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Biomedical subjects

M Krishna

Publications and source records attributed to M Krishna.

At least 37 records · Page 2Linked to original sources
PubMed1999

Perturbations in phosphoinositide metabolism and protein kinase C activity in mouse liver following whole body irradiation.

The involvement of the signal transduction pathway in mouse liver following whole body irradition was investigated. Mice were exposed to 60Co gamma rays (3 Gy) and sacrificed after different time intervals. Various elements of phosphatidyl inositol signal transduction pathway were investigated. Alterations could be seen as early as 15 min of irradiation. These changes are reflected in elevation in DAG levels and increased activation of PKC, an enzyme which is involved in tumorigenesis. The chronological appearance of various transducers following whole body irradiation is of significance since these early effects may set the stage for radiation-induced tumorigenesis and hence may be used to manipulate tumor response to radiotherapy.

Animals↗
PubMed1998

The cytotoxicity of nitroxyl: possible implications for the pathophysiological role of NO.

In addition to the broad repertoire of regulatory functions nitric oxide (NO) serves in mammalian physiology, the L-arginine:NO pathway is also involved in numerous pathophysiological mechanisms. While NO itself may actually protect cells from the toxicity of reactive oxygen radicals in some cases, it has been suggested that reactive nitrogen oxide species formed from nitric oxide synthase (NOS) can be cytotoxic. In addition to NO, the one electron reduction product NO- has been proposed to be formed from NOS. We investigated the potential cytotoxic role of nitroxyl (NO-), using the nitroxyl donor Angelis's salt, (AS; sodium trioxodinitrate, Na2N2O3) as the source of NO-. As was found to be cytotoxic to Chinese hamster V79 lung fibroblast cells over a concentration range of 2-4 mM. The presence of equimolar ferricyanide (Fe(III)-(CN6)3-), which converts NO- to NO, afforded dramatic protection against AS-mediated cytotoxicity. Treatment of V79 cells with L-buthionine sulfoximine to reduce intracellular glutathione markedly enhanced AS cytotoxicity, which suggests that GSH is critical for cellular protection against the toxicity of NO-. Further experiments showed that low molecular weight transition metal complexes associated with the formation of reactive oxygen species are not involved in AS-mediated cytotoxicity since metal chelators had no effect. However, under aerobic conditions, AS was more toxic than under hypoxic conditions, suggesting that oxygen dramatically enhanced AS-mediated cytotoxicity. At a molecular level, AS exposure resulted in DNA double strand breaks in whole cells, and this effect was completely prevented by coincubation of cells with ferricyanide or Tempol. The data in this study suggest that nitroxyl may contribute to the cytotoxicity associated with an enhanced expression of the L-arginine:NO pathway under different biological conditions.

Animals↗
PubMed1998

Cathepsin B expression and its correlation with tumor-associated laminin and tumor progression in gastric cancer.

OBJECTIVE: Cathepsin B, a lysosomal cysteine proteinase, is associated with degradation of laminin. Its activity has been shown to be increased in gastric carcinomas. Laminin is one of the major components of basement membrane involved in cell-matrix interactions and tumor progression. The objectives of this study were to correlate cathepsin B expression in tumor cells with tumor-associated laminin and to further correlate the two with tumor progression. DESIGN AND SETTING: Resected gastric carcinomas (n = 29) taken from the surgical pathology files of the University of Massachusetts Medical Center, Worcester, were immunostained with cathepsin B and laminin using the avidin-biotin complex technique. Statistical analysis was performed using the exact linear by linear association test and exact Kruskal-Wallis test. Kaplan-Meier curves were plotted, and survival analysis was performed using a nonparametric log-rank test. RESULTS: Cathepsin B was expressed in 27 (93%) of 29 tumors (11 weak and 16 strong). Staining of tumor-associated laminin showed patterns ranging from almost continuous (n = 4) to moderately discontinuous (n = 11) and highly fragmented (n = 14). The degree of cathepsin B staining in tumor cells significantly correlated with the laminin distribution pattern (P = .0001). The association between increased cathepsin B, decreased laminin, and higher tumor stage was also significant. CONCLUSIONS: Increased cathepsin B expression by tumor cells associated with decreased tumor-associated laminin may suggest a mechanism for local tumor progression and metastasis. Staining for cathepsin B and laminin may be of prognostic value in gastric carcinomas.

Adenocarcinoma↗
PubMed1998

Cathepsin B and tumor-associated laminin expression in the progression of colorectal adenoma to carcinoma.

