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Biomedical subjects

S Krishna

Publications and source records attributed to S Krishna.

At least 91 records · Page 5Linked to original sources
PubMed1994

A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor.

The class II major histocompatibility complex (MHC) molecules function in the presentation of processed peptides to helper T cells. As most mammalian cells can endocytose and process foreign antigen, the critical determinant of an antigen-presenting cell is its ability to express class II MHC molecules. Expression of these molecules is usually restricted to cells of the immune system and dysregulated expression is hypothesized to contribute to the pathogenesis of a severe combined immunodeficiency syndrome and certain autoimmune diseases. Human complementary DNA clones encoding a newly identified, cysteine-rich transcription factor, NF-X1, which binds to the conserved X-box motif of class II MHC genes, were obtained, and the primary amino acid sequence deduced. The major open reading frame encodes a polypeptide of 1,104 amino acids with a symmetrical organization. A central cysteine-rich portion encodes the DNA-binding domain, and is subdivided into seven repeated motifs. This motif is similar to but distinct from the LIM domain and the RING finger family, and is reminiscent of known metal-binding regions. The unique arrangement of cysteines indicates that the consensus sequence CX3CXL-XCGX1-5HXCX3CHXGXC represents a novel cysteine-rich motif. Two lines of evidence indicate that the polypeptide encodes a potent and biologically relevant repressor of HLA-DRA transcription: (a) overexpression of NF-X1 from a retroviral construct strongly decreases transcription from the HLA-DRA promoter; and (b) the NF-X1 transcript is markedly induced late after induction with interferon gamma (IFN-gamma), coinciding with postinduction attenuation of HLA-DRA transcription. The NF-X1 protein may therefore play an important role in regulating the duration of an inflammatory response by limiting the period in which class II MHC molecules are induced by IFN-gamma.

Amino Acid Sequence↗
PubMed1994

Isoform-specific induction of nuclear free calcium oscillations by platelet-derived growth factor.

Confocal laser scanning microscopy was used to analyze alterations in nuclear free calcium (Ca2+n) levels induced by platelet-derived growth factor (PDGF) isoforms in BALB/c3T3 fibroblasts loaded with the calcium-sensitive fluorescent indicator Fluo-3. Both AA-PDGF and BB-PDGF caused a transient increase in Ca2+n. Analysis of PDGF-induced Ca2+n alterations as a function of time revealed that BB-PDGF stimulation resulted in the generation of Ca2+n oscillations that diminished over time. The frequency of BB-PDGF-stimulated oscillations was modulated by extracellular Ca2+ and could not be mimicked by increasing intracellular inositol 1,4,5-trisphosphate levels in the absence of growth factor stimulation. Caffeine alone had no effect on Ca2+n levels, but exposure of cells to caffeine after BB-PDGF stimulation augmented Ca2+n oscillations, either by increasing the frequency or reinitiating preexisting oscillations. The genesis of these oscillations in Ca2+n appears to be in the region just outside of the nucleus, as perinuclear cytoplasmic free calcium (Ca2+i) increased just prior to Ca2+n. In contrast, AA-PDGF stimulation resulted in the generation of one or two irregular, transient Ca2+n spikes. Caffeine pretreatment followed by AA-PDGF stimulation resulted in Ca2+n oscillations very similar to those produced by BB-PDGF alone. Additionally, the AA-PDGF and BB-PDGF isoforms appeared to modulate distinct pools of cellular Ca2+, as BB-PDGF was still capable of inducing Ca2+n oscillations subsequent to prior induction of oscillations by AA-PDGF/caffeine. These PDGF isoform-specific changes in nuclear free Ca2+ could serve as a mechanism by which isoform-specific cellular signaling pathways may be manifested by the growth factors.

3T3 Cells↗
PubMed1994

Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment.

Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P > .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P < .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria.

Acidosis, Lactic↗
PubMed1994

Oesophageal carcinoma: laser palliation in 231 cases.

