Defining functional gene-circuit interfaces in the mouse nervous system.

Complexity in the nervous system is established by developmental genetic programs, maintained by differential genetic profiles and sculpted by experiential and environmental influence over gene expression. Determining how specific genes define neuronal phenotypes, shape circuit connectivity and regulate circuit function is essential for understanding how the brain processes information, directs behavior and adapts to changing environments. Mouse genetics has contributed greatly to current percepts of gene-circuit interfaces in behavior, but considerable work remains. Large-scale initiatives to map gene expression and connectivity in the brain, together with advanced techniques in molecular genetics, now allow detailed exploration of the genetic basis of nervous system function at the level of specific circuit connections. In this review, we highlight several key advances for defining the function of specific genes within a neural network.

Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients.

BACKGROUND: Combination therapy utilizing agents with complementary mechanisms of action is recommended by acne guidelines to help simultaneously target multiple pathogenic factors. A unique, topical, fixed-dose combination gel with adapalene 0.1% and benzoyl peroxide (BPO) 2.5% has recently been developed for the once-daily treatment of acne. OBJECTIVES: To evaluate the efficacy and safety of adapalene 0.1%-BPO 2.5% fixed-dose combination gel (adapalene-BPO) relative to adapalene 0.1% monotherapy (adapalene), BPO 2.5% monotherapy (BPO), and the gel vehicle (vehicle) in a large population for the treatment of acne vulgaris. METHODS: In total, 1670 subjects were randomized in a double-blind controlled trial to receive adapalene-BPO, adapalene, BPO or vehicle for 12 weeks (1 : 1 : 1 : 1 randomization). Evaluations included success rate (subjects 'clear' or 'almost clear'), percentage change in lesion count from baseline, cutaneous tolerability and adverse events. RESULTS: Adapalene-BPO was significantly more effective than corresponding monotherapies, with significant differences in percentage lesion count change observed as early as 1 week. Cutaneous tolerability profile was similar to adapalene. Adverse events were more frequent with the combination therapy (mainly due to an increase in mild-to-moderate dry skin), occurred early in the study, and were transient. CONCLUSIONS: Adapalene-BPO provides significantly greater and synergistic efficacy and a faster onset of action with an acceptable safety profile in the treatment of acne vulgaris when compared with the corresponding vehicle and the adapalene and BPO monotherapies.

Spread of strain W, a highly drug-resistant strain of Mycobacterium tuberculosis, across the United States.

Strain W, a highly drug-resistant strain of Mycobacterium tuberculosis, was responsible for large nosocomial outbreaks in New York in the early 1990s. To describe the spread of strain W outside New York, we reviewed data from epidemiologic investigations, national tuberculosis surveillance, regional DNA fingerprint laboratories, and the Centers for Disease Control and Prevention Mycobacteriology Laboratory to identify potential cases of tuberculosis due to strain W. From January 1992 through February 1997, 23 cases were diagnosed in nine states and Puerto Rico; 8 were exposed to strain W in New York before their diagnosis; 4 of the 23 transmitted disease to 10 others. Eighty-six contacts of the 23 cases are presumed to be infected with strain W; 11 completed alternative preventive therapy. Strain W tuberculosis cases will occur throughout the United States as persons infected in New York move elsewhere. To help track and contain this strain, health departments should notify the Centers for Disease Control and Prevention of cases of tuberculosis resistant to isoniazid, rifampin, streptomycin, and kanamycin.

Low-dose mifepristone 200 mg and vaginal misoprostol for abortion.

