Short course chemotherapy for tuberculous lymphadenitis in children.

OBJECTIVE: To assess the efficacy of a short course chemotherapy regimen for treating tuberculosis of the lymph nodes in children. DESIGN: Open, collaborative, outpatient clinical trial. SETTING: Outpatient department of the Tuberculosis Research Centre, paediatric surgery departments of the Institute of Child Health and Hospital for Children and the Government Stanley Hospital, Madras, South India. PATIENTS: Children aged 1-12 years with extensive, multiple site, superficial tuberculous lymphadenitis confirmed by biopsy (histopathology or culture). INTERVENTIONS: Patients were treated with a fully supervised intermittent chemotherapy regimen consisting of streptomycin, rifampicin, isoniazid, and pyrazinamide three times a week for two months followed by streptomycin and isoniazid twice a week for four months on an outpatient basis. Surgery was limited to biopsy of nodes for diagnosis and assessment. MAIN OUTCOME MEASURES: Response to chemotherapy was assessed by regression of lymph nodes and healing of sinuses and abscesses during treatment and follow up. Compliance with treatment and frequency of adverse reactions were also estimated. RESULTS: 197 Patients were admitted to the study and 168 into the analysis. The regimen was well tolerated and compliance was good with 101 (60%) patients receiving the prescribed chemotherapy within 15 days of the stipulated period of six months. Those whose chemotherapy extended beyond that period received the same total number of doses. Clinical response was favourable in most patients at the end of treatment. Sinuses and abscesses healed rapidly. Residual lymphadenopathy (exceeding 10 mm diameter) was present in 50 (30%) patients at the end of treatment; these nodes were biopsied. Fresh nodes, increase in size of nodes, and sinuses and abscesses occurred both during treatment and follow up. After 36 months of follow up after treatment only 5 (3%) patients required retreatment for tuberculosis. CONCLUSION: Tuberculous lymphadenitis in children can be successfully treated with a short course chemotherapy regimen of six months.

Effects of postweaning protein malnutrition on intestinal inositol phosphatase activities in normally weaned and neonatally undernourished rats.

Postweaning protein malnutrition imposed on normally weaned or neonatally undernourished rats fed a low-protein diet induced retardation of body and small intestinal growth. A sparing effect on intestinal growth as compared to body growth was observed during protein malnutrition. Postweaning protein malnutrition in normally weaned rats resulted in a significant elevation of specific activities of inositol triphosphatase and phytase in duodenum and jejunum without affecting the activity in ileum. On the other hand, protein malnutrition imposed on neonatally undernourished rats resulted in a significant decrease of enzyme activities in small intestinal segments. These results suggest altered activity of intestinal inositol phosphatase in postweaning protein malnutrition with the direction of effects dependent on the neonatal nutritional status.

Effect of undernutrition on the chemical composition and the activity of alkaline phosphatase in soluble and particulate fractions of the newborn rat calvarium and femur. I: Effect of gestational undernutrition in the rat.

We studied the effect of maternal protein deficiency on the development of the rat calvarium and femur. The results show that maternal protein deficiency during gestation leads to fetal growth retardation, and that the calvarium is more affected than the femur. A significant decrease in the activity of alkaline phosphatase was found in the soluble fraction in both the calvarium and the femur. However, this was not true in the case of the particulate fraction in which a significantly increased activity was found. This increase was not associated, however, with a concomitant increase in calcium and phosphorus (per 100 g fresh bone).

Effect of undernutrition on the chemical composition and the activity of alkaline phosphatase in soluble and particulate fractions of the rat calvarium and femur. II: Effect of preweaning undernutrition in the suckling rat.

