Multicentric reticulohistiocytosis. Detailed immunophenotyping confirms macrophage origin

A case study of multicentric reticulohistiocytosis is presented with extensive immunohistochemical studies of the infiltrate in both paraffin and cryostat sections. These studies showed that the cells are of monocyte/macrophage origin. B- and T-cell gene rearrangement analysis of multicentric reticulohistiocytosis was also performed and showed a germline configuration.     

Pharmacokinetics of terodiline and a major metabolite in dogs with a correlation to a pharmacodynamic effect

The pharmacokinetics and pharmacodynamics of the anticholinergic and calcium antagonistic drug terodiline, N-tert-butyl-1-methyl-3,3-diphenylpropylamine, have been studied in beagle dogs. The bioavailability was about 25% (0.15 and 0.5 mg/kg), the terminal half-life 3 hr, the systemic clearance 40 ml/min..kg, the volume of distribution (V beta) about 7 l/kg and the unbound fraction in serum 0.14. p-Hydroxyterodiline and p-hydroxy-m-methoxyterodiline were quantitated and constituted 15-40% and 25%, respectively, of the amount excreted in urine (about 60% of the dose) and were the main metabolites, as in man. The dog was used as an experimental model to study the chronotropic effect. An increased heart rate was observed after acute administration of high doses of terodiline as well as after p-hydroxyterodiline. A 20% increase in heart rate was observed at a mean serum concentration of 1086 and 1010 micrograms/l following intravenous injection of terodiline or p-hydroxyterodiline, respectively. The corresponding unbound concentrations were 150 and 474 micrograms/l. The potency ratios of terodiline/p-hydroxyterodiline was 0.9 +/- 0.2 (based on total concentrations) and 3.2 +/- 0.8 (based on unbound concentrations). The estimated potency of parent drug and main metabolite and the fact that p-hydroxyterodiline constitutes 10-20% of the terodiline steady-state level in man, indicate that the contribution of the metabolite to the chronotropic effect observed in clinical studies is minor.     

Marine biodiversity as a source of chemical diversity

Total global biodiversity is estimated at between 3 and 500 × 10⁶ species of prokaryote and eukaryote organisms spread across 70 or more phyla. The marine macrofauna alone are estimated between 0.5 and 30 × 10⁶ species and represents a broader range of taxonomic diversity than that found in the terrestrial environment, which has been the traditional source of natural products. With a typical eukaryote possessing 50,000 genes, the global marine macrofauna are the source of 2.5 × 10¹⁰ to 1.5 × 10¹² primary products and an associated extensive range of secondary products. However, only a few thousand novel compounds from marine organisms have been described. These compounds have proven unique in chemical and pharmacological terms but, as yet, no therapeutic agents have resulted. Given a broader drug discovery strategy, and facilitated by technological advances, it is predicted that the characterisation of marine chemical diversity will be accelerated. Strategies for drug discovery from the virtually untapped chemical diversity of marine organisms are discussed. © 1994 Wiley-Less, Inc.     

Radical prostatectomy and prostate cancer screening: the need for national audit and research.

Public awareness of prostate cancer is increasing. Growing numbers of middle-aged men are seeking screening tests for prostate cancer and advice about its surgical treatment. Contrary to the hopes of many, the benefit of early diagnosis and by radical prostatectomy remains in doubt. Recent analyses suggest that ''watchful waiting'', with no immediate treatment, may be an equally effective option. If this is true, why screen? Why operate? These questions should be a cause of concern to more than 1 million British men who are unaware that they have prostate cancer and to the providers of health care who have failed to address this dilemma. A national audit and randomised clinical trial are indicated.     