Two hundred and thirty-one patients of advanced oesophageal carcinoma were treated with Neodymium: Yttrium-Aluminium-Garnet (Nd:YAG) laser photocoagulation of tumour tissue to relieve distressing dysphagia. There were 155 males (67.1%) and 76 females (32.9%). The mean age was 59.6 years. Eighty-five percent (196 cases) were above 50 years of age. Distribution of tumour by site was as follows: upper one-third--24 cases (10.4%), mid one-third--98 cases (42.4%) and lower one-third--109 cases (47.1%). Squamous cell carcinomas accounted for 83.5% (193) of cases. Nearly two-thirds (144 cases, 62.3%) were more than 4 cm in length. Tumour deposits were found at more than one site in 11 cases (4.7%). Oesophageal lumen was restored in all cases but was poorly sustained in 19 cases (8.2%). Further sessions of laser therapy were required in all these cases. A mean of 2.7 sessions of laser treatment was required to achieve adequate lumen. One hundred and eighty-nine patients (82%) had good relief of dysphagia to liquids and semi solids. Complications were seen in 20 cases (8.6%). There were no deaths related to the procedure. Mean survival was 5.5 months (1-14 months). Nd:YAG laser therapy offers effective palliation of dysphagia in carcinoma of the oesophagus with acceptable morbidity and no mortality.

Adenocarcinoma↗
PubMed1994

Nd-YAG laser therapy for palliation of obstructed colorectal carcinomas.

Twenty three cases of colorectal carcinoma with partial or complete obstruction were managed by laser ablation of tumour tissue. There were 14 males and 9 females with a mean age of 63 years (30-87). Nineteen cases (82.6%) were in the rectosigmoid while two cases each were in the anal canal and descending colon. Fifteen (65.2%) were proliferative growths and the remaining (8, 34.7%) were circumferential growths. Prior dilatation under fluoroscopic control was done where required. Lumen was achieved in a single sitting in 14 (60.8%) cases, while in the others two to five sittings were required. None of the patients required colostomy. Thirteen (56.5%) of these patients have died during the follow up period, lasting from 4 to 27 months (mean 10.4 months). There were no major complications related to the procedure.

Adenocarcinoma↗
PubMed1994

Neodymium: YAG laser in the management of tracheal stenosis.

Thirty-five cases of benign stenotic lesions involving the upper respiratory passages were managed by laser photocoagulation of the scar tissue. The stenosed segment was around the site of tracheostomy in 28 cases (80%), subglottic in five cases (14.3%), and as a result of congenital webs, at the level of the larynx in two cases (5.7%). Adequate lumen was achieved in 29 cases (83%). The procedure was unsuccessful in five patients (all with subglottic stenosis). One to 11 laser settings (mean 2.8) were required to achieve satisfactory lumen. Complications (three cases, 8.5%) included bleeding in two cases and cervical emphysema in one case. Patients have been followed-up for two to 34 months (mean 23 months). One patient (2.8%) had recurrent stricture formation for which recanalisation was done. There were no procedure-related deaths. Neodymium: Yttrium-Aluminium-Garnet (Nd: YAG) laser photocoagulation is effective in the management of tracheal stenosis due to benign lesions except when they are located in the subglottic region. It carries minimal morbidity and no mortality risks.

Adolescent↗
PubMed1994

Laser therapy of solitary rectal ulcers: a new concept.

Fourteen cases of histologically proven benign solitary rectal ulcer were managed with Neodymium: Yttrium-Aluminium-Garnet (Nd:YAG) laser (contact mode) over a three-year period. All patients were symptomatic at presentation (bleeding, mucus or pus discharge per rectum, with or without diarrhoea). Thirteen of the 14 (93%) were relieved of symptoms after a mean of 2.3 sittings of laser (range 1-8). None of the patients had associated rectal prolapse. Successfully treated patients have been followed up for a mean of 14.2 months (two to 25 months) and are symptom free. There was minimal morbidity and no death. Nd:YAG laser excision of benign solitary rectal ulcers is a safe, new and patient-friendly technique.

Adolescent↗
PubMed1994

Neodymium: YAG laser therapy for obstructing tracheobronchial tumours.

