Socio-clinical profile of rabis cases in anti-rabies clinic, M. K. C. G. Medical College, Orissa.

A hospital based study was conducted in the anti-rabies clinic of a medical college of Orissa during April 1988 to May 2002. Of 24 clinically diagnosed and reported rabies cases during the four years study period, 62.5% were children below 15 years of age, 67% were males, 87.5% were victims of stray dogs, 79% had not taken any anti-rabies treatment though all had undergone treatment by traditional systems of medicine.

Multicentric clinical trials for safety and efficacy evaluation of alpha;beta arteether in complicated P. falciparum malaria.

OBJECTIVE: To evaluate efficacy of alpha;beta arteether in patients of P. falciparum malaria presenting with complications was undertaken in a multicentric clinical trial. METHOD: Each patient who consented to undergo clinical trial with parenteral Arteether was treated with a fixed dose schedule of Arteether given intramuscularly in a dose of 150 mg once a day on three consecutive days. Every patient was followed upto 28 days with clinical, haematological and parasitological monitoring every day upto one week and thereafter at 14, 21 and 28 days. The response was assessed in terms of fever clearance time, parasite clearance time, cure rate and parasite reappearance rate. RESULTS: A total of 211 patients of P. falciparum malaria were included in the study from four centres (Bhilai, Guwahati, Jamshedpur and Rourkela). Results of this study showed that fever clearance time ranged between 24-168 hours, parasite clearance time ranged between 24-120 hours and overall mortality ranged between 4-8.5%. Out of 211, only 14 patients expired during the study, of these, 10 patients expired within first two days i.e. before completing the three day schedule of arteether therapy. Tolerability to arteether injection was good in all these patients and no untoward effects were experienced or reported during the study. Overall cure rate observed in these studies was 93%. CONCLUSION: This study shows a rapid parasite and fever clearance in patients of complicated P. falciparum malaria.

Effectiveness of alpha,beta-arteether in acute falciparum malaria.

With the emergence of widespread chloroquine resistance and a world-wide scarcity of quinine, a search for newer antimalarial drugs has become imperative. Different derivatives of qinghaosu have been successfully tried. alpha,beta-Arteether, an ethyl derivative of qinghaosu, was administered to 51 patients with Plasmodium falciparum malaria, in a dose of 150 mg intramuscularly once a day on 3 consecutive days. Complete parasite clearance from the peripheral blood was observed in 80% of the patients at 48 h and in 98% at 72 h. The median parasite clearance time was 2 d (range 1-4 d). 65% of the patients became afebrile within 48 h and 81% by 72 h. The mean fever clearance time was 52.04 h (standard deviation 27.09). No side effect was seen. Patients were followed-up for 4 weeks; 7 were readmitted with P. falciparum infection but it could not be ascertained definitely whether these cases were reinfections or recrudescences. alpha-beta Arteether was a safe, effective and convenient drug for treating P. falciparum malaria. This is the first clinical study with arteether in falciparum malaria.

Vascular clogging, mononuclear cell margination, and enhanced vascular permeability in the pathogenesis of human cerebral malaria.

To document histopathologic evidence on the pathogenic mechanism of human cerebral malaria, we used light microscopy to study brain specimens from 23 patients who died of central nervous system involvement with Plasmodium falciparum. Sequestration of parasitized red blood cells (PRBCs) leading to cerebral capillary clogging was seen. In a few specimens, vascular clogging by PRBCs was associated with margination of mononuclear cells. In others, capillaries were virtually empty and lymphocytes and monocytes were seen in apposition (marginated) to the capillary endothelial surface. The endothelial cells appeared plump, hypertrophied, and prominent. The capillary wall appeared thickened by fibrinous material. Massive intercellular brain edema along with extravasated red blood cells, mononuclear cells, and plasmatic fluid was also noticed. In addition to hypoxia induced by PRBC-mediated vascular clogging, marginating mononuclear cells may contribute to the pathogenesis of cerebral malaria. The precise role played by this phenomenon needs further evaluation.

Plasma antioxidants and lipid peroxidation products in falciparum malaria.

