The anticonvulsant effects of progesterone and 5alpha-dihydroprogesterone on amygdala-kindled seizures in rats

PURPOSE: Progesterone has been shown to be anticonvulsant in several animal seizure models. The purpose of the present study was to investigate the anticonvulsant actions of progesterone and its primary metabolite 5alpha-dihydroprogesterone in the amygdala kindling model. METHODS: Female Wistar rats were implanted in the right basolateral amygdala with a long-term, bipolar electrode. The subjects were kindled to 30 stage 5 seizures and stability tested. Multiple doses of progesterone and 5alpha-dihydroprogesterone were then tested for anticonvulsant activity against focal electrographic and generalized convulsive kindled seizures. The time course of progesterone's anticonvulsant action also was examined. RESULTS: Progesterone had a median effective dose (ED50) of 103 mg/kg against generalized convulsions at 15 min after injection. Subjects were not sedated at the time of seizure testing, although sedation developed later (40-60 min after injection). In time-course experiments, it was found that 120 mg/kg of progesterone caused complete suppression of the generalized convulsion from 20 to 160 min after injection. Suppression of the focal discharge also was seen in some animals between 20 and 160 min. 5alpha-dihydroprogesterone had an ED50 of 2.9 mg/kg against generalized kindled convulsions and an ED50 of 4.3 mg/kg against focal afterdischarge 15 min after injection. 5alpha-dihydroprogesterone did not produce sedation 15 min after injection, or at any later time interval. CONCLUSIONS: Progesterone is anticonvulsant only at high doses when tested against amygdala kindled seizures. 5alpha-dihydroprogesterone is considerably more potent than progesterone. At low, nonsedative doses, it was effective against both the kindled amygdala focal afterdischarge and the generalized convulsion.     

Parental opinions about facial plastic surgery for individuals with down syndrome

Facial plastic surgery is an intervention that some have proposed to improve the physical functioning, appearance, and social acceptance of individuals with Down syndrome. Our purpose in this study was to examine the opinions of parents of children with Down syndrome about this practice. Two hundred and fifty parents responded with usable surveys and were generally familiar with the practice, yet the majority of respondents did not support the surgery. The literature on this topic is reviewed, and related issues are discussed.     

A systematic review of economic analyses of low-molecular-weight heparin for the treatment of venous thromboembolism

INTRODUCTION: Public concerns about the increase in health care expenditure have prompted investigators to analyze the costs and benefits of health care interventions. We conducted a systematic review of economic analyses of venous thromboembolism treatment focusing on studies evaluating low-molecular-weight heparin. MATERIALS AND METHODS: We identified studies by a MEDLINE search and a review of bibliographies of retrieved articles. From each eligible study, we extracted data on the study characteristics, the effectiveness, and the cost of managing the venous thromboembolism with respect to treatment. We critically appraised the studies according to the framework from the Users' Guides to the Medical Literature XIII: How to Use an Article on Economic Analysis of Clinical Practice. RESULTS: Six of these eight economic analyses of venous thromboembolism treatment that met the inclusion criteria for this review showed that low-molecular-weight heparin is associated with less recurrent venous thromboembolism and is less costly than treatment with unfractionated heparin. Although discrete recurrent venous thromboembolism event rates were not included in the seventh study, these investigators concluded that the cost of low-molecular-weight heparin for the treatment of venous thromboembolism treatment was offset by the savings associated with fewer hospital admissions when low-molecular-weight heparin was used. In the eighth study, although the cost of treatment with low-molecular-weight heparin was higher than treatment with unfractionated heparin, the investigators concluded that low-molecular-weight heparin is cost-effective for inpatient management. CONCLUSIONS: Low-molecular-weight heparin treatment may confer economic advantages over unfractionated heparin therapy because it does not require anticoagulant monitoring and it facilitates outpatient therapy.     

Vancomycin analogues active against vanA-resistant strains inhibit bacterial transglycosylase without binding substrate

Bacterial transglycosylases are enzymes that couple the disaccharide subunits of peptidoglycan to form long carbohydrate chains. These enzymes are the target of the pentasaccharide antibiotic moenomycin as well as the proposed target of certain glycopeptides that overcome vancomycin resistance. Because bacterial transglycosylases are difficult enzymes to study, it has not previously been possible to evaluate how moenomycin inhibits them or to determine whether glycopeptide analogues directly target them. We have identified transglycosylase assay conditions that enable kinetic analysis of inhibitors and have examined the inhibition of Escherichia coli penicillin-binding protein 1b (PBP1b) by moenomycin as well as by various glycopeptides. We report that chlorobiphenyl vancomycin analogues that are incapable of binding substrates nevertheless inhibit E. coli PBP1b, which shows that these compounds interact directly with the enzyme. These findings support the hypothesis that chlorobiphenyl vancomycin derivatives overcome vanA resistance by targeting bacterial transglycosylases. We have also found that moenomycin is not competitive with respect to the lipid II substrate of PBP1b, as has long been believed. With the development of suitable methods to evaluate bacterial transglycosylases, it is now possible to probe the mechanism of action of some potentially very important antibiotics.     