The objectives of this study were to determine the effectiveness, side effects, and acceptability of one-third the standard 600 mg dose of mifepristone (200 mg) to induce abortion. A prospective trial at seven sites enrolled women > or = 18 years, up to 8 weeks pregnant, and wanting an abortion. The women received 200 mg mifepristone orally, self-administered 800 micrograms misoprostol vaginally at home 48 h later, and returned 1-4 days later for ultrasound evaluation. Surgical intervention was indicated for continuing pregnancy, excessive bleeding, persistent products of conception 5 weeks later, or other serious medical conditions. Of the 933 subjects, 906 (97%) had complete medical abortions, 22 had surgical intervention, two were protocol failures, and three were lost to follow up. Of the 746 subjects who had no or minimal bleeding before misoprostol, 80% bled within 4 h and 98% within 24 h of using misoprostol. By day 7, 95% of women had a complete abortion. Side effects were aceptable in 85% of subjects, and 94% found the procedure acceptable. Low-dose mifepristone followed by vaginal misoprostol was highly effective as an abortifacient.

PIP: The effectiveness, side effects, and acceptability of 200 mg of mifepristone (one-third the standard dose) to induce medical abortion were investigated in a trial conducted at 7 centers in the US. 933 women with pregnancies up to 8 weeks' gestation were enrolled. They were given a 200-mg oral dose of mifepristone to be followed 48 hours later by home administration of 800 mcg of vaginal misoprostol and instructed to return 1-4 days later for ultrasound evaluation. 906 women (97%) experienced complete medical abortion, 22 required surgical abortion, 2 were protocol failures, and 3 were lost to follow-up. The most common indication for surgery was persistent or severe bleeding. Of the 746 women who had little or no bleeding before misoprostol administration, 593 (80%) bled within 4 hours and 731 (98%) within 24 hours of misoprostol. By day 7, 95% of women had experienced a complete abortion. The mean duration of bleeding was 17.4 days. 73% of subjects used an oral narcotic for pain. The most common mifepristone-related side effects were nausea and cramping; misoprostol-related side effects included cramping, fever, and chills. 74% found the pain related to the procedure acceptable and 85% rated its side effects as tolerable. Overall, 94% of subjects rated the medical abortion regimen as acceptable. These findings indicate that low-dose mifepristone is highly effective and acceptable as a self-administered abortifacient. The advantages of a lower dose of mifepristone include reduced manufacturing costs and less exposure to potential side effects.

Transmission of a highly drug-resistant strain (strain W1) of Mycobacterium tuberculosis. Community outbreak and nosocomial transmission via a contaminated bronchoscope.

CONTEXT: Nosocomial transmission of multidrug-resistant tuberculosis (MDR TB) has been reported primarily in New York State and has generally been presumed to occur via respiratory aerosols. OBJECTIVE: To assess nosocomial transmission of MDR TB. In 1995, 8 patients with MDR TB were identified in South Carolina; all were resistant to 7 drugs and had matching DNA fingerprints (strain W1). Community linkswere identified for 5 patients (Patients 1-5). However, no links were identified forthe other 3 patients (Patients 6-8) except being hospitalized at the same hospital as 1 community patient. DESIGN: Outbreak investigation. SETTING: Community and hospital. PATIENTS: Eight patients whose MDR TB isolates had DNA fingerprint patterns matching strain W1. MAIN OUTCOME MEASURES: Clinical characteristics of patients with strain W1 Mycobacterium tuberculosis isolates. RESULTS: Patient 5 (community patient) and Patient 8, diagnosed April 1995 and November 1995, respectively, had clinical courses consistent with MDR TB, with smear-positive and culture-positive specimens and cavitary lesions on chest radiograph; both died of MDR TB less than 1 month after diagnosis. Patients 6 and 7 (diagnosed May 1995) each had 1 positive culture for MDR TB; specimens were collected during bronchoscopy. Patient 6 had a skin test conversion after bronchoscopy. Neither Patient 6 nor Patient 7 had a clinical course consistent with MDR TB, neither was treated for MDR TB, and both are alive and well. No evidence of laboratory contamination of specimens, transmission on inpatient wards, or contact among patients was found. All 4 received bronchoscopies in May 1995; Patients 6, 7, and 8 had bronchoscopies 1, 12, and 17 days, respectively, after Patient 5. Observations revealed that bronchoscope cleaning was inadequate, and the bronchoscope was never immersed in disinfectant. CONCLUSIONS: Inadequate cleaning and disinfection of the bronchoscope after the procedure performed on Patient 5 led to subsequent false-positive cultures in Patients 6 and 7 and transmission of infection to Patient 6 and active MDR TB to Patient 8.

