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.     

Community psychiatry then and now: An introduction

Allen R. Dyer is Professor of Psychiatry at Albany Medical College and Professor of Health Policy and Management at the State University of New York at Albany, Albany, New York. Effective March 1, 1992, he becomes Professor and Chairman, Department of Psychiatry and Behavioral Sciences, James H. Quillen College of Medicine, East Tennessee State University.     

Naltrexone in organic bulimia: A preliminary report

Multiple lines of experimental evidence point to the involvement of endogenous opiates in appetite regulation. Post brain injury patients often exhibit driven eating behaviour. Since this problem fails to respond to behaviour modification, appetite suppressants, lithium, or any other usual approach, the use of the oral narcotic antagonist, Naltrexone, was given to three such patients. Naltrexone binds multiple opiate receptor sites in the hypothalamus, including the kappa receptors which have been implicated in appetite regulation, the use of this narcotic antagonist in hypothalamic hyperphagia appears to be a rational approach to this intractable problem.

In this open trial, lasting from 4 1/2 to 9 months, the minimal effective dose appeared to be in the range of 100 mg per day. No side-effects (for example elevations in liver enzymes) were noted.

All of the patients had an improved sense of well-being and their behaviours were less difficult to manage when on the Naltrexone.

The significance of this preliminary trial is that narcotic antagonists may have a role in the treatment of brain-injured patients with bulimia. Also, Naltrexone may be useful in treating other maladaptive behavioural consequences of head trauma such as stealing, manipulation, demandingness, and depression. Likewise, the effects on the deranged endocrine system, such as the hypogonadism, are significant and deserve further exploration.     

Plasma cell granuloma of the lacrimal sac

A 31-year-old man with a 2-year history of recurrent dacryocystitis underwent dacryocystorhinostomy. An unexpected operative finding was a polyp in the lacrimal sac. Histopathological examination revealed a plasma cell granuloma. The nature of this uncommon inflammatory pseudotumour of the lacrimal sac is discussed.     

Salivary dermal analogue tumors arising in lymph nodes

Dermal analogue tumor, an unusual type of monomorphic salivary adenoma, occurs in the parotid gland and rarely in other salivary tissues. This report describes three patients with dermal analogue tumors arising from ectopic salivary tissue in lymph nodes. Two tumors appeared in the periparotid lymph nodes and one in the lateral upper cervical region. All of the patients were men, aged 50 to 60 years, who all had a painless neck mass for 1 year or longer. Currently, the patients are free of disease 14, 3, and 2 years, respectively, after surgical excision. Dermal analogue monomorphic adenomas join several other salivary tumors in possible intranodal origin and should not be confused with metastases.     

Insights from latent partition analysis into categories inherent in wellness-illness

How health–disease is perceived or conceptualized is important for nursing research There is increasing evidence that individual representations are important in constructing the experience of health–disease What is the personal saliency of health–disease for the individual? To explore the patterns of meaning inherent in health–disease, a card sort was undertaken among 15 healthy individuals and 15 individuals with chronic renal disease Both groups were given 28 cards to sort twice once for when they felt ‘well’ and again for when they felt ‘ill’ The theoretical basis underlying the items of the card sort was a model of wellness-illness being developed Latent partition analysis was used to cluster the concepts from each data set followed by multi-dimensional scaling to analyse the structure of the intercategory probability estimates A possible unidimensional pattern of meaning (harmony) emerged for the ‘well’ data and a two-dimensional pattern (disharmony and optimism) for the ‘ill’ data This represents a preliminary step in the development of a theoretical model that would permit assessment of the meaning of health–disease for the individual     

Evidence for opioid modulation and generation of prostaglandins in sulphur dioxide (SO)2-induced bronchoconstriction.

BACKGROUND: Inhalation of sulphur dioxide (SO2) provokes bronchoconstriction in asthmatic subjects. Cholinergic mechanisms contribute, but other mechanisms remain undefined. The effect of morphine, an opioid agonist, on the cholinergic component of SO2-induced bronchoconstriction was investigated, and the effect of indomethacin, a cyclooxygenase inhibitor, on SO2-induced bronchoconstriction and tachyphylaxis was studied. METHODS: In the first study 16 asthmatic subjects inhaled either ipratropium bromide or placebo 60 minutes before an SO2 challenge on days 1 and 2. On day 3 an SO2 challenge was performed immediately after intravenous morphine. In the second study 15 asthmatic subjects took either placebo or indomethacin for three days before each study day when two SO2 challenges were performed 30 minutes apart. The response was measured as the cumulative dose causing a 35% fall in specific airways conductance (sGaw; PDsGaw35). RESULTS: Ipratropium bromide significantly inhibited SO2 responsiveness, reducing PDsGaw35 by 0.89 (95% CI 0.46 to 1.31) doubling doses. This effect persisted after correction for bronchodilatation induced by ipratropium bromide. The effect of ipratropium bromide and morphine on SO2 responsiveness also correlated (r2 = 0.71). In the second study SO2 tachyphylaxis developed with PDsGaw35 on repeated testing, being reduced by 0.62 (95% CI 0.17 to 1.07) doubling doses. Indomethacin attenuated baseline SO2 responsiveness, increasing PDsGaw35 by 0.5 (95% CI 0.06 to 0.93) doubling doses. CONCLUSIONS: These results suggest that opioids modulate the cholinergic component of SO2 responsiveness and that cyclooxygenase products contribute to the immediate response to SO2.     

Effect of Renal Impairment on the Pharmacokinetics and Tolerability of Tiagabine

Summary: Purpose: We wished to determine the effect of renal impairment on the pharmacokinetics and tolerability of the new antiepileptic drug tiagabine (TGB).
Methods: We assessed TGB pharmacokinetics and tolerability in 25 subjects with various degrees of renal function (based on creatinine clearance, n = 4–6 per group) from healthy (group I) to requiring hemodialysis (group V) in a single and multiple dose (every 12h), one-period (groups I-IV) or a single dose, two-period (group V) study (4-mg oral doses of TGB · HCl). Blood samples were collected after the first dose (both periods for group V) and after the last dose on day 5 (groups I-IV). TGB plasma concentrations and plasma protein binding were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively.
Results: TGB was well tolerated by all study subjects. The pharmacokinetics of TGB were similar in all subjects; no pharmacokinetic parameter (based on either total or unbound concentrations) was statistically correlated with creatinine clearance. For total TGB in plasma, single-dose mean values of the maximum plasma concentration, clearance, and half-life (t1/2) ranged from 52 to 108 ng/ml, from 7.14 to 11.02 I/h, and from 6.4 to 8.4 h, respectively.
Conclusions: TGB pharmacokinetics and tolerability were independent of renal function; therefore, dosage adjustment is unnecessary for epilepsy patients with renal impairment.