Histamine N-methyltransferase inhibitor potentiates histamine- and antigen-induced airway microvascular leakage in guinea pigs

Background: Histamine N-methyltransferase (HMT) modulates histamine- and antigen-induced bronchoconstriction. However, it is unclear whether vascular permeability evoked by an allergic reaction can be exaggerated by inhibition of HMT activity. Methods: We studied the effects of intravenously injected SKF 91488, a specific HMT inhibitor, on increases in plasma extravasation induced by intravenously injected histamine in unsensitized guinea pigs and by intravenously injected ovalbumin antigen in guinea pigs sensitized to ovalbumin in vivo with Evans blue dye as a marker. Results: Pretreatment with SKF 91488 shifted, in a dose-dependent fashion, the dose-response curves of the leakage of dye to histamine to lower concentrations in the trachea, main bronchi, and nasal mucosa. Likewise, pretreatment with SKF 91488 (20 mg/kg intravenously) significantly increased the leakage of dye induced by ovalbumin antigen (200 μg/kg intravenously) in three parts of the airway (p < 0.05). In contrast to SKF 91488, intravenously injected aminoguanidine, a specific inhibitor of diamine oxidase (16 mg/kg intravenously), did not alter the leakage of dye induced by histamine (from 0.001 μg/kg to 10 μg/kg intravenously) (p > 0.20). HMT activities were observed in the nasal mucosa, as well as in the trachea and main bronchi, as shown in a previous study. Conclusion: These findings suggest that HMT modulates the effects of exogenous histamine and endogenously released histamine induced by antigen challenge on plasma extravasation in the airway in guinea pigs in vivo. (J ALLERGY CLIN IMMUNOL 1995;96:910-6.)     

Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy

BACKGROUND: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. OBJECTIVE: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. METHODS: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m2) and methylprednisolone (40 mg/1.73 m2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. RESULTS: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. CONCLUSIONS: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy.     

HSP 60 expression in mucocutaneous lesions of Behçet''s disease

BACKGROUND: Heat shock protein (60 kd HSP) has been implicated in the etiology of Beh?et's disease, but its expression at sites of inflammation is unknown. OBJECTIVE: Our aim was to investigate local HSP 60 expression and to quantify T-cell receptor (TCR) gamma delta-positive cells, which are known to respond to HSP peptides. METHODS: Patients with active Beh?et's disease (n = 21) and controls (n = 18) were included. Flow cytometric analysis was performed on peripheral blood to investigate TCR gamma delta-positive cell counts. Biopsies were performed on active skin lesions, and immunohistochemical analysis was performed by a streptavidin-biotin method using the monoclonal ML-30 antibody; HSP staining intensity and distribution were evaluated in a blinded fashion. Immunohistochemical studies were performed to quantify TCR gamma delta-positive cells at lesional sites. RESULTS: Mucocutaneous lesions of patients with Beh?et's disease had statistically significantly increased expression of HSP 60/65. Peripheral blood TCR gamma delta-positive cell counts were similar in both groups. However, lesional skin of patients with Beh?et's disease had significantly increased gamma delta-positive T-cell counts. CONCLUSION: Up-regulation of HSP expression was found at lesional skin sites in Beh?et's disease. The increased number of TCR gamma delta-positive cells, which are known to respond to HSP peptides, may support the function of HSPs in the etiology of Beh?et's disease. However, these findings may also be an epiphenomenon that needs to be further investigated.     

