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Biomedical subjects

S Krishna

Publications and source records attributed to S Krishna.

At least 127 records · Page 7Linked to original sources
PubMed1990

Telomere-related sequences at interstitial sites in the human genome.

The ends (telomeres) of eukaryotic chromosomes are protected from degradation and from loss during DNA replication by buffers of simple tandem repetitive sequence. The nucleotide sequence of these telomeric arrays is fundamental to telomere function as a site for protein and ribonucleoprotein binding and varies only slightly in a wide range of organisms. We present evidence that arrays of this human telomeric sequence, TTAGGG, are present not only at the ends of human chromosomes but also at numerous interstitial sites. These interstitial loci share nucleotide sequence similarity outside the repetitive array, suggesting that they are related functionally or have evolved from a common progenitor locus.

Base Sequence↗
PubMed1990

Glucose metabolism in quinine-treated patients with uncomplicated falciparum malaria.

To investigate host and drug effects on glucose metabolism in acute falciparum malaria, 10 previously untreated, fasting Thai males with uncomplicated infections were given a 2-h intravenous glucose infusion (5 mg/kg ideal body weight min) with an infusion of quinine dihydrochloride (10 mg/kg body weight) during the second hour. Eight patients were restudied in convalescence. Fasting plasma glucose (mean +/- SD) and insulin (geometric mean (-SD to + SD] were higher during acute illness (5.5 +/- 1.0 mmol/l and 6.2 (5.0-7.7) mU/l) than in convalescence (4.2 +/- 0.25 mmol/l and 3.7 (2.1-6.7) mU/l; P less than 0.001 and P = 0.058 respectively). After 1 h, both plasma glucose (9.3 +/- 1.4 vs 7.5 +/- 0.8 mmol/l, P less than 0.001) and insulin (21.2 (13.8-32.5) vs 15.2 (11.2-20.8) mU/l, P = 0.089) remained higher during acute illness; mathematical model (CIGMA) assessment of these values indicated lower tissue insulin sensitivity on admission (97% (71-134] than in convalescence (139% (109-178), P less than 0.025) but normal beta-cell function on both occasions. Two-hour plasma glucose (9.5 +/- 2.0 mmol/l) and insulin (81.8 (51.5-129.9) mU/l) concentrations during acute illness were also significantly higher than in convalescence (7.2 +/- 1.2 mmol/l and 40.1 (23.5-68.4) mU/l, P less than or equal to 0.025) despite similar end-infusion free plasma quinine concentrations (P greater than 0.5). Basal plasma free fatty acid concentrations were increased in acute illness (0.68 +/- 0.24 vs 0.21 +/- 0.12 mmol/l, P less than 0.001) but fell to low levels at 2 h in both studies. These data suggest tissue insulin resistance and augmented quinine-stimulated insulin secretion in acute falciparum malaria, factors which are likely to influence the clinical situation in which malaria-associated hypoglycaemia occurs.

Acute Disease↗
PubMed1990

Erythrocyte sequestration and anemia in severe falciparum malaria. Analysis of acute changes in venous hematocrit using a simple mathematical model.

Microvascular erythrocyte sequestration, the characteristic pathological feature of falciparum malaria, was evaluated using a mathematical model in 46 patients with severe infections. From admission radioisotopic circulating red cell volumes and simultaneous venous hematocrits, the model-derived sequestrum hematocrit (mean [95% confidence limits]: 0.70 [0.43-0.97], n = 29) was twice that of peripheral blood (0.33 [0.30-0.36]). Serial reticulocyte and radiolabeled erythrocyte counts indicated that small numbers of cells enter the circulation during initial therapy. The mean fall in hematocrit over 84 h in 26 nontransfused patients conformed to a three-term equation. A first-order decline (t1/2 2.0 h [0.6-3.4]) suggested an average 7.5% plasma volume expansion through rehydration. A zero-order 6.3% (3.1-9.5) fall (t1/2 25.7 h [21.2-30.2]) occurred contemporaneously with a fall in mean parasitemia from 4.5% (3.6-5.4); from these data the model-derived average sequestered erythrocyte volume (4.8% of the admission hematocrit) was similar to the peripheral parasite burden. A second, first-order fall (t1/2 1,047 h [278-1,816]) indicated loss of uninfected erythrocytes with mean lifespan 62 d. Predicted total plasma volume expansion during initial therapy (21.2%) was similar to radioisotopic estimates in 11 patients (17.3% [2.0-33.1]). Application of the model to individual patient data showed wide variations in relative proportions of circulating and sequestered parasitized cells. The model provides evidence of the nature and fate of all parasitized erythrocytes in malaria.