We studied the effects of undernutrition during the suckling period on the development of the calvarium and the femur of rat pups suckling dams fed a 20% or 5% protein diet. The results show that the maturation of bone is delayed by undernutrition. In both the calvarium and the femur, the particulate fraction alkaline phosphatase reflects the rate increments in calcium and phosphorus uptake in control animals. This association is affected in the undernourished pups, as both the alkaline phosphatase activity in particulate fraction and the calcium and the phosphorus uptake decreased. However, the extent of disturbance was more prominent in the femur than in the calvarium, suggesting that during postnatal undernutrition the calvarium is less affected when compared to prenatal undernutrition, where the femur is less affected. The results from these studies suggest that proper nutrition is necessary for bone development during both the prenatal and postnatal period.

Alcohol exposure and undernutrition: effects on lipid metabolism and alcohol partitioning in rat brain regions in vitro.

The effects of maternal alcohol consumption and undernutrition on lipid metabolism and alcohol partitioning in brain cortical and stem slices of pups were studied under in vitro conditions. Alcohol administration along with a normal diet during gestation and lactation resulted in an increase in the synthesis of cholesterol in cortical and stem slices associated with decreased entry of alcohol. Phospholipid metabolism was not affected in the cortex, whereas the incorporation of [32P] was found to be altered in the brain stem, indicating regional differences with respect to alcohol effects. Undernutrition induced by feeding the mothers a low protein diet, on the other hand, decreased the incorporation of labelled precursors into lipids in cortex and stem. The changes in lipid metabolism observed in the high protein alcohol pups were not evident in the brain regions of undernourished pups exposed to alcohol and the partitioning of alcohol was not altered.

Lipid composition of brain regions during chronic maternal alcohol treatment and withdrawal in the rat.

The lipid composition of whole brain, cerebrum, cerebellum and brain stem was studied in rat pups exposed to alcohol during prenatal and postnatal period and subsequent withdrawal or continuation during postweaning period. The concentrations of cholesterol and galactolipids were increased in the whole brain and brain regions of the pups exposed to alcohol. Even after 6 weeks of withdrawal from alcohol during postweaning period, the lipid levels were significantly higher compared to the controls. These observations suggest possible alterations in the functions of CNS related to membrane integrity.

Interaction of alcohol and protein deficiency on rat brain synaptosomal (Na+-K+)-ATPase.

Administration of low amounts of ethanol for a prolonged period increases rat brain synaptosomal (Na+-K+)-ATPase activity, the increase being less in the protein deficient rats. The adaptive mechanism to offset the stress imposed by the continued presence of ethanol seems to be depressed by low plane of nutrition. In vivo and in vitro effects of ethanol on (Na+-K+)ATPase seems to be different.

Effect of maternal alcohol consumption on the lipid composition of CNS in the offspring.

Maternal alcohol consumption at a level that does not affect calorie intake increases cholesterol concentration and content as well as incorporation of labeled glucose into cholesterol in the brain and spinal cord of newborn rat pups. Continued consumption of alcohol during lactation also affects the galactolipid concentration in the brain and spinal cord of pups at 21 days of age, and this increase seems mainly to be due to an increase in content of myelin lipids. Analysis of myelin shows that the concentration of phospholipids also increases in this fraction. The increase in incorporation of labeled glucose into these membrane lipids suggests an increase in the synthesis of these lipids, which prevents fluidization of the membrane by alcohol. That in the brainstem the increase in levels of cholesterol and galactolipids is higher than in other regions and that there is also an increase in content of sphingomyelin, phosphatidylcholine, and phosphatidylethanolamine suggest that the brainstem needs better protection against fluidization.

Role of microorganisms in improving nutritional status of the poor.

The intestinal microflora as well as bacteria involved in fermentation of foods ordinarily consumed in India may contribute substantially for the improvement of nutritional status of poor Indians.

Effects of pre-weaning undernutrition and post-weaning rehabilitation on polyphosphoinositide pools in rat brain regions.