Cathepsin B is a lysosomal cysteine proteinase associated with degradation of laminin. It is increased in colorectal carcinoma (CA). Laminin is a major component of basement membrane involved in cell-matrix interactions and tumor progression. The aim of this study was to correlate cathepsin B and tumor-associated laminin in colorectal adenomas (ADs) with increasing grades of dysplasia and in invasive CAs. Forty-five ADs (8 tubular, 16 tubulovillous, 21 villous), 13 adenomas with high-grade dysplasia/carcinoma in situ (AHDs), and 17 invasive CAs were immunostained with polyclonal antibodies to cathepsin B and laminin. Statistical analysis was performed using exact linear by linear association test and Spearman rank correlation coefficient. Cathepsin B-positive tumor cells were seen in 30 (67%) ADs, 13 (100%) AHDs, and 17 (100%) CAs. The grade of cathepsin B staining was significantly increased in AHDs and CAs, compared with ADs (P < .0001). Laminin was continuous in all of the ADs and discontinuous or fragmented in the AHDs and CAs (P < .0001). The degree of cathepsin B staining in tumor cells also correlated with breakdown of laminin. Increased cathepsin B expression and decrease in tumor-associated laminin might suggest a mechanism for progression of ADs to CAs.

Adenoma↗
PubMed1997

Modulation of aflatoxin B1 activated protein kinase C by phenolic compounds.

Several natural phenolic compounds were tested in vitro for their effect on the activity of protein kinase C isolated from liver cytosol, particulate and nuclear fractions of normal and aflatoxin B1 treated rats. Quercetin and kaempferol inhibited the enzyme activity of all these fractions at very low dose levels. These phenolics were particularly effective in inhibiting the elevated enzyme activity following aflatoxin B1 administration. Ellagic acid and curcumin were found to be inhibitory only towards particulate enzymes obtained after carcinogen treatment, while curcumin and rutin were moderately active against nuclear enzymes. Constitutive activation of protein kinase C can drive the cell to a proliferative state, thereby initiating the process of carcinogenesis, however, suppression of this activation by phenolic compounds may be an effective way to control carcinogenesis.

Aflatoxin B1↗
PubMed1997

9-O-Acetylation of sialomucins: a novel marker of murine CD4 T cells that is regulated during maturation and activation.

Terminal sialic acids on cell surface glycoconjugates can carry 9-O-acetyl esters. For technical reasons, it has previously been difficult to determine their precise distribution on different cell types. Using a recombinant soluble form of the Influenza C virus hemagglutinin-esterase as a probe for 9-O-acetylated sialic acids, we demonstrate here their preferential expression on the CD4 T cell lineage in normal B10.A mouse lymphoid organs. Of total thymocytes, 8-10% carry 9-O-acetylation; the great majority of these are the more mature PNA-, HSA-, and TCRhi medullary cells. While low levels of 9-O-acetylation are seen on some CD4/CD8 double positive (DP) and CD8 single positive (SP) cells, high levels are present primarily on 80- 85% of CD4 SP cells. Correlation with CD4 and CD8 levels suggests that 9-O-acetylation appears as an early differentiation marker as cells mature from the DP to the CD4 SP phenotype. This high degree of 9-O-acetylation is also present on 90-95% of peripheral spleen and lymph node CD4 T cells. In contrast, only a small minority of CD8 T cells and B cells show such levels of 9-O-acetylation. Among mature peripheral CD4 T lymphocytes, the highly O-acetylated cells are Mel 14(hi), CD44(lo), and CD45R(exon B)hi, features typical of naive cells. Digestions with trypsin and O-sialoglycoprotease (OSGPase) and ELISA studies of lipid extracts indicate that the 9-O-acetylated sialic acids on peripheral CD4 T cells are predominantly on O-linked mucintype glycoproteins and to a lesser degree, on sialylated glycolipids (gangliosides). In contrast, sialic acids on mucin type molecules of CD8 T cells are not O-acetylated; instead these molecules mask the recognition of O-acetylated gangliosides that seem to be present at similar levels as on CD4 cells. The 9-O-acetylated gangliosides on mouse T cells are not bound by CD60 antibodies, which recognize O-acetylated gangliosides in human T cells. Tethering 9-O-acetylated mucins with the Influenza C probe with or without secondary cross-linking did not cause activation of CD4 T cells. However, activation by other stimuli including TCR ligation is associated with a substantial decrease in surface 9-O-acetylation, primarily in the mucin glycoprotein component. Thus, 9-O-acetylation of sialic acids on cell surface mucins is a novel marker on CD4 T cells that appears on maturation and is modulated downwards upon activation.