Thirty-nine patients with obstructing tracheobronchial tumours were treated with Neodymium: Yttrium-Aluminium-Garnet (Nd: YAG) laser photocoagulation over a period of six years. There were 29 males and ten females with a mean age of 44.3 years (range 6-79 years). Eight benign and 31 malignant lesions were treated with a total of 94 sessions of laser photocoagulation (mean 2.4 sessions). The anatomical distribution of lesions was as follows: larynx--six (three benign and three malignant); trachea--seven (one benign and six malignant), left main bronchus--ten (all malignant), right main bronchus--11 (one benign and ten malignant), and vocal cords--five (three benign and two malignant). There were 21 patients with squamous cell carcinoma, two adenocarcinomas, one adenoid cystic carcinoma, three cases of locally infiltrating tumours, four cases of carcinoid tumour and eight benign lesions. Twenty-one patients had the tracheostomy tube in place when treatment was started. Eighteen of the 21 patients with tracheostomies were weaned off the tube in a mean of 5.5 days from the start of the treatment. Lumen was restored in 31 (79.4%) patients. In the other eight (20.6%), lumen was achieved, but not sustained. Complications included bleeding in three cases which were managed conservatively, two cases of pneumothorax and four cases of bronchospasm. There were six deaths during follow-up (mean 21.2 months), but none attributable to the procedure. Laser photocoagulation offered effective treatment in the majority of patients with obstructing tracheobronchial tumours, with acceptable morbidity.

Adenocarcinoma↗
PubMed1993

Plasmodium falciparum: in vitro studies of the pharmacodynamic properties of drugs used for the treatment of severe malaria.

The speed and stage specificity of antimalarial drug action on the metabolic activities of cultured Plasmodium falciparum were studied for chloroquine (CQ), quinine (QN), artemisinin (AR), and sodium artelinate (SA). CQ had the most rapid onset of action on [3H]hypoxanthine and [3H]isoleucine uptake, reaching 50% of its maximum effect in 1.8 hr compared with 3.5-7.4 hr for the other three drugs. In contrast there was a lag time of 1-4 hr before AR and SA had a measurable inhibitory effect, although after this delay antimalarial action was very rapid. Parasite glycolysis was relatively drug resistant; the inhibition of lactate production was < 60% of that for [3H]hypoxanthine and [3H]isoleucine uptake. The susceptibility of P. falciparum changed markedly as the parasite matured. Maximum drug effects occurred at the late ring and early trophozoite stage, which corresponds to the time at which the most rapid increases in synthetic and glycolytic activities occur. Mature schizonts and young rings were relatively unaffected by the antimalarial drugs. Young rings were particularly resistant to QN. Schizonts multiplied successfully in the presence of relatively high concentrations of all four drugs. The two artemisinin compounds had the broadest time window of action and may be particularly suitable for the treatment of severe malaria.

Animals↗
PubMed1993

A family of cation ATPase-like molecules from Plasmodium falciparum.

We report the nucleotide and derived amino acid sequence of the ATPase 1 gene from Plasmodium falciparum. The amino acid sequence shares homology with the family of "P"-type cation translocating ATPases in conserved regions important for nucleotide binding, conformational change, or phosphorylation. The gene, which is present on chromosome 5, has a product longer than any other reported for a P-type ATPase. Interstrain analysis from 12 parasite isolates by the polymerase chain reaction reveals that a 330-bp nucleotide sequence encoding three cytoplasmic regions conserved in cation ATPases (regions a-c) is of constant length. By contrast, another 360-bp sequence which is one of four regions we refer to as "inserts" contains arrays of tandem repeats which show length variation between different parasite isolates. Polymorphism results from differences in the number and types of repeat motif contained in this insert. Inserts are divergent in sequence from other P-type ATPases and share features in common with many malarial antigens. Studies using RNA from the erythrocytic stages of the malarial life cycle suggest that ATPase 1 (including the sequence which encodes tandem repeats) is expressed at the large ring stage of development. Immunolocalization has identified ATPase 1 to be in the region of the parasite plasma membrane and pigment body. These findings suggest a possible model for the genesis of malarial antigens.

Adenosine Triphosphatases↗
PubMed1993

Pharmacokinetics, efficacy and toxicity of parenteral halofantrine in uncomplicated malaria.