A multicenter dose-escalation trial with denileukin diftitox (ONTAK, DAB389IL-2) in patients with severe psoriasis

Background: Denileukin diftitox, a fusion protein targeting both malignant and normal activated lymphocytes, has been shown previously to have antipsoriatic activity. However, the ideal dosing regimen for treating psoriasis was not established. Objective: We examined the safety and efficacy of denileukin diftitox in patients with severe plaque-type psoriasis. Methods: This was a cohort dose-escalation trial. Patients were administered denileukin diftitox on 3 consecutive days every other week. Patients were evaluated for toxicity, improvement in psoriasis, immunogenicity, and serum levels. Results: Thirty-five patients were treated at 3 dose levels. Eight patients had a 50% decrease or more in Psoriasis Area and Severity Index score from baseline (0/10 at 0.5 μg/kg per day, 1/10 at 1.5 μg/kg per day, and 7/15 at 5 μg/kg per day). Adverse events primarily consisted of constitutional events and skin reactions. Conclusions: The potential antipsoriatic activity of denileukin diftitox demonstrated in this study was comparable to that observed in other psoriasis studies with this agent. However, this dosing regimen was better tolerated than the dosing regimen used in the last study with denileukin diftitox in psoriasis patients. (J Am Acad Dermatol 2001;45:871-81.)     

Low-dose levalbuterol in children with asthma: Safety and efficacy in comparison with placebo and racemic albuterol

BACKGROUND: Racemic albuterol (RAC) is an equal mixture of (R)-albuterol and (S)-albuterol. Only the (R)-isomer, levalbuterol (LEV), is therapeutically active. Lower doses of LEV, devoid of (S)-albuterol, have demonstrated efficacy comparable to that of higher doses of the (R)-isomer administered as a component of RAC. OBJECTIVE: The purpose of this study was to determine whether LEV results in improved safety and efficacy in children. METHODS: Asthmatic children aged 4 to 11 years (n = 338; FEV(1), 40% to 85% of predicted) participated in this multicenter, randomized, double-blinded study and received 21 days of 3-times-a-day treatment with nebulized LEV (0.31 or 0.63 mg), RAC (1.25 or 2.5 mg), or placebo. The primary endpoint was FEV(1) (peak percent change). Adverse events, clinical laboratory test results, vital signs, and electrocardiograms were evaluated for safety. RESULTS: All active treatments significantly improved the primary endpoint in comparison with placebo (P < .001). Significant differences in FEV(1) were noted immediately after nebulization (median change, 2.0%, 19.0%, 18.1%, 12.4%, and 15.6% for placebo, LEV 0.31 and 0.63, RAC 1.25 and 2.5 mg, respectively; P < .05 vs placebo; P < .05 for LEV 0.31 and 0.63 vs RAC 1.25 mg). LEV 0.31 mg was the only treatment not different from placebo for changes in ventricular heart rate, QT(c) interval, and glucose (P > .05). All active treatments decreased serum potassium (range, -0.3 to -0.6; P < .002 vs placebo), and RAC 2.5 mg caused the greatest change (P < .005 vs other actives). In a patient subset with severe asthma, a dose-response relationship was observed for levalbuterol, indicating that higher doses were more effective. CONCLUSION: LEV was clinically comparable to 4- to 8-fold higher doses of RAC, and it demonstrated a more favorable safety profile. LEV 0.31 mg should be used as the starting dose in 4-11 year old children with mild to moderate persistent asthma. Patients with severe disease might benefit from higher doses.     

Site-specific fascial defects in the diagnosis and surgical management of enterocele

Objective: The aim of this study was to assess the surgical feasibility and clinical outcomes of a vaginal enterocele repair that was based on the theory of site-specific defects in the vaginal fascia. Study Design: Seventeen patients during a 2-year period with a diagnosis of enterocele and vaginal vault descensus with or without coexisting rectocele underwent surgical correction with a site-specific fascial defect repair. An enterocele was defined as vaginal wall prolapse seen during the operation in which the peritoneum was found to be in direct contact with the vaginal epithelium, with no intervening fascia. Patients were examined at 4 weeks after the operation and then at 6-month intervals, with site-specific analysis of pelvic prolapse at the vaginal apex and posterior vaginal segment. Results: Identification and site-specific fascial defect repair of the enterocele were successfully performed in all 17 cases. All patients also underwent a uterosacral ligament vaginal vault suspension, and 15 patients (88%) underwent concurrent posterior colporrhaphy. There were no intraoperative complications. At a mean follow-up of 6.3 months (range 1-17 months), 2 patients (12%) had mild, asymptomatic vaginal vault descensus but no patients (0/17) had evidence of a recurrent enterocele or rectocele. Conclusion: Enterocele correction through a fascial defect repair is easily performed through the vaginal route and is associated with excellent surgical outcomes on short-term follow-up. (Am J Obstet Gynecol 1998;179:1418-23.)     

