Strategy for child immunization in Malaysian plantations.

An outline is given of a simple cost-effective strategy aimed at the immunization of all children and pregnant women residing in the plantation sector of Malaysia. It is based on a partnership between government, nongovernmental organizations and the private sector, and is supported by UNICEF.

PIP: A cost-effective strategy aimed at the immunization of all children and pregnant women residing in the plantation sector of Malaysia is outlined. It is based on a partnership between government, nongovernmental organizations and the private sector, and is supported by UNICEF. Over a million people reside on the Malaysian plantation estates: only 17% of the estates have their own hospitals; immunization services exist on only 1.5%; 40% of the estates are at least 5 kilometers from the nearest government health facility; and 64% lack transport for workers and their dependents to seek care away from the plantations. Two nongovernmental organizations, the Malaysian Paediatric Association and the Malaysian Society of Health, initiated discussions with the United Planting Association of Malaysia. A pilot study was undertaken by the groups on 6 estates in Selangor State, which included all the children at their first birthday. Tuberculosis, diphtheria/pertussis/tetanus, poliomyelitis, and measles immunization coverages were 88%, 44%, 59%, and 66%, respectively. The association of plantations accepted the organizations' proposals for all estates to: register all births; provide free transportation to government health clinics for the immunization of all eligible children and pregnant women; and enforce immunization schedules and record-keeping. The Ministry of Health agreed to provide free immunization of children and pregnant women; send mobile teams to estates that could assemble 20 or more eligible people for immunization; provide the estates with educational materials dealing with immunization; arrange that the maintenance of the cold chain be supervised by local medical officers of health; consider the training of estate hospital assistants with the help of the nongovernmental organizations. The total immunization plan was launched in September 1990. A manual was distributed to the estate managers, hospital assistants on the estates, and the medical officers who would implement and monitor the program. It is expected that total child immunization will be achieved in the foreseeable future in the estate sector.

Reye and Reye-like syndromes: results of a pilot study in Peninsular Malaya, 1986.

A pilot epidemiologic study of all cases of Reye and Reye-like syndromes was undertaken at 8 representative major hospitals in Peninsular Malaya from January 1st to December 31st 1986. The cases were classified as definitive Reye's syndrome, clinical Reye's syndrome and encephalo-hepatopathies. Less than 50% of cases reviewed fulfilled the National Center for Disease Control criteria for clinical Reye's syndrome. Causes of Reye-like syndromes/encephalo-hepatopathies included fulminant hepatitis, Japanese B encephalitis, dengue, septicaemia, and complex febrile fits. It was not possible to differentiate clinical Reye's syndrome from the other encephalo-hepatopathies by either the clinical features (except for jaundice) or biochemical parameters. Liver biopsy is necessary for a definitive diagnosis of Reye's syndrome in Malaysia, because of the high prevalence of Reye-like diseases. The mortality rate in the 2 groups of patients is similar. Ingestion of salicylates was not found to be significantly associated with Reye and Reye-like syndromes in this study.

Evaluation of the possible role of glucose, carnitine, coenzyme Q10 and steroids in the treatment of Reye's syndrome using the margosa oil animal model.

Glucose and steroids have been used in the treatment of children with Reye's syndrome, while carnitine and coenzyme Q10 have been the subject of some recent studies which suggest that these agents may have a role in the treatment of Reye's syndrome and Reye-like syndrome due to margosa oil poisoning. Because of the paucity of causes of Reye's syndrome seen at any one centre, the clinical variability of the disease, and limited knowledge of definite aetiologic factors, controlled clinical trials are not easy to carry out or to interpret in human cases. These caveats were overcome by evaluation of these four treatment modalities in an established margosa-oil-induced animal model of Reye's syndrome. Effectiveness of the treatment modalities was determined from clinical response and histopathologic parameters (grading of light microscopic fatty changes and ultrastructural changes in the hepatocytes). Results show that carnitine per se produces a small improvement in survival, but statistically, more significant benefit is seen with glucose administration. Carnitine plus 10% dextrose appears to produce better results. Evaluation of coenzyme Q10 and carnitine on histopathologic parameters in the liver after a sublethal dose of margosa oil showed no obvious ameliorating effect on liver pathology. Steroids (dexamethasone/methylprednisolone) had no beneficial effects in reducing mortality, affecting glycogen storage or lipid accumulation. Changes in the mitochondria, ribosomes and endoplasmic reticulum were unaltered from the groups treated with margosa oil alone. While glucose and carnitine supplements appear to be beneficial, the other modes of therapy do not seem to hold much promise in the treatment of Reye-like syndrome in the margosa-oil-induced animal model.