Acetylation↗
PubMed1997

Detection of albumin messenger RNA in hepatic and extrahepatic neoplasms. A marker of hepatocellular differentiation.

Albumin is a ubiquitous protein synthesized only by hepatocytes. Detection of albumin messenger RNA (mRNA) in neoplastic and non-neoplastic tissues using in situ hybridization may be useful in demonstrating hepatocellular differentiation. We investigated the presence of albumin mRNA by in situ hybridization in 69 hepatic and 29 extrahepatic tumors to determine its sensitivity and specificity for hepatocellular differentiation. Albumin mRNA was detected in 22 of 23 hepatocellular carcinomas (96%); all hepatoblastomas, hepatocellular adenomas, and focal nodular hyperplasias; and within the hepatoid areas of an extrahepatic malignant mixed germ cell tumor. All other hepatic and extrahepatic tumors were negative for albumin mRNA. The staining was intense in focal nodular hyperplasias, weak in hepatocellular adenomas, and variable in hepatocellular carcinomas and hepatoblastomas. Non-neoplastic, noncirrhotic liver was present in 50 cases; all were positive for albumin mRNA with variable staining, which was usually more intense than in the neoplasms. A zonal pattern of staining was present in 49 (98%) of these, with more intense staining within acinar zone 1 and least in zone 3. This study shows that albumin mRNA is a specific marker of hepatocellular differentiation but may be present in extrahepatic germ cell tumors with hepatoid features. For primary hepatocellular carcinomas, in situ hybridization for albumin mRNA is a useful adjunct diagnostic method.

Adenoma, Liver Cell↗
PubMed1997

Phosphoinositide signal transduction pathway during regeneration following partial hepatectomy.

Phosphorylation of endogenous phosphatidylinositol was transiently increased following partial hepatectomy but was suppressed during peak DNA synthesis. Formation of inositol trisphosphate was decreased while generation of diacylglycerol and its breakdown to phosphatidic acid was increased. In response to partial hepatectomy protein kinase C was activated due to translocation from cytosol to particulate fraction, but the membrane bound activity was decreased during regeneration. Alteration of certain parameters in the signal transduction pathway apparently facilitates cell proliferation.

Animals↗
PubMed1996

Activation of ras oncogenes during hepatocarcinogenesis induced by N-nitrosodiethylamine: possible involvement of PKC and GAP.

The expression of H-ras and N-ras was found to be increased in liver of rats fed with the carcinogen N-nitrosodiethylamine (NDEA). There were, however, variations in time at which these were expressed and in the extent of expression of the two genes. N-ras appeared to be more aggressive than H ras. This overexpression could be correlated with an inhibition in the functioning of GTPase activating protein (GAP). The activity of GAP in increasing the intrinsic GTPase activity of p21RAS was found to be much less in NDEA-treated rats as compared to that in control rats. It was observed that GAP isolated from NDEA-treated rats was extensively phosphorylated by protein kinase C, and this might be the reason for its decreased activity. It is speculated that phosphorylated GAP helps keep the p21RAS in the more active GTP-bound state.

Animals↗
PubMed1996

Increased limb lengths in patients with shortened spines due to tuberculosis in early childhood.

STUDY DESIGN: The spine and limb lengths of 26 patients who had a severe spinal deformity due to tuberculosis in childhood were measured and compared with similar data from 79 normal adult volunteers. OBJECTIVES: The aim of the study was to assess whether there are any compensatory growth mechanisms present in patients who had stunted spinal growth in childhood. SUMMARY OF BACKGROUND DATA: Previous studies have documented increased leg lengths in patients with adolescent idiopathic scoliosis who have had spinal fusions done. The aim of this study was to ascertain if this response was unique to scoliosis or was a more general response to the interruption of normal spine growth. METHODS: The standing height, spine height, leg length, and upper limb length were measured in 26 adults with stunted spinal growth due to tuberculosis of the spine contracted in early childhood, and compared with similar measurements in 79 normal volunteers. RESULTS: The patients with spinal deformity due to tuberculosis had significantly shorter mean standing and spine heights compared to the volunteers. However, the mean leg length of these patients was 19.4 mm longer than the volunteers and their mean upper limb length was 18.9 mm longer than the volunteers. These differences were statistically significant. CONCLUSION: Patients whose spinal growth was stunted due to disease in childhood have longer legs and upper limbs than healthy people. A compensatory stimulatory growth mechanism may be responsible for this. This has implications for the whole gamut of childhood spinal disorders that result in stunted spinal growth.