In order to assess the effects of undernutrition during the pre-weaning period on polyphosphoinositide (PolyPI) pools in rat cerebral cortex, brain stem, and cerebellum, dams were fed 5% (L-) or 22% (L+) protein diets from birth to weaning and the pups were used at this age for analyses. To examine rehabilitation post-weaning, L- and L+ pups were fed 22% protein diets (P+) for an additional six week period. Rats were decapitated and the dissection begun either immediately ("0 min" samples) or 10 min later (10 min samples). Body and tissue weights, and cerebroside levels were determined in addition ot PolyPI concentrations. In brain the extent of disappearance of PolyPI during the 10 min post-mortem period paralleled the content of gray matter: cerebral cortex greater than cerebellum greater than brain stem in all groups regardless of diet. Levels of PtdIns4P and PtdIns4,5P2 were decreased by 40% and 70% respectively in cerebral cortex of L- "0 min" samples. Deficits of both lipids in brain stem and cerebellum were 40-50%. In the L- 10 min samples, deficits were 20-30% in all three regions as compared with L+ 10 min levels, indicating the presence of a portion of both lipids affected only moderately by nutritional insufficiency. The effects on this relatively inert pool, much of it localized in myelin, were reversed on nutritional rehabilitation. The PolyPI pool lost post-mortem in L+ brain regions was practically absent in L- brain regions and was not restored in L-P+ animals. Thus, this study indicates that a metabolically labile pool, primarily located in gray matter structures, is more sensitive to nutritional deprivation during the pre-weaning period than the more stable pool. The precise role and function of these pools remain to be determined.

Developmental pattern of alkaline phosphatase in soluble and particulate fractions of rat skull cap and femur.

Alkaline phosphatase is detected in both soluble and particulate fractions of rat bone. The concentration of alkaline phosphatase in the particulate fraction of rat skull cap bone and femur is high during the peak period of calcification of these bones suggesting the possibility of using it as a marker for the rate of bone calcification.

Effects of neonatal undernutrition and subsequent nutritional rehabilitation or administration of thyroxine and hydrocortisone on the inositol phosphatase activities in rat intestine.

Undernutrition during the suckling period imposed by maternal protein deficiency during lactation resulted in elevated inositol triphosphatase activity (units per gram of wet tissue) in the ileum and lower phytase activity in the duodenum and jejunum. Activities of inositol triphosphatase in the duodenum and jejunum and phytase in ileum were unaffected. Postweaning nutritional rehabilitation resulted in elevated specific activities of both enzymes in all segments; however, activities of whole segments were similar to the corresponding control values. Elevation of inositol triphosphatase (ileum) and decline of phytase (duodenum and jejunum) activities due to undernutrition were reversed by the administration of hydrocortisone or thyroxine during undernutrition. These results suggest that maturation of activities of inositol triphosphatase in ileum (by hydrocortisone) and phytase in all segments (by both hydrocortisone and thyroxine) is under hormonal regulation, and the effects of neonatal undernutrition may be partly due to hormonal imbalances.

Effects of pre- and postweaning undernutrition on polyphosphoinositide pools in rat kidney.

The effects of undernutrition on polyphosphoinositide levels in rat kidneys removed and frozen immediately after animal death or 10 min later were determined. Weanling (21-day-old) rats of dams fed a 5 or 22% protein diet and litters fed either normal or protein-deficient diets for an additional six wk were used. Nutritional deprivation lowered phosphatidylinositol-4-phosphate (PtdIns4P) preferentially (35-40%) but preserved phosphatidylinositol-4,5-bisphosphate (PtdIns4,5P2) at weaning. This effect was not completely reversed in animals nutritionally rehabilitated after weaning. Postweaning protein deficiency did not reduce the levels of these lipids. Postmortem loss was the same for all five groups, minimal for PtdIns4P and about one-third for PtdIns4,5P2.

Three chemotherapy studies of tuberculous meningitis in children.