To investigate the influence of Plasmodium falciparum malaria on plasma antioxidants and lipid peroxidation, plasma ascorbate, urate, total protein and albumin, ceruloplasmin and malondialdehyde (MDA) were determined in two groups of 42 patients each, one with mild and the other with severe falciparum malaria, and in an equal number of age- and sex-matched control subjects. Plasma MDA was found to be significantly higher in malaria patients, and the increase was proportional to the severity of the disease. Of the antioxidants, ascorbate and albumin decreased with severity of disease while urate and ceruloplasmin increased. Only ascorbate correlated inversely with MDA both in mild (r = -0.341, P < 0.05) and severe malaria (r = 0.545, P < 0.01). While plasma albumin correlated inversely (r = -0.442, P < 0.01), urate and ceruloplasmin correlated directly (r = 0.419, P < 0.01 and r = 0.349, P < 0.05, respectively) only in patients with severe malaria. These antioxidants also correlated well with markers of disease severity, indicating the influence of disease severity in regulating their levels in plasma. The presence of significant quantities of ascorbate and albumin, along with increases in some of the other antioxidants and MDA, indicates ineffectiveness of the antioxidant defense system in controlling plasma lipid peroxide content. Increased amounts of thiobarbituric acid-reactive material could have been the result of spillover from increased tissue peroxidation or the presence of pro-oxidants in malarial plasma.

Altered plasma lipid pattern in falciparum malaria.

Plasma levels of HDL, LDL, total cholesterol and triglycerides were measured in 60 patients with falciparum malaria (37 severe cases and 23 mild) and in 83 healthy individuals, to study malaria-induced changes in plasma lipids. Triglyceride levels were lower in the patients than in the controls but the difference was significant only for those with severe malaria (P < 0.001). In contrast, the levels of all the other plasma lipids were significantly higher (P < 0.001) in those with severe malaria than in those with mild malaria, and in the mild malaria cases compared with the controls. Initially LDL cholesterol was estimated by the Friedwald formula, but this gave negative values in a few cases of severe malaria. Plasma lipoproteins were therefore also measured by nephelometry; the estimated levels of S particles, corresponding to LDL, were then found to be lower in all malaria cases than in the controls (P < 0.001) but never negative. Interestingly, levels of L particles in the patients with severe malaria were significantly elevated compared with the other patients and controls (P < 0.001), indicating impaired metabolism of chylomicrons. Plasma albumin, considered a negative acute phase protein (i.e. its level decreases as a consequence of the acute phase response), was reduced significantly and was directly correlated to HDL cholesterol levels (r = 0.715 and r = 0.895, respectively) in both mild and severe malaria. Follow-up of 22 of the severe malaria cases three weeks after treatment indicated that, while triglycerides had returned to similar levels to those in the controls, total cholesterol levels were still elevated and could give misleading results if lipid profiles were used, immediately after malaria infection, to assess an individual's risk of developing atherosclerosis.

Hepatic changes in P. falciparum malaria.

Liver function tests were performed in 165 hospitalized patients suffering from P. falciparum malaria with complications. Serum bilirubin was found increased in 33 patients, and 22 of them had unconjugated hyperbilirubinaemia. Serum alanine aminotransferase was increased in 5 patients, but only to mild to moderate levels. Serum alkaline phosphatase was increased in 11 patients, gamma-glutamyl transpeptidase in 3 patients. Serum total protein and albumin were significantly decreased but these were considered more as indicator of acute phase response. Liver cell necrosis was observed in one patient, and oedema and mononuclear cell infiltration in two patients. Though hepatomegaly and mild elevation of enzymes can be observed in a significant proportion of patients, involvement of liver leading to acute hepatitis or liver cell necrosis is a relatively uncommon complication in P. falciparum malaria.

Incidence of hypoglycaemia in children with severe Plasmodium falciparum malaria around Rourkela, Orissa state.

To determine the incidence of hypoglycaemia in children suffering from severe falciparum malaria, 23 patients from Rourkela (Orissa), were investigated. Plasma glucose and immunoreactive insulin were estimated before and at hourly intervals during quinine infusion. No child had hypoglycaemia at the time of admission. Correlation between parasite count and prequinine plasma glucose was not significant. In the period of quinine infusion, 20 patients showed fall in plasma glucose during all the three hours (P less than 0.05, P less than 0.01, P less than 0.01 at the end of 1st, 2nd, and 3rd h respectively) but the decrease to hypoglycaemic level (plasma glucose less than or equal to 40 mg/dl) was observed in only one child. Concomitant increase in plasma insulin was noticed in 18 of these patients. Decrease in plasma glucose and increase in plasma insulin was found to correlate well (r-0.78, P less than 0.001). Hypoglycaemia was found to be an infrequent complication of severe falciparum malaria in children from the area studied. Though decrease in plasma glucose was observed after quinine infusion, it was less severe and did not reach the hypoglycaemic level.