Angiomyolipoma of the parotid glandA case report

Angiomyolipoma is a hamartomatous process that most frequently occurs as a single lesion or multiple foci in the kidneys of patients affected by tuberous sclerosis. Angiomyolipoma can also arise in extrarenal sites, among which the liver is the most frequently recorded. Only rare cases of angiomyolipoma located in the head and neck region (ear and oral and nasal cavity) have been described. The purpose of the present article is to report a case of angiomyolipoma of the parotid gland. A 68-year-old woman appeared for treatment with a slow-growing nodule located in her right parotid gland. Ultrasound examination revealed a heterogeneous nodule with well-defined margins. The nodule was surgically removed by total parotidectomy and showed the characteristic appearance of angiomyolipoma, with an admixture of fat smooth muscle cells, and tortuous, thick-walled blood vessels. Careful physical examination of the patient failed to reveal features of tuberous sclerosis. Angiomyolipoma should be considered in the differential diagnosis of mesenchymal lesions involving the salivary gland.     

Concordance and interrelationship of atopic diseases and markers of allergic sensitization among adult female twins

BACKGROUND: Previous twin studies of asthma and allergy implicate both genetic and environmental factors in disease risk, but few have related the occurrence of clinical disease to objective markers of allergic sensitization in twins. OBJECTIVE: We sought to investigate the concordance and interrelationships of self-reported allergic disease and total and aeroallergen-specific IgE levels within pairs of British adult female twins. METHODS: Three hundred forty monozygotic and 533 dizygotic pairs, aged 18 to 72 years, completed questionnaires about allergic disease. Of these, 282 monozygotic and 270 dizygotic pairs were tested for total IgE and specific IgE to Der p 1, mixed grass pollen, and cat dander by means of fluoroimmunoassay. RESULTS: Concordance rates for all variables were higher for monozygotic than for dizygotic twins, significantly (P < .05) so for hay fever, eczema, and specific IgE positivity but not (P > .05) for self-reported asthma or allergies. Within-pair correlations of log-transformed IgE were 0.59 for monozygotic twins and 0.29 for dizygotic twins, implying heritability of 60%. Within both monozygotic and dizygotic pairs discordant for hay fever or reported allergies, the affected twin had significantly higher total and specific IgE levels. Within pairs who were doubly discordant for 3 allergic diseases, associations between diseases were of similar strength for monozygotic and dizygotic pairs. CONCLUSIONS: These results confirm that genetic factors influence susceptibility to aeroallergen sensitization and clinical allergic disease. However, genetically identical twins are often discordant in their expression of atopy, suggesting a substantial modifying role for environmental factors.     

Teaching the Pelvic Organ Prolapse Quantitation system

Objective: The objective of this study was to determine the ease with which the new Pelvic Organ Prolapse Quantitation system could be learned by residents and medical students. Study Design: Standardized multiple-choice tests were administered to 51 obstetric and gynecology residents and medical students from 4 community-based and university-based programs. Parallel pretests and posttests were administered in conjunction with a 17-minute video demonstration of the Pelvic Organ Prolapse Quantitation system and with the addition of a visual memory aid. The posttest was repeated 3 months after the video presentation. Results: The use of a 17-minute video significantly enhanced participants’ ability to interpret examination findings when expressed in the terminology of the system (mean improvement in scores 33%, P < .0001). Posttest scores were similar regardless of the type of program or exposure to urogynecology faculty. These scores were maintained at the 3-month retesting. Conclusion: The Pelvic Organ Prolapse Quantitation system can be effectively taught by means of a public-domain video presentation. (Am J Obstet Gynecol 1998;179:1458-64.)