Anemia↗
PubMed1989

Open comparison of intramuscular chloroquine and quinine in children with severe chloroquine-sensitive falciparum malaria.

An open paired randomised comparison of intramuscular chloroquine (3.5 mg base/kg every 6 h) and intramuscular quinine (20 mg salt/kg followed by 10 mg/kg every 12 h) was carried out in 50 Gambian children with severe falciparum malaria. 8 children died, 6 from the quinine-treated and 2 from the chloroquine-treated group. Chloroquine reduced parasitaemia significantly more rapidly than did quinine, but other measures of the therapeutic response were similar in the two groups. Quinine injections were painful. These findings do not support the proposition that quinine is intrinsically superior to chloroquine in the treatment of severe drug-sensitive falciparum malaria.

Administration, Oral↗
PubMed1989

Intracellular distribution and pharmacokinetics of daunorubicin in anthracycline-sensitive and -resistant HL-60 cells.

Anthracycline-sensitive (HL-60) and -resistant (HL-60/AR) cells, which do not overexpress the P-glycoprotein, each transport and distribute daunorubicin (DNR) into distinct intracellular locations, as visualized by digitized video fluorescence microscopy. At pH 7.4, the fluorescence of DNR in HL-60 cells appears distributed diffusely in both the nucleus and cytoplasm. In contrast, HL-60/AR cells show much less fluorescence in the nucleus and cytoplasm; most of the fluorescence localizes first to the Golgi apparatus and is then gradually shifted to the lysosomes and/or mitochondria. In pharmacokinetic studies, HL-60/AR cells exposed to different extracellular concentrations of [14C]DNR consistently accumulated less radioactive drug than the parent HL-60 cells. Incubation of HL-60/AR cells with sodium azide and deoxyglucose blocked the efflux of [14C]DNR and also prevented the shift of DNR fluorescence from the Golgi apparatus to the lysosomes/mitochondria. The efflux and the intracellular shift of DNR could also be inhibited by lowering the temperature to 18 degrees C, which stops endosomal membrane fusion. When DNR was allowed to accumulate in HL-60 or HL-60/AR cells at pH 5 there was an increase in the proportion of drug fluorescence in the membranes of both HL-60 and HL-60/AR cells; a decrease in the amount of drug retained by HL-60, but not by HL-60/AR cells; and a decrease in the cytostatic effects of DNR on both HL-60 and HL-60/AR cells. These data suggest that DNR resistance is associated with a failure of DNR to pass through membranes and to bind to cytoplasmic and nuclear structures. Instead, most of the drug is taken up by the Golgi apparatus from which it is then shifted to the lysosomes or to mitochondria, or out of the cell.

Antibiotics, Antineoplastic↗
PubMed1989

Role of glutathione and dependent enzymes in anthracycline-resistant HL60/AR cells.

We studied the cellular enzymatic defenses against anthracycline-induced free radical damage in the HL60 human myelogenous leukemia cell line and in its anthracycline-resistant subline, HL60/AR. Intracellular glutathione (GSH) levels and gamma-glutamyl transpeptidase activity were lower in HL60/AR than in HL60 cells. Glutathione-S-transferase (GST) and glutathione peroxidase activities were similar in both cell lines. The intracellular distribution of GSH/GST was visualized by digitized video fluorescence microscopy, utilizing the fluorescent probe monochlorobimane fluorescence microscopy, utilizing the fluorescent probe monochlorobimane (MBCl), which is specifically conjugated to GSH by GST. In HL60 cells stained with the MBCl probe, a bright diffuse cytoplasmic and nuclear fluorescence pattern was observed, whereas in HL60/AR cells, the fluorescence was mostly localized to the Golgi apparatus with a lesser component of diffuse cytoplasmic and nuclear fluorescence. Pretreatment of HL60/AR cells with buthionine sulfoximine (BSO) partially reversed resistance to daunorubicin. This effect of BSO on resistance was associated not only with the abolition of localized MBCl fluorescence to the Golgi apparatus but also with increased intracellular accumulation and retention of daunorubicin. The results of our studies demonstrate that inhibition of GSH synthesis in HL60/AR cells results in significant sensitization to daunorubicin and suggest that changes in the intracellular distribution of GSH/GST and/or increased drug retention may be involved in mediating this effect.