A controlled study of diffuse idiopathic skeletal hyperostosis. Clinical features and functional status.

Diffuse idiopathic skeletal hyperostosis (DISH) is a common but little-studied disorder in the elderly that is infrequently recognized by physicians. Its prevalence in adults over 40 years of age is estimated at 3.8% for men and 2.6% for women. The present case-control study evaluated the history of pain and stiffness, radicular pain and enthesitis, physical findings on the musculoskeletal examination, and level of physical and psychologic disability in 130 persons: 56 patients with DISH, 43 control patients with spondylosis of the lumbar spine, and 31 healthy control patients. DISH patients were more likely to report a past history of upper extremity pain, medial epicondylitis of the elbow, enthesitis of the patella or heel, or dysphagia than spondylosis patients. They had more extremity and spinal stiffness and pain than healthy controls. DISH patients weighed more at a young age and their body mass index was greater at the time of the clinical evaluation than either spondylosis or healthy control patients. On musculoskeletal examination, DISH patients had a greater reduction in neck rotation and thoracic movements than either spondylosis patients or healthy controls, and had a greater reduction in lumbar movement than healthy controls. DISH patients had similar levels of spinal disability and physical disability overall, as measured by standardized indices, as spondylosis patients. No differences were found among the 3 groups of patients for the laboratory tests evaluated. DISH is clearly a distinct disorder with signs and symptoms that distinguish it from other causes of spinal complaint and from healthy individuals. It has the potential to cause major disability. Future studies need to address the natural history of DISH, pursue pathogenic mechanisms, and evaluate treatment modalities.

Allergen-induced increase in airway responsiveness is not inhibited by acute treatment with ketotifen or clemastine.

Allergen-induced increase in airway responsiveness to histamine or methacholine provides a useful model for investigation of prophylactic or "antiinflammatory" asthma treatments. This can be inhibited by corticosteroids or by sodium cromoglycate but not by beta agonists or by theophylline. A single-blind, crossover, random-order trial was conducted to compare ketotifen, clemastine, and placebo in six atopic subjects undergoing allergen inhalation tests. Ketotifen, 2 mg; clemastine, 1 mg; and placebo one tablet were administered twice daily for four days (eight doses) up to and including one hour before allergen inhalation. None of the three produced a significant reduction in the allergen-induced early or late asthmatic responses, or in the allergen-induced fall in methacholine PC20. There was a subtle nonsignificant suggestion of a reduction in the early portion of the early asthmatic response induced by both ketotifen and clemastine. Both ketotifen and clemastine produced a similar 8-fold inhibition of histamine skin test endpoint indicating equal systemic H1 blocking effect at the time of allergen inhalation. Sodium cromoglycate, 10 mg, single dose, by metered dose inhaler ten minutes before allergen challenge, added as an unblinded "positive control", inhibitory effects on the allergen-induced late and presumed inflammatory sequelae. It is possible that longer treatment periods (several weeks or months) might prove effective.

Sensitivity and specificity of histamine PC20 determination in a random selection of young college students.