Chemotherapy studies were undertaken in 180 patients with tuberculous meningitis. They were treated for 12 months with 1 of 3 regimens: the first consisted of streptomycin, isoniazid and rifampicin daily for the first 2 months, followed by ethambutol plus isoniazid for 10 months; in the second, pyrazinamide was added for the first 2 months, and in the third, rifampicin was reduced to twice weekly in the first 2 months. Steroids were prescribed for all the patients in the initial weeks of treatment. Approximately 50% of the patients were aged less than 3 years. On admission, 13% of the patients were classified as stage I, 77% as stage II and 9% as stage III. Cerebrospinal fluid (CSF) culture results were available for all the 180 patients and M. tuberculosis was isolated in 59 (33%). CSF smear results for acid fast bacilli were available only for the 103 patients admitted to the second and the third studies, and of these in 60 (58%) the CSF was positive either by smear or culture. The response to therapy was similar in the 3 studies. Despite administration of rifampicin for 2 months, the mortality was high. In all, 27% of the patients died of tuberculous meningitis, 39% had neurological sequelae and 34% recovered completely. There was a strong association between the stage on admission and the mortality rate, the deaths being highest in stage III. In the first study, when isoniazid was prescribed daily in a dosage of 20 mg/kg, 39% of the patients developed jaundice; however, when the dosage was reduced to 12 mg/kg, the incidence fell to 16%. In the third study, where rifampicin was administered twice a week, the incidence of jaundice was much lower (5%).

Inositol phosphatase in developing rat duodenum, jejunum and ileum.

Inositol phosphatase and phytase activities in different segments of the rat small intestine were measured during postnatal development. In the duodenum and jejunum, inositol phosphatase activity (units/g tissue) was low during the suckling period and increased at weaning, reaching a peak of activity at 4 weeks of age. In the ileum, peak activity was observed during the suckling period with a sharp decline at weaning. Phytase activity was very low during the suckling period in all segments, and increased to exhibit a peak at 4 weeks of age in the duodenum, and to a lesser extent in the jejunum (low activity was maintained in the ileum). The content of inositol phosphatase activity in the duodenum increased rapidly during the suckling period to reach its maximum at 4 weeks of age. This suggests a relationship to cell proliferation rate in the small intestinal mucosa.

Studies on inositolphosphatase in rat small intestine.

The possibility that inositolphosphatase differs from other intestinal phosphatases was tested by comparing several enzymatic characteristics of phosphatase activities of rat intestinal homogenate acting on various specific substrates. Optimum pH and temperature, Km, Vmax, heat stability, inhibition and metal ion requirement studies suggest that inositolphosphatase differs from phytase and p-nitrophenylphosphatase. Furthermore, we found that inositolphosphatase activity was about 2 times higher in duodenum and jejunum than ileum. It sedimented (90-100%) with a high-speed particulate fraction of mucosal homogenate; 42% of the activity was separated with the brush border membrane isolated from mucosal homogenate. Partial separation by gel filtration on Sephadex G200 and chromatography on phenyl Sepharose CL 4B provided additional evidence to suggest that inositolphosphatase and phytase are different enzymes.

Effect of ethanol on rat brain polyphosphoinositides.

Female rats were allowed to consume ethanol during gestation and lactation, and brain polyphosphoinositides of the 21-day-old pups were quantified. Ethanol intake prevented the disappearance of the metabolically labile pools of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bis-phosphate, which are rapidly degraded in the control group. In contrast, preweaning undernutrition left the size of these pools virtually unchanged, indicating a differential effect of the two nutritional regimens.

Effects of preweaning undernutrition and continued postweaning protein deficiency or nutritional rehabilitation on polyphosphoinositides in rat brain.

Metabolically inert polyphosphoinositides seem to play an important role in the structural development of neurons, glia, and myelin. The metabolically active pool of PhIpp appears to be important for the functional development of glia and myelin during the postweaning period, whereas PhIp seems to be more important for the functional development of neurons during the preweaning period. Neonatal undernutrition reduces the concentrations of structural polyphosphoinositides and metabolic PhIp while metabolic PhIpp remains unaltered. These effects can be reversed by postweaning nutritional rehabilitation. A continued postweaning protein deficiency of neonatally undernourished rats affects structural PhIpp more than PhIp. Metabolically active PhIpp is drastically reduced.