Antibiotics, Antineoplastic↗
PubMed1989

Expression of glycoprotein D of herpes simplex virus type 1 in a recombinant baculovirus: protective responses and T cell recognition of the recombinant-infected cell extracts.

Recombinant baculoviruses expressing glycoprotein D (gD) of herpes simplex virus type 1 (HSV-1) have been generated. The proteins expressed from the recombinants have been characterized using monoclonal antibodies on Western blots and by immunoprecipitation. Partially glycosylated 48K polypeptides have been identified as products of the gD gene. Polyclonal sera from H-2k mice infected with HSV-1 recognized the same polypeptides. Furthermore, draining lymph node cells from H-2k mice infected with HSV-1 proliferated in vitro in response to recombinant-infected cell extracts. Immunization with such extracts generated high titre complement-dependent and -independent neutralizing antibody and the mice were protected against a challenge with HSV-1.

Animals↗
PubMed1989

Regulated nocturnal hypothermia induced in pigeons by food deprivation.

The daily body temperature (Tb) cycle of pigeons is altered by food deprivation in that Tb falls to lower and lower levels on consecutive nights after the onset of deprivation, whereas the Tb levels during corresponding days remain nearly unchanged. Manipulations of spinal cord temperature, a major feedback parameter in the avian thermoregulatory system, reveal that episodes of nocturnal hypothermia are regulated. The spinal cord threshold temperature for inducing increases in metabolic heat production falls to progressively lower levels each night and returns to normal euthermic levels during the day.

Animals↗
PubMed1988

Cerebral anaerobic glycolysis and reduced cerebral oxygen transport in human cerebral malaria.

In 12 patients comatose with cerebral malaria, cerebral blood flow was 52.2 (SE 4.0) ml/100 g per min, within the reported range for healthy controls, but cerebral vascular resistance was raised at 1.66 (0.19) mm Hg/ml per 100 g per min. Cerebral oxygen consumption (1.90 [0.23] ml/100 g per min), and cerebral arteriovenous oxygen content difference (3.5 [0.43] ml/dl) were subnormal, while cerebral venous pO2 (5.7 [0.2] kpA) was raised. After recovery of consciousness there were significant decreases in arterial lactate concentration (2.44 [0.45] to 1.19 [0.45] mumol/l) and cerebral lactate production (17.4 [7.9] to 5.6 [1.1] mmol/100 g per minute). These results provide evidence of cerebral anaerobic glycolysis associated with inadequate oxygen delivery to the brain consistent with either inhibition of cerebral oxidative metabolism or the microcirculatory obstruction envisaged in the "mechanical" hypothesis for cerebral malaria.

Adolescent↗
PubMed1987

Influence of spinal and hypothalamic warming on metabolism and sleep in pigeons.

Animals were prepared with electrooculogram (EOG), cortical electroencephalogram (EEG), and electromyogram (EMG) electrodes and with spinal and/or hypothalamic thermodes. Experiments were run at a cold and a neutral ambient temperature (Ta) during the dark portion of a 24-h light-dark cycle. Metabolic rate, temperatures, EEG, EMG, and EOG were measured continuously for 4-h periods with hypothalamic or spinal temperature unmanipulated or warmed to the level measured during the light. The cold Ta increased metabolic rate over the neutral Ta, but did not influence total sleep time (TST) or rapid-eye-movement sleep (REM) as percent TST. At the cold Ta, spinal warming resulted in reduction in REM as a percent TST. Spinal warming frequently caused a fall in body temperature (Ta). A plot of REM as a percent TST vs. the fall in Tb, including data for all animals and all conditions, revealed a clear correlation between fall in Tb and reduction in REM. Hypothalamic warming had no influence on metabolic rate, Tb, or distributions of arousal states. Cold thermal stimuli caused by a fall in Tb can inhibit REM in birds as it can in mammals independently of thermoregulatory drive.

Animals↗
PubMed1987

Carbamazepine and carbamazepine-10,11-epoxide pharmacokinetics in an overdose patient.

A case report on a 13-year-old girl with idiopathic grand mal epilepsy who ingested 34 g carbamazepine (CBZ) and 80 mg clonazepam is presented. The patient survived but suffered severe temporary neurological toxicity characteristic of CBZ. CBZ was 79.6 +/- 2.8% bound to serum protein and carbamazepine-10,11-epoxide (CBZ-E) binding was essentially concentration dependent. CBZ and CBZ-E elimination half-lives were 26 and 16.5 h respectively. An inhibitory metabolic interaction with the co-ingested clonazepam is suggested.