Animal model of margosa oil ingestion with Reye-like syndrome. Pathogenesis of microvesicular fatty liver.

The aetiology and pathogenesis of Reye's syndrome (RS) are incompletely understood. A number of environmental toxins and biological agents, including viruses, have been postulated to cause RS, either acting alone or synergistically. Most investigations have suggested that the primary insult is in the liver mitochondria, leading to a complex biochemical catastrophe, with death from encephalopathy. Margosa oil (MO), a long-chain fatty acid compound, has been shown to cause a Reye-like syndrome with death from hepatoencephalopathy, in children in Malaysia and India. The present time-course study performed in MO-administered mice showed the development of hepatic lesions with many features of RS. MO acts rapidly, within 30 min, on the nuclei of hepatocytes inducing mitoses and binucleated cells. This is followed by mitochondrial injury, with swelling, rarefaction of matrix, loss of dense bodies, pleomorphism, and loss of ribosomes starting at 60 min. There is loss of liver glycogen, and proliferation and hypertrophy of the endoplasmic reticulum (ER), followed by the presence of lipid droplets in the hyaloplasm, and globules within dilated cisterns of the ER. Additional fatty acids from lipolysis of body adipocytes, and fat globules from intestinal MO ingestion further aggravate the liver fatty change. There is evidence of fat globule ingestion by endocytosis into hepatocytes at the level of the sinusoids. The development of microvesicular liver steatosis and glycogen depletion due to involvement of liver cell organelles occur rapidly as in RS.

Effects of drugs and fatty acids related to Reye syndrome on brain water content in rats.

Brain water content was measured by gas-chromatography in rats following intraperitoneal injection of drugs and fatty acids related to the etiology of Reye syndrome. A statistically significant increase in brain water content was observed following injection of 5% glucose solution, valproic acid, acetyl salicylic acid, calcium hopantenate, margosa oil, 4-pentenoic acid, linolenate and arachidonate. Seizures occurred in all animals given valproic acid, margosa oil and 4-pentenoic acid, and in 25% of those given 5% glucose solution + anti-diuretic hormone. The results of these studies may help in the selection of appropriate agents for experimental induction of acute encephalopathy and brain edema in animal models of Reye syndrome.

Inhibition of mitochondrial functions by margosa oil: possible implications in the pathogenesis of Reye's syndrome.

Margosa oil (MO), a fatty acid-rich extract of the seeds of the neem tree and a reported cause of Reye's syndrome, has been used in the induction of an experimental model of Reye's syndrome in rats. It has been reported that MO causes a decrease in in vivo mitochondrial enzyme activity similar to that seen in Reye's syndrome. We have attempted to uncover some of the biochemical mechanisms of MO's toxicity by examining its effect in vitro on isolated rat liver mitochondria. Male rat liver mitochondria were isolated by centrifugation; oxygen uptake, reduced forms of cytochrome b, c + c1, a + a3, and flavoprotein, intramitochondrial concentrations of acetyl coA, acid-soluble coA, acid-insoluble coA, and ATP content were measured after incubation with and without MO. Our results reveal that MO is a mitochondrial uncoupler. State 4 respiration was increased while the respiratory control ratio was decreased. The intramitochondrial content of ATP was also decreased. There were substantial changes in the reduction of the respiratory chain components after incubation of mitochondria with MO. This decelerative effect on mitochondrial electron transport was alleviated by the addition of coenzyme Q and/or carnitine. These effects of MO on mitochondrial respiration may be due to changes in fatty acid metabolism caused by MO as MO caused a shift in the proportion of acid-soluble or acid-insoluble coA esters. Supplementary therapy with L-carnitine and coenzyme Q may be useful in the management of MO-induced Reye's syndrome.