Increased cerebrospinal fluid protein and lipid peroxidation products in patients with cerebral malaria.

Membrane lipid peroxidation by reactive oxygen species leading to increased capillary permeability is considered an important event in the pathogenesis of severe malaria. A significant decrease in plasma albumin and increases in cerebrospinal fluid (CSF) protein and malondialdehyde (MDA) were observed in 73 patients with cerebral malaria, compared to values in 23 control patients. The greatest effect was noticed in the most severely ill patients. The ratio of CSF protein to plasma albumin was increased in the patients compared to the controls, and in fatal cases of cerebral malaria compared to non-fatal cases. Brain necropsies showed oedema, fibrin deposits and mononuclear cell infiltration. It is proposed that cerebral oedema due to enhanced permeability of vascular endothelium induced by increased lipid peroxidation plays a crucial role in the causation of cerebral malaria.

Increased plasma lipid peroxidation in riboflavin-deficient, malaria-infected children.

Plasma lipid peroxides were measured as malonyldialdehyde (MDA) by the thiobarbituric acid (TBA) method in 75 children suffering from Plasmodium falciparum malaria. Their riboflavin status was assessed by measuring erythrocyte glutathione reductase activation coefficients (EGRACs), and values greater than 1.40 were regarded as indicating biochemical deficiency. Plasma MDA was higher (p less than 0.001) in patients than in control subjects; the concentrations were 3.65 +/- 0.70 and 1.77 +/- 0.45 mumol/L (means +/- SD), respectively. The riboflavin-deficient group had higher plasma MDA values (3.98 +/- 0.70 mumol/L) than did the nondeficient group (3.30 +/- 0.68 mumol/L, p less than 0.001). Plasma MDA concentrations correlated with EGRACs (r = 0.46, p less than 0.01) in the patients. It is proposed that riboflavin deficiency restricts regeneration of reduced glutathione making the parasitized erythrocytes more vulnerable to destructive lipid peroxidation and increasing plasma lipid hydroperoxides.

Hepatic morphology in reactional states of leprosy.

Liver function tests and liver biopsies were studied in 23 leprosy patients in reaction and 10 without reaction. The liver biopsies in leprosy patients with reaction showed exudative lesions, epithelioid and tuberculoid granulomas, and foam-cell granulomas. Portal vasculitis was encountered in a few cases. Neutrophilic infiltration into the foam-cell granulomas was seen in a few cases of lepromatous (LL) leprosy with reaction. In six cases of borderline (BL, BB and BT) leprosy with reaction, a spectrum of lesions bearing footprints of exudative lesions were seen evolving into epithelioid-cell granulomas. Foam-cell granulomas and tuberculoid and epithelioid granulomas along with exudative lesions were encountered in two cases on individual biopsy strips. An altered albumin-to-globulin ratio was the chief functional derangement observed in these cases. The spectrum of changes observed in borderline leprosy with reaction could be discrete steps in the evolution of upgrading reaction.

Riboflavin deficiency and severity of malaria.

The riboflavin status of 64 children suffering from malarial infection was assessed by measuring the activation coefficient of erythrocyte glutathione reductase. Thirty-five children were found to be deficient in riboflavin whereas in 29 children riboflavin status was within the normal range. The median parasite count and its range on admission in the deficient group (2.7 per cent, range 0.3-13.6) was lower than that in the non-deficient group (5.3 per cent, range 0.6-30.2). The correlation between activity coefficient and parasite count was significant (R = -0.49). The recovery process was slower in the deficient group even though they had a relatively lower parasite count. It is inferred that riboflavin deficiency leads to inhibition of growth and multiplication of plasmodia. Its beneficial effects in malaria infection needs further evaluation.

Hypoglycaemia in severe falciparum malaria.

The incidence of hypoglycaemia and the role of quinine in its causation was assessed in 46 patients with severe Plasmodium falciparum malaria. Plasma glucose and immunoreactive insulin were estimated before, during and after quinine therapy. In 5 patients the plasma glucose was in the hypoglycaemic range, the lowest value being 0.67 mmol/litre (12 mg/dl) in a pregnant patient. Most of the remaining patients showed a significant fall in plasma glucose (P less than 0.05), but not to the hypoglycaemic range, and an increase in plasma insulin after quinine (P less than 0.01). A good correlation was found between these changes (r = 0.79, P less than 0.01). Patients with severe P. falciparum malaria, particularly those on quinine therapy, should be watched carefully for developing hypoglycaemia.