Adolescent↗
PubMed1983

Severe hypoglycemia and hyperinsulinemia in falciparum malaria.

We studied the occurrence, clinical manifestations, and mechanism of hypoglycemia in patients with falciparum malaria in eastern Thailand. Hypoglycemia, which was often severe and recurrent, occurred in 17 patients, including 12 in a series of 151 patients with cerebral malaria. Thirty episodes were investigated. Plasma concentrations of insulin and C peptide were inappropriately high, and lactate and alanine concentrations were significantly higher than in patients with falciparum malaria who were normoglycemic (P less than 0.05). Sixteen patients had received quinine; plasma quinine and insulin concentrations were correlated at the time of hypoglycemia (P = 0.007). In seven healthy fasting volunteers intravenous quinine increased the mean plasma insulin concentration (+/- S.D.) from 8.9 +/- 3.1 to 17.1 +/- 8.4 mU per liter (P = 0.02) and reduced the mean plasma glucose concentration from 88 +/- 20 to 68 +/- 23 mg per deciliter (P = 0.002). Our observations indicate that in falciparum malaria quinine-induced insulin secretion may precipitate hypoglycemia, but other factors, including the large glucose requirements of the malaria parasites may also contribute. This important complication, associated with pregnancy and severe disease, must be excluded in all patients with falciparum malaria who have impaired or deteriorating consciousness.

3-Hydroxybutyric Acid↗
PubMed1983

Plasmodium yoelii: blood oxygen and brain function in the infected mouse.

The carriage of oxygen by the blood and the in vivo response of the brain were investigated in mice infected with a lethal strain of Plasmodium yoelii. All mice with parasitaemia exceeding 70% were severely anaemic (Hb 3.5 +/- 1.8 g/dl; mean +/- 1 SD), acidotic (blood pH 7.04 +/- 0.06) and hypoglycaemic (blood glucose 0.6 +/- 0.76 mumol/ml). The oxyhaemoglobin dissociation curve (ODC) of blood from heavily infected mice was shifted right as compared to controls, but the increase in p50 was less than expected from the accompanying acidosis. The reduced shift right was due to a decrease in the 2,3-DPG/Hb ratio in infected animals (0.72 +/- 0.12, n = 17 vs 1.10 +/- 0.09, n = 12 in controls). Despite the severity of terminal infection, the cerebral pH and the relative steady-state concentrations of PCr, ATP and Pi measured in vivo by nuclear magnetic resonance (31P NMR) were normal. Alterations in brain energy status and pH cannot account for cerebral signs or death in this proposed mouse model of cerebral malaria.

Adenosine Triphosphate↗
PubMed1983

Quinine disposition kinetics.

Intravenous quinine dihydrochloride (5 mg kg-1 over 5 min) was given to seven healthy male volunteers. There were minor subjective symptoms in all subjects but no significant changes in pulse or blood pressure. There was significant prolongation of the electrocardiographic QRS and rate corrected QT intervals which was greatest between 1 and 4 min after completion of the quinine infusion. Values then returned towards baseline. Plasma concentrations of quinine were measured spectrophotofluorimetrically after benzene extraction. Peak plasma concentrations (mean +/- 1 s.d.) after the infusion were 5.1 +/- 1.3 mg 1(-1). Pharmacokinetic analysis fitted a two compartment open model in each case; distribution half-time (t 1/2, lambda 1) was 1.89 +/- 0.54 min (mean +/- 1 s.d.), elimination half-time (t 1/2, z) 11.1 +/- 2.1 h, apparent volume of the central compartment (V1) 0.57 +/- 0.32 1 kg-1, total apparent volume of distribution 1.80 +/- 0.37 1 kg-1 and total clearance 1.92 +/- 0.45 ml min-1 kg-1.

Adolescent↗
PubMedDate not supplied

Management of severe malarial infection.

Severe malaria is a major cause of infant and childhood death in the tropics. Effective management relies on rapid diagnosis, prompt administration of parenteral schizonticidal antimalarial drugs, careful fluid balance, prevention of convulsions and early recognition of complications such as hypoglycemia, metabolic acidosis, anemia, pulmonary edema, renal failure, bleeding and supervening bacterial sepsis. The mortality of treated cerebral malaria remains 20%. New, more rapidly acting antimalarials and earlier referral of children with complicated infections should reduce this unacceptable death rate.

Acute Disease↗