Mutational analysis of familial and sporadic hyperekplexia

Hyperekplexia is a rare, autosomal dominant neurological disorder characterized by hypertonia, especially in infancy, and by an exaggerated startle response. This disorder is caused by mutations in the ?1 subunit of the inhibitory glycine receptor (GLRA1). We previously reported two GLRA1 point mutations detected in 4 unrelated hyperekplexia families; both mutations were at nucleotide 1192 and resulted in the replacement of Arg²⁷¹ by a glutamine (R271Q) in one case and a leucine (R271L) in the other. Here, 5 additional hyperekplexia families are shown to have the most common G-to-A transition mutation at nucleotide 1192. Haplotype analysis using polymorphisms within and close to the GLRA1 locus suggests that this mutation has arisen at least twice (and possibly four times). In 2 additional families, a third mutation is also presented that changes a tyrosine at amino acid 279 to a cysteine (Y279C). Five patients with atypical clinical features and equivocal or absent family history of hyperekplexia and 1 patient with a classical presentation but no family history are presented in whom a mutation in the GLRA1 gene was not detected. Thus, only clinically typical hyperekplexia appears to be consistently associated with GLRA1 mutations, and these affect a specific extracellular domain of the protein.     

Tick Bites and Lyme Disease in an Endemic Setting: Problematic Use of Serologic Testing and Prophylactic Antibiotic Therapy

Context.— The use of serologic testing to diagnose Lyme disease (LD) is a source of controversy. Expert recommendations also discourage the routine use of antibiotic therapy for prophylaxis of LD following tick bites, but the extent to which physicians in endemic areas have adopted these recommendations is not known. Objective.— To assess the pattern of use of serologic testing and antibiotic therapy for tick bites and LD and associated charges for management in an endemic area. Design.— Active surveillance of patient-physician encounters for tick bites and LD. Setting.— Primary care practices on the Eastern Shore of Maryland. Patients.— Consecutive sample of 232 patients with tick bites, LD (defined by physician diagnosis in medical record), and suspected LD (physician notation of possible, but not definite LD) seen in 1995. Main Outcome Measures.— Serologic testing for LD, test results, antibiotic therapy, and direct costs of management. Results.— Surveillance identified 142 patients (61.2%) with diagnoses of tick bites, 40 patients (17.2%) with LD, and 50 patients (21.6%) with suspected LD. Of the 142 patients seen for tick bites, 95 (67%) underwent serologic testing for LD. Of these, 93 patients had initial negative or equivocal results; 24 (26%) of the 93 had convalescent testing, with 1 seroconversion. Seventy-eight patients (55%) with a diagnosis of tick bite received antibiotic therapy. No patients with tick bite developed clinical LD. Serologic testing for LD was performed for 36 patients (90%) with a diagnosis of LD and 46 patients (92%) with suspected LD. In most cases, antibiotics were prescribed before serologic test results became available. Convalescent testing was not performed for 37 (86%) of the 43 patients with suspected LD who had initial negative or equivocal results. Of these 37 patients, 25 (68%) did not receive antibiotic therapy. Direct charges for treatment of these 232 patients totaled $47595, one third of which was attributable to serologic testing. A total of 32% of direct charges were for patients with tick bites, 48% were for patients with LD, and 20% were for patients with suspected LD. Conclusions.— In this setting, most patients consulting physicians for tick bites received prophylactic antibiotic therapy of unproven efficacy and underwent unnecessary, costly serologic testing. Despite almost universal use in this study, serologic testing for LD did not appear to influence treatment of patients diagnosed as having LD.      

Synthesis and Antitumour Activity of New Derivatives of Flavone-8-acetic Acid (FAA). Part 1: 6-Methyl Derivatives

A range of 17 derivatives of flavone-8-acetic acid (FAA) with a 6-methyl substituent have been prepared and their anti-tumour activity evaluated in vitro against a panel of human and murine tumour cell lines and in vivo against MAC 15A. While many of the compounds show activity comparable to FAA in vitro, this essentially disappears in vivo, possibly due to degradation before the compounds can reach the tumour site.     

An expert system for determining medicaid eligibility

The eligibility requirements for AFDC Medicaid are so extensive and complicated that most health care providers do not attempt to ascertain whether or not a particular patient is eligible for the program, even when no other source of payment is available. This results in lost revenue for health service providers nationwide amounting to hundreds of millions of dollars per year. Computer technology, in the form of expert systems, offers an opportunity to rationalize the Medicaid eligibility determination process and to do real-time assessment of patient eligibility. This article presents an expert system called MEDELEX (MEdicaidELigibilityEXpert) for determining Medicaid eligibility. The program (when run on an 8 MHz MS-DOS microcomputer with at least 640 KB of RAM) requires about 20 min for data entry and 5 sec for the actual eligibility determination. The expert system was written in Prolog and has been designed in such a way that it can be readily modified to take into account the state-to-state variability in eligibility requirements for AFDC Medicaid.     

Involvement of Ca+ mobilization in the amplifying effect of serotonin on responses of rabbit isolated ear artery to exogenous noradrenaline

Summary The present study examined the involvement of Ca⁺ mobilization in the amplifying effect of serotonin on steady-state responses of rabbit isolated perfused ear artery to exogenous noradrenaline (NA; 0.001–3 ol/l). In contrast to its marked amplifying effect on responses to NA, serotonin in the subconstrictor concentration of 100 nmol/l had no effect on responses to KCl. The Ca⁺-entry blocking drug diltiazem (10 gmol/1) decreased responses to NA; in addition, the amplifying effect of serotonin on responses to NA was reduced by diltiazem. Lowering the concentration of Ca⁺ in the Krebs-Henseleit perfusion solution from 2.5 to 0.25 mmol/l also reduced both responses to NA and the amplifying effect of serotonin. Using the method of Manzini et al. (1982), separate intra- and extracellular Ca⁺-dependent responses to NA were obtained. Serotonin had no effect on intracellular Ca⁺-dependent responses to NA but enhanced extracellular Ca²⁺-dependent NA responses. These results suggest that the amplifying effect of serotonin on responses of rabbit ear artery to exogenous NA involves a selective enhancement of the component of the NA response which is dependent on extracellular Ca⁺; serotonin may increase NA-evoked entry of Ca²⁺ into the vascular smooth muscle cells through receptor-operated Ca⁺ channels. Send offprint requests to A. G. Meehan at the above address