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Biomedical subjects

M Krishna

Publications and source records attributed to M Krishna.

At least 19 recordsLinked to original sources
PubMed2005

Review of 31 cases of morphologic hepatitis in liver transplant patients not related to disease recurrence.

AIMS: We examined the clinical and pathologic features of morphologic hepatitis occurring after liver transplantation (LT) that is unrelated to disease recurrence. METHODS: Between February 1998 and December 2003, 704 primary LTs were performed at our center. Patients transplanted for diagnoses with low risk of disease recurrence were considered for our study (n = 282). Those with hepatitis C (HCV), hepatitis B (HBV), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis (AIH) were excluded. Those with morphologic hepatitis comprised our case series and had medical records reviewed for clinical associations, duration, and outcome. RESULTS: Thirty-one cases were identified. They were transplanted for cryptogenic cirrhosis (n = 13), steatohepatitis (n = 12), alpha-1-antitrypsin deficiency (n = 3), tumor (n = 2), and acetaminophen toxicity (n = 1); 22 cases (67%) presented within the first 8 months post-LT (range, 0.5-72 months). Histological activity was mild in 19 and moderate in 12. Associated conditions were identified in 19 patients (57%) with 3 categories being identified: probable drug toxicity (n = 7), systemic infection (n = 4), and mechanical or hemodynamic abnormalities (n = 8). Of the 25 cases that underwent follow-up biopsy 2 to 32 months (mean, 15.5 months) after the index biopsy, 10 cases had resolution and 15 cases had persistence of the infiltrate. One patient had evidence of de novo HBV infection. CONCLUSIONS: Morphologic hepatitis occurred in 11% of patients at low risk for disease recurrence. Associated conditions could be grouped into three categories: drug toxicity, systemic infection, and mechanical or hemodynamic factors. Most cases did not appear to progress or improved over time, with no allograft loss occurring as a result of chronic hepatitis.

Biopsy↗
PubMed2005

Clinicopathological review of 18 cases of liver allografts lost due to bile duct necrosis.

Clinical, radiographic, and pathological features of 18 patients with biliary necrosis in their explanted liver allografts were reviewed. Twelve patients were men and ages ranged from 27 to 72 years. Indications for initial liver transplant (LT) were viral hepatitis (n = 7), steatohepatitic cirrhosis (n = 3), cryptogenic cirrhosis (n = 3), secondary sclerosing cholangitis (n = 2), primary sclerosing cholangitis (n = 1), biliary atresia (n = 1), and nodular regenerative hyperplasia (n = 1). Donor age ranged from 16 to 75 years. Duct-to-duct biliary anastomoses were fashioned in 13 cases; warm and cold ischemia times were not significantly different from general LT population. Seventeen allograft biopsies after recirculation had no significant findings. Post-LT, clinical and radiographic evaluation indicated biliary strictures (n = 7), bile leak (n = 7), intrahepatic abscess (n = 1), and duodenal perforation (n = 1). Radiographic vascular studies suggested hepatic arterial thrombosis or stenosis in 11 cases. Biopsies prior to retransplantation were performed on 17 patients and showed acute rejection (n = 10), biliary outflow impairment (n = 4), normal histology (n = 2), and centrilobular necrosis (n = 1). Retransplantation was performed 14 to 334 days after initial LT. Pathological examination of explants revealed perihilar duct necrosis in all cases, with bacterial colonies (n = 10) and fungal organisms (n = 2). Arterial thrombi were seen in 10 cases, and two had prominent arteriosclerosis. Infarction and centrilobular necrosis were seen in 9 and 13 cases, respectively. Four explants showed features of biliary outflow impairment. Twelve patients were alive 6 to 18 months following retransplantation. We conclude that post-LT biliary necrosis is associated with ischemia, and such a complication is rarely evident in allograft biopsies. Biliary and vascular imaging studies are essential in evaluating patients for this complication.

Adolescent↗
PubMed2004

Hepatitis C-related posttransplant plasma cell proliferative disorder with hepatitis C virus in neoplastic plasma cells: a new posttransplant disease entity?