Crystal structure of the MurG:UDP-GlcNAc complex reveals common structural principles of a superfamily of glycosyltransferases

MurG is an essential glycosyltransferase that forms the glycosidic linkage between N-acetyl muramyl pentapeptide and N-acetyl glucosamine in the biosynthesis of the bacterial cell wall. This enzyme is a member of a major superfamily of NDP-glycosyltransferases for which no x-ray structures containing intact substrates have been reported. Here we present the 2.5-A crystal structure of Escherichia coli MurG in complex with its donor substrate, UDP-GlcNAc. Combined with genomic analysis of other superfamily members and site-specific mutagenesis of E. coli MurG, this structure sheds light on the molecular basis for both donor and acceptor selectivity for the superfamily. This structural analysis suggests that it will be possible to evolve new glycosyltransferases from prototypical superfamily members by varying two key loops while maintaining the overall architecture of the family and preserving key residues.     

Autoantibody-associated congenital heart block: The clinical perspective

Congenital heart block (CHB) can occur in association with structural heart disease, such as atrioventricular septal defects, left atrial isomerism, and abnormalities of the great arteries, with tumors, such as mesotheliomas, or as an isolated defect. In 1928, Aylward reported the occurrence of CHB in two children whose mother “suffered from Mikulicz’s disease.” This curious clinical observation was further solidified by the 1970s, with reports of CHB in children whose mothers had autoimmune diseases and that the maternal sera contained antibodies to Ro ribonucleoproteins. It was subsequently reported that many mothers also had antibodies to La. Other abnormalities affecting the skin, liver, and blood elements were associated with anti-Ro/La antibodies in the maternal and fetal circulation, and are now grouped under the heading of neonatal lupus syndromes. Neonatal lupus was termed because the cutaneous lesions of the neonate resembled those seen in systemic lupus erythematosus.     

Mechanisms for a novel immune evasion strategy in the scabies mite sarcoptes scabiei: a multigene family of inactivated serine proteases

Parasitic infestation of the skin by the mite Sarcoptes scabiei is a significant problem worldwide, particularly in socially disadvantaged communities. A multigene family of at least 24 homologs of a serine protease allergen have been identified in S. scabiei. Surprisingly, the products of all but one of these genes are predicted to be catalytically inactive, due to mutations at a critical triad of amino acids at the active site. We discuss the possibility that these genes for inactivated proteases have been conserved because they mediate a novel host defense evasion strategy that the mite has evolved as an adaptation to parasitism of the epidermis. The identification of this family, and elucidation of its value to the parasite, may present an unanticipated approach to protective vaccination.     

The emotional experience of intercourse and sexually transmitted diseases: a decision-tree analysis

BACKGROUND: Epidemiologic data document high risks for many sexually transmitted diseases (STDs) among US adolescents and young adults. GOAL: This case-control study used decision trees to investigate the relationship between STD incidence and emotional reactions to intercourse. STUDY DESIGN: For this study, 188 adolescents and young adults (mean age, 24.9 years [SD = 8.2]) at a regional public STD clinic completed a behavioral and psychological questionnaire and underwent a workup for STD. RESULTS: The prevalence of STD in this group was 44.8%. Decision-tree analysis identified emotional reactions to intercourse that were associated with STD diagnosis for some patients: feeling good about oneself after sex half the time or less (OR = 3.21; 95% CI = 1.73-5.95), feeling comfortable during sex half the time or less (OR = 2.17; 95% CI = 1.07-4.40), and feeling angry after sex (OR = 1.90; 95% CI = 0.91-3.99). Findings of a logistic regression model of emotional reactions to intercourse were significant (chi-square = 24.6; df = 8; P < 0.002), but adding behavioral variables did not improve prediction. CONCLUSIONS: For some of these young adults at the time of life when they are at highest risk of STD, emotional factors have higher odds ratios for STD diagnosis than the traditionally assessed behavioral variables. This underscores the need for interventions targeted to specific subgroups and for readily available mental health services.