Use of phytohaemagglutinin stimulated lymphocytes to study effects of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency on polynucleotide and protein synthesis in the Lesch-Nyhan syndrome.

The incorporation of [14C]thymidine and [14C]uridine into the nucleoprotein, and [14C]phenylalanine into the protein by phytohaemagglutinin (PHA) stimulated lymphocytes from a patient with the Lesch-Nyhan syndrome [hypoxanthine-guanine phosphoribosyl transferase (EC 2.4.2.8 HGPRT) deficiency] and controls, was studied over 72 hours of incubation, with and without azaserine to block de novo purine biosynthesis. No difference was observed between the values obtained for Lesch-Nyhan and control lymphocytes, when PHA-stimulated without added azaserine. The percentage reduction in the incorporation of precursors into nucleoprotein and protein after PHA stimulation in the presence of azaserine was more obvious in the lymphocytes of the patient with the Lesch-Nyhan syndrome than in the controls after the shorter incubation periods at the lower rates of synthesis. Blocking the de novo purine biosynthetic pathway, in control PHA stimulated lymphocytes, inhibited transformation, whereas loss of the purine salvage enzyme HGPRT did not have this effect. These results are compatible with the view that the brain and bone-marrow damage that occur in the Lesch-Nyhan syndrome are the result of lack of HGPRT in tissues with little de novo purine biosynthetic capability. Other tissues with both pruine biosynthetic and salvage pathways are less vulnerable to the enzyme defect. Some possible mechanisms by which HGPRT deficiency could act are discussed. We suggest that inability to increase the supply of guanylic acid (GMP) in response to a mitotic stimulus may mediate the effect of HGPRT deficiency

Prevalence of multiple sclerosis in a south London borough.

A survey of multiple sclerosis in the London Borough of Sutton, population 169,600, yielded 195 cases, giving an overall prevalence of 115/100,000. This is the third highest prevalence for a first survey of a geographical area in the United Kingdom, exceeded only by 127/100,000 in north east Scotland and 134/100,000 in Shetland. On the classification system of Allison and Millar, three quarters of the cases were classified as probable multiple sclerosis, 15% as early probable and latent multiple sclerosis, and 10% as possible multiple sclerosis. The mean age was 49 years, the mean age at onset was 34 years, and the mean duration of the disease was 15.4 years. The age standardised female to male ratio was 2:1. The prevalence found in this survey does not differ significantly from that recorded in the first north east Scotland survey. This study suggests that, firstly, the prevalence of multiple sclerosis in south east England is probably about 100/100,000 and, secondly, the latitudinal effect on the prevalence of multiple sclerosis in the United Kingdom is less appreciable than previously believed

Increased myofibrillar protein catabolism in Duchenne muscular dystrophy measured by 3-methylhistidine excretion in the urine.

Myofibrillar protein catabolic rate was calculated in seven patients with Duchenne muscular dystrophy from the amount of 3-methylhistidine excreted in the urine, and found to be over three times that found in a control series when expresses as the percentage of myofibrillar protein catabolised per day. It is suggested that measurement of myofibrillar protein catabolic rate may add a useful parameter in the study of muscle disorders

The value of the measurement of cerebrospinal fluid levels of lysozyme in the diagnosis of neurological disease.

A turbidimetric technique has been adapted to yield maximum sensitivity for the measurement of lysozyme in cerebrospinal fluid. One hundred and ninety-eight patients were studied over a total period of 9 months using this technique. In addition to the considerably elevated levels known to occur in cases of bacterial and fungal meningitis, increased activity was also demonstrated in cases of subarachnoid haemorrhage and in certain inflammatory conditions. Normal or marginally increased levels were seen in cases of viral meningitis and encephalitis

Studies on the intracerebral injection of bleomycin free and entrapped within liposomes in the rat.

Reverse phase prepared liposomes of defined composition (dipalmitoyl phosphatidyl choline, cholesterol and dipalmitoyl phosphatidic acid; 7:2:1; DPC) when injected intracerebrally in the rat produced no tissue damage beyond that of the penetrating wound, or altered behaviour pattern over 1 week of observation. The cerebral tissue response and behaviour of rats injected with bleomycin of increasing concentration, free and entrapped within liposomes was studied in short and long term experiments. In separate experiments blood, urine and tissue levels of bleomycin were measured after intracerebral injection of free and liposome entrapped bleomycin in the rat. These studies demonstrated that bleomycin when entrapped within liposomes and injected intracerebrally was of low toxicity to normal cerebral tissue, and was cleared more slowly from the injection site than when the free drug was injected. The results obtained indicated a potential application for drugs entrapped within liposomes acting as a depot preparation in the treatment of cerebral gliomas

3-Methylhistidine excretion as an index of myofibrillar protein catabolism in neuromuscular disease.

Myofibrillar protein catabolism has been calculated in a variety of neuromuscular diseases from the amount of 3-methylhistidine excreted in the urine. It was found to be significantly raised in Duchenne type muscular dystrophy, motor neurone disease, polymyositis, and thyrotoxic myopathy. In Becker type muscular dystrophy the level was slightly raised. It was normal in scapuloperoneal and limb girdle dystrophy, dystrophia myotonica, extrapyramidal disease, and multiple sclerosis. It was significantly decreased in hypothyroid myopathy

Mortality rates from multiple sclerosis: geographical and temporal variations revisited.

A review of the United Kingdom (UK) multiple sclerosis (MS) literature suggests that over the last three decades prevalence and estimated incidence rates have increased, while mortality rates have been declining. UK mortality data over a 30 year period have been studied to examine temporal and geographical variations, to estimate changes in survival, and to examine the relationship between mortality and morbidity trends. The study has shown an overall decline in mortality throughout the UK of approximately 25% over the 30 year period ending in 1983, and a reduction in the mortality differential between Scotland, and England and Wales, but no positive correlation has been found between mortality and morbidity. The overall decline in death rate in females was 23% and in males 30% over the 30 years of the survey. The total number of deaths declined by 39% between the five year periods 1954-58 and 1979-83 in Scotland compared with a 10% decline for England and Wales. Estimated median age of death increased from 52 to 59 years and the improvement in survival over the period of study was similar for both countries and is unlikely to have contributed to the reduction in mortality differential. Within England and Wales regional mortality rates did not show a clear north-south gradient. The decline in the mortality differential between Scotland and England (if not artefactual) may provide an important aetiological clue in the search for the cause of multiple sclerosis, and the rate of decline suggests an environmental rather than a genetic aetiology