Plasma cell proliferative disorder (PCPD) developed in two patients with actively replicating hepatitis C virus (HCV) in neoplastic plasma cells after orthotopic liver transplantation for HCV-related end-stage liver disease. PCPD was confined to the transplanted liver and was associated with monoclonal proteins in blood. Bone marrow biopsy did not show any evidence of PCPD. Epstein-Barr virus was not detected by in situ hybridization in either case. In situ hybridization for HCV RNA with sense and antisense probes in liver biopsy specimens showed signals in neoplastic plasma cells as well as in hepatocytes. We suggest that our patients had posttransplant PCPD resulting from HCV. It may represent a new posttransplant disease entity different from previously described posttransplant lymphoproliferative disorder. The findings raise intriguing questions about the role of HCV in PCPDs in patients with chronic HCV infection.

Antigens, CD↗
PubMed2004

Photodynamic therapy and endoscopic metal stent placement for esophageal papillomatosis associated with squamous cell carcinoma.

Esophageal squamous papillomatosis is a rare condition associated with human papilloma virus infection and has been complicated by the development of squamous cell carcinoma. Photodynamic therapy using porfimer sodium has been used for the treatment of esophageal cancer but has not been utilized in the treatment of esophageal squamous papillomatosis. We report here the first case of papillomatosis and obstructing squamous cell carcinoma of the esophagus palliated with porfimer sodium photodynamic therapy indicating successful photosensitizer uptake in papilloma-laden tissue. Extensive debulking of papilloma and tumor allowed esophageal recanalization and placement of a self-expanding metal stent for long-term dysphagia palliation. This unique case highlights the combined use of endoscopic techniques for optimal treatment results.

Aged↗
PubMed2004

Mitogen-activated protein kinases: specificity of response to dose of ionizing radiation in liver.

Ionizing radiation is known to activate both the cytotoxic stress-activated kinases (SAPK/JNK, p38) and the cytoprotective mitogen-activated protein kinases (MAPKs, ERKs), which send divergent signals to the nucleus. However, all these kinases could not be activated simultaneously and at all the doses. An attempt has been made in this study to establish the dose and temporal response of these kinases with a view to establish the identity of the transcription factors that remain activated because only these will be translated into an effect. The study indicates that the stress-activated kinases (SAPK/JNK and p38) are activated by very low doses (0.1 Gy) of ionizing radiation. An induction of expression of MKK4, precursor to SAPK and p38, was found at lower doses (0.1-0.5 Gy). However, the cytoprotective ERK2 showed a progressive increase in expression with dose, except at 3 Gy where it shows a marginal decline. The stress-activated kinases show an increased expression or activation at early periods, unlike ERK2, which shows a prolonged response to stimuli. This study reveals that in the in vivo condition there is a chronological order of activation of the kinases and a dose-dependent activation. The activations of the cytoplasmic kinases and the transcription factors, Elk-1 and c-Jun, both show prolonged activation and maximum response at high doses.

Animals↗
PubMed2001

Modulation of radiation-induced protein kinase C activity by phenolics.

Natural phenolic compounds were tested in vitro for their effect on the activity of protein kinase C (PKC) isolated from the liver cytosol and the particulate fraction of unirradiated mice and mice irradiated at 5 Gy. Following irradiation, the PKC activity was found to be increased in both cytosolic and particulate fractions. Curcumin, ellagic acid and quercetin were effective in inhibiting radiation-induced PKC activity. Curcumin and ellagic acid were found to be more inhibitory towards radiation-induced PKC activity, while quercetin was the least effective. Curcumin was found to inhibit the activated cytosolic and particulate PKC at very low concentrations. Activation of PKC is one of the means of conferring radioresistance on a tumour cell. Suppression of PKC activity by phenolics may be one of the means of preventing the development of radioresistance following radiotherapy.

Animals↗
PubMed2001

Alterations in hepatic kinase activity following whole body gamma-irradiation of mice.

The chronological activation of the signaling molecules following whole body gamma-irradiation was investigated in mouse liver. The activity of two kinases, tyrosine kinase and protein kinase C (PKC), was found to respond differently to gamma-irradiation. Tyrosine kinase was found to respond to much lower doses of irradiation (10 cGy), whereas PKC was found to be activated at comparatively higher doses (3 Gy). Tyrosine kinase showed a sharp activation at 30 min and then a decline to normal values at 1 h. Activation of PKC was apparent at as early as 15 min of irradiation and showed a maximal increase at 30 min. This was followed by a decline to normal values at 1 h. The response of the whole organ was found to be different from that of reported effects on a single cell. These results suggest that the data obtained from the single-cell studies would have limited application in the experiments involving the whole animal. Interruption of these signals at various steps is currently being used to manipulate tumor response to radiotherapy. In such cases, the difference in response of a single cell and a whole animal must be considered.

