant, immunologic symptoms caused by TMA primarily in the high-exposure group. Specific IgG, IgE, and total antibody binding to TM-HSA and PA-HSA were found exclusively in the high-exposure workers. One worker was identified with PA-associated rhinitis, high total antibody binding, and specific IgG and IgE to PA-HSA by means of the ELISA. The ELISA was as sensitive as the PTRIA in detecting the presence of specific IgE to TM-HSA. The present study demonstrates that an itemized questionnaire, combined with ELISA IgG and IgE determinations, may be a sensitive method for identifying workers who have or are at risk for developing TMA-induced respiratory symptoms.

The use of HSV1 as a retrograde transneuronal marker for the CNS was assessed in several neuroanatomical systems of the rat brain including the olfactory, visual and somatosensory systems. In all systems, retrograde transneuronal transport was observed; with appropriate survival times transport was evident in third and fourth order neurons in established neuronal circuits. A striking observation was the high frequency of neurons labelled in a Golgi-like manner. The visualization of even the finest dendritic processes provides information about the architecture of neurons several synapses removed from the site of injection. The Golgi-like labelling is so complete that it is possible to identify and process distal parts of dendrites for EM analysis. Thus, it should be feasible to identify synaptic inputs to the dendrites of neurons two or more synapses removed from the site of injection. There was spotty evidence for anterograde transport but the vast majority of the labelling could be accounted for by retrograde transport. With increased survival time, some regions, especially those located one synapse removed from the injection site, became necrotic and the virus spread to glia cells in addition to neurons in those regions. However, in regions more than one synapse removed from the injection there was negligible labelling of glial cells. Taken together, these results suggest that transneuronal retrograde labelling with HSV1 is a useful tool in the analysis of neural circuits.

The efficacy of terfenadine, a nonsedating H1 antihistamine, in the management of chronic idiopathic urticaria was compared with chlorpheniramine and placebo in a parallel multicenter trial. Subjects with symptoms of hives for 3 days per week for at least 6 weeks were initially screened and admitted if no identifiable cause for symptoms could be determined. Patients entered a single-blind placebo period, and if hives of moderate severity were present for at least 3 days during the week, they were randomly assigned in a double-blind fashion to take terfenadine, 60 mg twice daily, chlorpheniramine, 4 mg three times a day, or placebo for 6 weeks. Data were analyzed for 122 patients. Those patients receiving both active treatments noted significant improvement in symptoms: pruritus, redness, number of hives, and waking hours during which hives were present, at the end of the first day of therapy. Symptom control by terfenadine was statistically superior to placebo during all 6 weeks, as rated by both patients and investigators. However, statistical significance was not achieved for chlorpheniramine at all observation points. Diphenhydramine was permitted as a relief medication for refractory symptoms and was taken by 52% of subjects receiving placebo, 26% taking chlorpheniramine, and only 9% of patients who were receiving terfenadine. In addition to providing superior symptom control, terfenadine caused less drowsiness and fatigue than chlorpheniramine. Terfenadine is a useful therapeutic agent for primary management of chronic idiopathic urticaria.

The efficacy and safety of astemizole (AST), a new long-acting H1 antagonist with minimal sedative or anticholinergic side effects, were studied in an 8-week double-blind trial of 51 patients with chronic idiopathic urticaria. Patients with chronic idiopathic urticaria were randomized to AST-treated (10 mg every day) or placebo-treated groups. Patients were followed at weekly intervals and evaluated for pruritus, erythema, extent of wheals, frequency of urticarial episodes, and total control of urticaria. Only three of 27 AST-treated patients stopped the double-blind phase before 8 weeks because of inadequate response as compared to 11 of 24 placebo-treated subjects (p = 0.027). On the last evaluable visit of the double-blind phase of the study, 85% of the AST-treated patients reported an excellent or good response compared to 30% of the placebo-treated group (p = 0.0001). AST-treated patients also reported significant improvement compared to placebo-treated patients in pruritus (p = 0.0001), erythema (p = 0.0001), and extent of wheals (p = 0.003). Mild sedative effects were observed in only two of 27 patients receiving AST. It was concluded that AST is a potent and safe drug for symptomatic control of chronic idiopathic urticaria.

The reactogenicity and immunogenicity of whole-virus and split-product influenza vaccines were studied in 77 children between the ages of 6 and 36 months. Subjects initially received monovalent vaccine containing either A/USSR/77 (H1N1) antigen in 1978 or A/Brazil/78 (H1N1) antigen in 1979. One month later a trivalent preparation was given which contained the respective H1N1 antigen plus A/Texas/77 (H3N2) and B/Hong Kong/72 antigens. Temperatures of greater than or equal to 37.8 C (greater than or equal to 100 F) were observed more commonly after initial vaccination with whole-virus vaccine (35%) than after split-product vaccine (14%). No child had a temperature of greater than or equal to 39.4 C (103 F) or a febrile convulsion. The trivalent vaccines were more reactogenic than the monovalent vaccines although none of the reaction indices exceeded 0.9. The whole-virus vaccine appeared to be more immunogenic, especially in those children who were initially seronegative (preimmunization hemagglutination-inhibiting antibody titer (less than 5). Only 50% of children vaccinated with split-product vaccines with initial hemagglutination-inhibiting titers of less than 5 achieved titers of greater than or equal to 20 to the H1N1 antigen after two doses of vaccine compared with 97% in similar whole-virus vaccine recipients. The degree of antibody response to the A/Texas/77 component of the vaccines was greater than the response to the A/Brazil/78 or A/USSR/77 antigens.