1 The pharmacokinetics, efficacy and toxicity of a new parenteral formulation of halofantrine hydrochloride were evaluated in 12 adults with acute uncomplicated falciparum malaria and nine adults who attended in convalescence. 2 Intravenous halofantrine (1 mg kg(-1) infused in 1 h) was given every 8 h for a total of three doses in the acute study. Halofantrine cleared parasitaemia rapidly in all but one patient, with a mean (s.d.) parasite clearance time of 71 (29) h. Convalescent patients received a single infusion (1 mg kg(-1) in 1 h). 3 An open two-compartment model with the following parameters described the pharmacokinetics of halofantrine in acute malaria (mean (s.d)): V1 = 0.36 (0.18) l kg(-1); CL = 0.355 (0.18) l h(-1) kg(-1); t1/2alpha = 0.19 (0.12) h; t1/2beta = 14.4 (7.5) h. 4 Intravenous halofantrine in acute malaria produced significant prolongations of the QT and QTc intervals (mean (s.d.)) of 20 (15%) and 8.2 (5.6)%, respectively (P < 0.001) after the third dose, but no clinically significant cardiotoxcity. Eight patients experienced mild to moderate thrombophlebitis at the halofantrine infusion site which had resolved in six by the time of follow-up. In the single treatment failure who received oral quinine, there was a large rise in plasma halofantrine concentration but this did not result in detectable toxicity. 5 These data provide the basis for the design of improved dosing regimens for the use of parenteral halofantrine in malaria.

Adolescent↗
PubMed1992

Homogeneously staining region in anthracycline-resistant HL-60/AR cells not associated with MDR1 amplification.

Anthracycline-resistant HL-60/AR cells and their drug-sensitive HL-60/S counterparts were characterized by karyotypic analysis and examined for the overexpression of DNA and mRNA sequences coding for P-glycoprotein (Pgp). The HL-60/S cells were karyotypically stable over a 5-year period of study (1986-1991), except for an additional small Giemsa-positive band noted at 7q22 in cultures harvested in 1987, but not in 1986. This change did not affect drug sensitivity. The drug-resistant HL-60/AR cells examined in 1986, 1987, and 1991 demonstrated a very stable karyotype. The most striking feature was a large homogeneously staining region in the long arm of chromosome 7 (7q11.2), and translocation of the remainder of the long arm to another centromere. Other changes in the HL-60/AR cells included inversion in 9q, partial deletion of the short arm of chromosome 10p, addition of material to the p arm of der(16), loss of chromosome 22, and the appearance of a new marker chromosome. Both HL-60/S and the HL-60/AR cells were found not to amplify DNA or mRNA sequences coding for the Pgp. Thus, although the HL-60/AR cells possess the classical multidrug resistance phenotype and demonstrate a homogeneously staining region near the region of the MDR1 gene, their resistance is due to mechanisms other than those coded for by MDR1.

Antibiotics, Antineoplastic↗
PubMed1992

The major histocompatibility complex class I antigen-binding protein p88 is the product of the calnexin gene.

A 90-kDa phosphoprotein (p90) of the endoplasmic reticulum was identified by a monoclonal antibody generated against human hepatoma cells. Pulse-chase experiments with [32P]phosphate and [35S]methionine demonstrated that p90 formed both stable and transient complexes with other cellular proteins, suggesting its role as a molecular chaperone. This protein associates with heavy chains of major histocompatibility complex class I proteins, suggesting that it is the human homolog of the recently described 88-kDa protein that transiently associates with murine class I molecules in the endoplasmic reticulum. The p90 protein also associates in B lymphocytes with membrane immunoglobulin mu heavy chains and may serve as a chaperone for many membrane-bound polypeptides. A partial human p90 cDNA was cloned from a lambda gt11 expression library and identified as the human homolog of calnexin, a major canine calcium-binding protein found to be associated with the signal-sequence receptor in endoplasmic reticulum membranes.

Amino Acid Sequence↗
PubMed1992

Tetrameric cell-surface MHC class I molecules.

Purified major histocompatibility complex (MHC) class I molecules have been studied at high resolution by X-ray crystallography; the structure is a complex of a single heavy chain, a beta 2-microglobulin light chain and a tightly bound peptide moiety. We show here that complete MHC class I molecules are post-translationally assembled into tetramers (made up of four heavy chains and four beta 2-microglobulin units) and that this tetrameric species is expressed on the cell surface. The multivalent tetrameric structure of class I molecules can be reconciled with models of T-cell activation that invoke antigen-receptor crosslinking, as opposed to models that depend on an allosteric change.

Animals↗