Histamine provocative concentration causing a 20% drop in FEV1 (PC20) was measured in 500, randomly selected, young (20 to 29 years) university students. Participation was 500/619, or 81%. In this population, by a research assistant-administered questionnaire, we identified 17 subjects with current asthma, 16 with asthma only on allergen exposure, 19 with past (more than 1 year ago) asthma, 158 with rhinitis (77 atopic and 81 nonatopic subjects), and 290 subjects with neither asthma nor rhinitis. Histamine airway hyperresponsiveness (PC20 less than or equal to 8 mg/ml) was observed in 58 subjects and included the 17 subjects with current asthma, 6/16 with asthma only on allergen exposure, 2/19 subjects with previous asthma, 20/158 with rhinitis, and 13/290 subjects with neither asthma nor rhinitis. With "current symptomatic asthma" as the diagnosis and PC20 less than or equal to 8 mg/ml as the positive test, the sensitivity was 100%, the specificity was 93%, and the negative predictive value was 100%; the positive predictive value (for current symptoms of asthma) was only 29%. The strength of this test with a cutoff of 8 mg/ml is the high sensitivity, indicating that a PC20 greater than 8 mg/ml is likely to indicate that current asthma is not present. The weakness is the failure to predict current symptoms of asthma. As the cutoff is lowered, for example, to PC20, 1 mg/ml, the sensitivity falls to less than 50% and the positive predictive value approaches 100%. These data indicate that a PC20 greater than 8 (or 16) mg/ml rules out current asthma in most instances, whereas a PC20 less than 1 mg/ml is almost diagnostic of current asthma. Values between 1 and 8 mg/ml are intermediate in these regards.

Importance of evaporative water losses during standardized nebulized inhalation provocation tests.

Evaporative water losses from jet nebulizers produce temperature drop, reduction in total nebulizer output with increased nebulization time, and increasing concentration of solute remaining in the nebulizer. These were documented and quantitated for the Wright nebulizer which is used for one histamine/methacholine inhalation test method. Indirect determination of nebulizer aerosol output, made by estimation of total sodium lost from the nebulizer, was about 25 percent of total output as determined by weight change. A similar tendency was seen for a De Vilbiss 40 nebulizer for both reduction in total nebulizer output with increasing duration of nebulization, and increased solute concentration remaining in the nebulizer. These data must be taken into account when standardizing inhalation provocation tests. Nebulizers should be calibrated under the same conditions that they are used during the test. Histamine and methacholine solutions should be discarded after a single use in the 2-min tidal breathing Wright nebulizer method.

Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine.

Allergen-induced increase in airway hyperresponsiveness can be used as a model of airway inflammation for assessing antiasthma pharmacologic agents. Steroids and cromolyn, but not beta-agonists, inhibit this increase; theophylline, recently suggested as having anti-inflammatory effects, has not been evaluated in this model. Six atopic subjects with asthma and with late asthmatic responses (N = 5) and postallergen reduction in a provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) (N = 6) were studied. Sustained-release theophylline (Theo-Dur; Astra Pharmaceuticals Canada, Ltd., Mississauga, Canada), 300 mg, and placebo were administered single-blind twice daily for eight doses up to 1 hour before allergen inhalation; cromolyn sodium, 10 mg, was administered in a single dose 10 minutes before allergen inhalation on another day as a "positive control." Mean theophylline levels were in the low therapeutic range, 57 +/- 17 and 58 +/- 13 mumol/L 1 and 8 hours after the last tablet. The FEV1 was 7% and 9% greater after the seventh and eighth doses of theophylline versus placebo (p less than 0.05). Theophylline also produced a significant (p less than 0.05) twofold increase in methacholine PC20. There was a 40% (p = 0.06) reduction in early asthmatic fall in FEV1 and a 25% (not significant) reduction in late FEV1 fall when theophylline was compared to placebo. Theophylline did not influence the geometric mean allergen-induced fall in methacholine PC20 delta log PC20; this was true individually in five of the six subjects. By contrast, cromolyn sodium inhibited all aspects of the allergen response completely.(ABSTRACT TRUNCATED AT 250 WORDS)

Cervical pregnancy managed by placement of a Shirodkar cerclage before evacuation. A case report.

Cervical pregnancy can be managed by cervical cerclage placement before evacuation. Prophylactic cerclage placement in the first trimester of cervical pregnancy may obviate further intervention to control bleeding.

A case of supernumerary ovary.

A case of supernumerary ovary is presented. This rare gynecologic abnormality, which is usually diagnosed on laparotomy or autopsy, was noted on laparoscopy.