Pulmonary alveolar septal calcinosis causing progressive respiratory failure in acute lymphoblastic leukemia in childhood.

A syndrome of pulmonary alveolar septal calcinosis, pneumothorax, and pneumomediastinum, leading to rapidly progressive acute respiratory insufficiency and death was observed in 2 children with acute lymphoblastic leukemia (ALL). Primary clinical and radiological considerations in these patients were pulmonary edema and infection, and the diagnosis of pulmonary alveolar septal calcification was established only at autopsy. One patient, a 15-year-old girl, was found also to have parathyroid hyperplasia typical of familial hyperparathyroidism. The other, a 16-month-old girl, showed osteitis fibrosa of the bones and parathyroid hyperplasia of secondary type, suggesting that the pulmonary calcinosis resulted from hypercalcemia caused by a parathormone or prostaglandin-secreting tumor. The cause of pneumothorax and pneumomediastinum may have been rupture of calcified alveolar septa induced by high PEEP during ventilation of these patients. Other possible mechanisms contributing to hypercalcemia and pulmonary calcinosis in children with acute leukemia include bone resorption due to marrow infiltration, immobilization syndrome, renal failure, and administration of calcium, phosphate, or bicarbonate. This complication of acute leukemia in childhood is rare (2 patients in 430 autopsied over the period 1961-1982 at Childrens Hospital of Los Angeles). How often the process can be reversed if diagnosed before severe respiratory insufficiency is present is not known.

Investigation of an animal model of a Reye-like syndrome caused by Margosa oil.

Following reports of a Reye-like syndrome in children resulting from Margosa oil (MO) ingestion, we administered MO to laboratory rats in an attempt to produce an animal model of Reye's syndrome. Male rats were injected intraperitoneally with either MO or corn oil and observed for clinical signs of a toxic response. After 15 h the animals were administered a second dose and the MO-treated animals developed florid neurological symptoms. The animals were then sacrificed and blood samples were analyzed for glucose, ammonia, aspartate aminotransferase, and alanine aminotransferase. Sections of liver, kidney, and brain were examined by light microscopy after Sudan black B, hematoxylin and eosin, and periodic acid-Schiff staining. Liver was additionally examined by electron microscopy. Liver samples were analyzed for hepatic enzyme levels and brain samples were analyzed for water content. There were greatly increased levels of ammonia, aspartate aminotransferase, and alanine aminotransferase and decreased glucose levels in the blood of MO-treated animals. Light microscopy of MO-treated livers revealed fatty infiltration, granularity of the cytoplasm with normal nuclei, and glycogen depletion; electron microscopy revealed mitochondrial pathology in the livers of MO-treated animals. There were no significant morphological changes in brain or kidney specimens although the kidneys did show some fatty infiltration. Hepatic mitochondrial enzyme levels were unchanged and there was no increase in brain water content in the MO-treated animals. Thus, many of the abnormalities seen in Reye's syndrome were seen in this model; however, there were no hepatic enzyme changes despite altered mitochondrial morphology and no evidence of cerebral edema despite a florid encephalopathy. Nonetheless, this model may have important implications for the understanding of the pathogenetic mechanisms of this Reye-like syndrome and, perhaps, Reye's syndrome.

Combination chemotherapy with cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) in children with brain tumors.

The chemotherapeutic combination of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) was used to treat 15 children with recurrent central nervous system tumors and seven children with newly diagnosed brainstem tumors. In patients with recurrent tumors, marginal activity was seen in various histologic types. COPP chemotherapy was clearly ineffective in patients with brainstem tumors. Toxicity consisted of mild to moderate myelosuppression and neurotoxicity.