Animals↗
PubMed2001

Effect of aflatoxin B1 on phosphoinositide signal transduction pathway during regeneration of liver cells following partial hepatectomy.

Aflatoxin B1 (AFB1) when administered to partially hepatectomised rats 4 hr prior to sacrifice, activated the signalling pathway in regenerating rat liver. The activity of phosphatidylinositol (PI) kinase was found decreased at 30 min but increased at 24 hr and returned to normal at 48 hr. At 30 min, inositol-1,4,5-triphosphate (IP3) level increased significantly whereas diacylglycerol (DAG) level dropped. However, at 24 hr and 48 hr, DAG and IP3 showed the same trend i.e. an increase in their levels. Phosphatidylinositol-4-phosphate levels were found to increase at 24 hr. Protein kinase C (PKC), activity from the particulate fraction was significantly inhibited at 30 min, followed by increase in activity at 24 hr and return to normal at 48 hr. Cytosolic PKC showed a decrease at 24 hr and a significant increase at 48 hr. At the peak of DNA synthesis (24 hr) following partial hepatectomy, all these signalling steps had earlier been found to be inhibited, but the present study shows that aflatoxin B1 administration 4 hr prior to sacrifice reverses the action. Activation of PKC by aflatoxin B1, during regeneration of liver cells when PKC in normally inhibited, may possibly create conditions conducive to carcinogenesis.

Aflatoxin B1↗
PubMed2000

Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group.

BACKGROUND: Chronic inflammation is believed to increase the risk of coronary events by making atherosclerotic plaques in coronary vessels prone to rupture. We examined blood constituents potentially affected by inflammation as predictors of risk in men with hypercholesterolemia who were enrolled in the West of Scotland Coronary Prevention Study, a trial that evaluated the value of pravastatin in the prevention of coronary events. METHODS: A total of 580 men who had had a coronary event (nonfatal myocardial infarction, death from coronary heart disease, or a revascularization procedure) were each matched for age and smoking status with 2 control subjects (total, 1160) from the same cohort who had not had a coronary event. Lipoprotein-associated phospholipase A2, C-reactive protein, and fibrinogen levels, and the white-cell count were measured at base line, along with other traditional risk factors. The association of these variables with the risk of coronary events was tested in regression models and by dividing the range of values according to quintiles. RESULTS: Levels of C-reactive protein, the white-cell count, and fibrinogen levels were strong predictors of the risk of coronary events; the risk in the highest quintile of the study cohort for each variable was approximately twice that in the lowest quintile. However, the association of these variables with risk was markedly attenuated when age, systolic blood pressure, and lipoprotein levels were included in multivariate models. Levels of lipoprotein-associated phospholipase A2 (platelet-activating factor acetylhydrolase), the expression of which is regulated by mediators of inflammation, had a strong, positive association with risk that was not confounded by other factors. It was associated with almost a doubling of the risk in the highest quintile as compared with the lowest quintile. CONCLUSIONS: Inflammatory markers are predictors of the risk of coronary events, but their predictive ability is attenuated by associations with other coronary risk factors. Elevated levels of lipoprotein-associated phospholipase A2 appear to be a strong risk factor for coronary heart disease, a finding that has implications for atherogenesis and the assessment of risk.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

Unique oxidative mechanisms for the reactive nitrogen oxide species, nitroxyl anion.

The nitroxyl anion (NO-) is a highly reactive molecule that may be involved in pathophysiological actions associated with increased formation of reactive nitrogen oxide species. Angeli's salt (Na2N2O3; AS) is a NO- donor that has been shown to exert marked cytotoxicity. However, its decomposition intermediates have not been well characterized. In this study, the chemical reactivity of AS was examined and compared with that of peroxynitrite (ONOO-) and NO/N2O3. Under aerobic conditions, AS and ONOO- exhibited similar and considerably higher affinities for dihydrorhodamine (DHR) than NO/N2O3. Quenching of DHR oxidation by azide and nitrosation of diaminonaphthalene were exclusively observed with NO/N2O3. Additional comparison of ONOO- and AS chemistry demonstrated that ONOO- was a far more potent one-electron oxidant and nitrating agent of hydroxyphenylacetic acid than was AS. However, AS was more effective at hydroxylating benzoic acid than was ONOO-. Taken together, these data indicate that neither NO/N2O3 nor ONOO- is an intermediate of AS decomposition. Evaluation of the stoichiometry of AS decomposition and O2 consumption revealed a 1:1 molar ratio. Indeed, oxidation of DHR mediated by AS proved to be oxygen-dependent. Analysis of the end products of AS decomposition demonstrated formation of NO2- and NO3- in approximately stoichiometric ratios. Several mechanisms are proposed for O2 adduct formation followed by decomposition to NO3- or by oxidation of an HN2O3- molecule to form NO2-. Given that the cytotoxicity of AS is far greater than that of either NO/N2O3 or NO + O2, this study provides important new insights into the implications of the potential endogenous formation of NO- under inflammatory conditions in vivo.