A Thalamic Contribution to Arousal-induced, Non-photic Entrainment of the Circadian Clock of the Syrian Hamster

It is well established that the circadian clock of the suprachiasmatic nuclei (SCN) is entrained by light. More recently, the potent effects of arousing, non-photic cues on the clock have been recognized. The neural mediators of non-photic entrainment are yet to be identified. To examine the contribution of the thalamic intergeniculate leaflet (IGL) and its NPY-immunopositive projection, the geniculo-hypothalamic tract to non-photic entrainment by arousal, male Syrian hamsters received lesions of the IGL (IGLX) which ablated NPY-immunoreactivity in the SCN. Their circadian responses to both photic and non-photic cues were then tested. Lesions resulted in a delay in the timing of activity onset following lights out, but had no effect on the behavioural or cellular circadian responses to phase-advancing light pulses presented at circadian time (CT) CT19 (where CT12 represents the time of activity onset). Injection with a benzodiazepine (chlordiazepoxide, 100 mg/kg) at CT6 suppressed wheel-running, increased general locomotion of intact controls and induced large phase advances of the circadian rhythm of wheel-running. Chlordiazepoxide also inhibited wheel-running in lesioned animals, but there was no significant increase in general locomotion and the lesioned animals did not phase advance. Serial arousal by injection of saline at intervals of 23.5 h for 6 days entrained the circadian rhythm of wheel-running of intact hamsters and was associated with an increase in general locomotor activity. Entrainment by serial arousal was abolished by IGLX. However, the lesioned animals did show a clear behavioural response to every presentation of the non-photic cue. These results show that the IGL is a necessary component of the neural pathways mediating both arousal- and benzodiazepine-induced non-photic entrainment.     

News for the Practitioner

News for the Practitioner     

Follow up study of children born elsewhere but attending schools in Seascale, West Cumbria (schools cohort)

Records on 1546 children who were identified as having attended schools in Seascale up to November 1984 and were born since 1950 but not in the civil parish were studied. These children lived in or near Seascale for a period of time while they were attending one or more of three local schools and are an additional group to the 1068 children who were identified as born to mothers resident in Seascale in an accompanying study. Even though some of the schoolchildren apparently remained in the village for a short period only all but 7% were followed up through the National Health Service Central Register. Mortality among these children to 30 June 1986 is comparable to that expected at national rates. From all causes there were 10 observed deaths compared with 12.69 expected--a ratio of 0.79 (95% confidence interval 0.38 to 1.45)--and from cancer one observed death compared with 2.04 expected--a ratio of 0.49 (95% CI 0.01 to 2.73). No deaths from leukaemia or lymphoma were reported, but only 0.83 was expected. Since 1971 (the year when cases of cancer were first notified to the NHS Central Register) three non-fatal cases of cancer were reported, including two lymphomas, compared with 2.04 expected and two cases of carcinoma in situ of the cervix compared with 1.79 expected. In addition, there was a case of leukaemia among the schoolchildren which was known previously and had been diagnosed in 1968. There is an interesting difference between the results of this study and the results of the study of children born to mothers who were resident in Seascale. In the latter study there was an excess of leukaemia and of other cancers, but a similar finding is not apparent among children who spent some time at schools in Seascale but were born elsewhere. This raises the question of whether one or more aetiological factors in childhood cancer were acting on a locality specific basis before birth or early in life. This cannot be answered from these cohort studies, but it is hoped that the case-control study that is under way in West Cumbria will provide relevant information.     

Colon perforation during colonoscopy: surgical versus conservative management

A survey of endoscopy units in the West Midlands, UK, was undertaken to ascertain the management of colonic perforation during colonoscopy. Fifteen perforations were reported from a total of 17,500 colonoscopies performed in 14 units (a rate of 0.09 per cent). In seven patients the diagnosis was suspected or diagnosed immediately and in the remaining eight 2-72 h later. Four patients with associated pathology (carcinoma, Crohn's disease, ulcerative colitis and a polyp) had resection and primary anastomosis. Seven patients had a simple oversew, four of these having had a delayed diagnosis. In four cases the site of perforation was not identified, but only one patient had conservative treatment. Three patients had drainage and a defunctioning colostomy. There was no significant morbidity following treatment. It is recommended that patients who have had a good bowel preparation should be treated conservatively unless there is a large perforation or an underlying carcinoma.