Nitrates↗
PubMed2000

Failure of presynaptic purinoceptors to modulate noradrenaline release from sympathetic nerves in human dental pulp.

The effects of putative presynaptic P1- and/or P2-purinoceptors on the release of noradrenaline from sympathetic nerves in human dental pulp were examined by testing the effects of agonists and an antagonist of these receptors on the stimulation-induced overflow of [(3)H]noradrenaline from tissue treated with desipramine (0.3 micromol/l) and preincubated with [(3)H]noradrenaline (0.6 micromol/l). The P1-purinoceptor agonists adenosine (1.0 mmol/l) and 2-chloroadenosine (0.01-1.0 mmol/l) and the antagonist 8-cyclopentyl-1,3-dipropyl xanthine (1.0 micromol/l), and the P2-purinoceptor agonists ATP (0.1 mmol/l) and beta, gamma-methylene-ATP (0.01 mmol/l), did not modulate the release of noradrenaline. Adenosine was also without effect in dental pulp treated with the alpha(2)-adrenoceptor antagonist rauwolscine. It is concluded that presynaptic P1-purinoceptors and those P2-purinoceptors activated by adenine nucleotides are either not present on sympathetic nerves in human dental pulp or that they exert little or no effect on the release of noradrenaline.

2-Chloroadenosine↗
PubMed1999

Modulation of NDEA activated ras expression and protein kinase C activity by nicotinamide.

Nicotinamide, an amide derivative of vitamin B3, was found to inhibit the increase in ras expression, protein kinase C (PKC) activity, and diacylglycerol (DAG) levels in rats treated with N-nitrosodiethylamine (NDEA). It effectively modulated the carcinogen induced increase in the cytosol and the particulate PKC activities but not the nuclear PKC activity. The DAG levels were also modulated by the endobiotic. It may serve as an ideal modulator of carcinogenesis. Nicotinamide is currently under trial as a radio sensitizer, and inhibition of these parameters may be one of the ways in which it confers radiosensitivity.

Alkylating Agents↗
PubMed1999

Differential responses of staurosporine on protein kinase C activity and proliferation in two murine neuroblastoma cell lines.

We studied the effect of staurosporine (SSP), a broad-spectrum protein kinase inhibitor, on the levels of protein kinase C (PKC) activity and proliferation in two murine neuroblastoma cell lines, Neuro2a and its clone NB41A3. The PKC activity was examined in whole cell lysate, cytosolic and particulate fractions. A differential response to SSP treatment in the enzyme activity in whole cell lysate and particulate fractions was demonstrated in the two cell lines. The data on proliferation indicated that Neuro2a cells were more sensitive to the SSP treatment with significant inhibition in DNA synthesis in a time course study. Our findings suggest that the data on basal levels of PKC activity in tumors will be of significance in studies using PKC inhibitors as an approach for therapeutic intervention.

Animals↗
PubMed1999

Alterations of phosphatidylinositol signal transduction pathway in hepatic mitochondria following aflatoxin B1 administration.

A single dose of aflatoxin B1 (7 mg/kg body wt) to male rats significantly stimulated the turnover of mitochondrial phosphoinositides 1-7 hr following its administration. The elevation of phosphatidylinositol 3,4,5-trisphosphate was most pronounced whose level continued to be moderately high even at 17 hr period. The level of diacylglycerol showed a marked increase from 4 hr till 7 hr after carcinogen treatment, whereas that of inositol 1,4,5-trisphosphate recorded an increase with a maximum at 7 hr followed by a gradual decrease to near normal level at 24 hr period. The activation of phosphatidylinositol cycle together with an activation of PI 3-kinase, whose product PIP3 is known to be involved in apoptosis might contribute to the early step in the manifestation of toxicity and/or carcinogenicity.

Aflatoxin B1↗