Adaptation, Physiological↗
PubMed1996

Spinal stenosis above a healed tuberculous kyphosis. A case report.

STUDY DESIGN: This case report illustrates two patients with paraplegia of late onset resulting from cord compression in the hyperlordotic thoracic or thoracolumbar spine proximal to a healed tuberculous kyphosis. OBJECTIVES: The objective of this paper is to highlight that degenerative stenosis of the thoracic spine proximal to a healed stable kyphosis can be a cause of paraplegia of healed disease. SUMMARY OF BACKGROUND DATA: Paraplegia resulting from tuberculosis of the spine can be of early or late onset. Early onset paraplegia is usually a result of cord compression by active disease. Late onset paraplegia can be due to disease reactivation, bony ridge compression, or unstable kyphosis. To our knowledge, compression of the cord proximal to a healed, stable kyphosis giving rise to paraplegia has never been reported. METHODS: Patient 1 presented with symptoms of spinal claudication and progressive paraparesis. He was found to have spinal stenosis in the hyperlordotic thoracolumbar spine proximal to a healed lumbosacral tuberculous kyphosis. Patient 2 presented with a 2-year history of progressive paraplegia. Imaging revealed cord compression at the hyperlordotic T10-11 segment by disc protrusion, and facet hypertrophy. RESULTS: Laminectomy successfully relieved the first patient of all symptoms but the second patient had significant deterioration of the neurologic status after surgery. CONCLUSION: Compensatory hyperlordosis of the thoracic or thoracolumbar spine commonly occurs in patients with severe tuberculous thoracolumbar or lumbosacral kyphosis. Degenerative spinal stenosis and cord compression at such hyperlordotic segment can cause late onset paraplegia. The blood supply of these chronically compressed cords is precarious and the risk of surgery is high.

Adult↗
PubMed1996

Signal transduction mechanism in response to aflatoxin B1 exposure: protein kinase C activity.

A single dose of the carcinogen aflatoxin B1 (7 mg/kg body weight) to male Wistar rats significantly enhanced the hepatic activity of protein kinase C in the particulate and nuclear fractions. The particulate fraction showed stimulation at 4 and 7 h, while the nuclear activity was increased at 17 h following administration of aflatoxin B1. The enzyme activity in cytosol revealed a significant decline corresponding to stimulation in particulate fraction. The carcinogen-activated protein kinase C stimulated autophosphorylation, and was found to accelerate in vitro phosphorylation of two model DNA synthesizing enzymes--the Klenow fragment of replicative DNA polymerase of E. Coli and a DNA primase-polymerase complex of yeast mitochondrial origin. Prior phosphorylation of these enzymes led to significant enhancement of their activities. The results imply that activation of protein kinase C and consequently the activation of DNA synthesizing enzymes may play an important role in the initiation of carcinogenesis.

Aflatoxin B1↗
PubMed1996

Cauda equina syndrome secondary to lumbar spondylodiscitis caused by Streptococcus milleri.

A 79-year-old Afro-Caribbean woman presented with a 5-month history of low back pain and a 2-month history of weakness of the lower limbs associated with cauda equina syndrome. A plain X-ray of the lumbar spine showed a collapse of the L4 body consistent with osteomyelitis. An MRI scan of the lumbar spine showed narrowing of the L3/4 disc space, destruction of the adjacent vertebral bodies and an epidural abscess. She was admitted to hospital and treated with a high dose of i.v. antibiotics followed by radical surgical excision of the lesion through a combined anterior and posterior approach with instrumentation. Tissue culture grew Streptococcus milleri. One week after surgery the patient developed septicaemia. A blood culture grew Pseudomonas aeruginosa, which was successfully treated with antibiotics. She eventually recovered bowel and bladder control and regained muscle power in the lower limbs. Streptococcus milleri is a rare causative organism in osteomyelitis, this being only the eighth reported case in the literature. Aggressive surgical treatment combined with a prolonged antibiotic regime is recommended to achieve a satisfactory result.

Abscess↗
PubMed1996

Interleukin-6 is required for a protective immune response to systemic Escherichia coli infection.

Interleukin-6 (IL-6) is a multipotential cytokine detected in the serum of patients or experimental animals undergoing bacterial sepsis. To date, the role of IL-6 in gram-negative sepsis models has been controversial. We have used IL-6-deficient mice to investigate the role of IL-6 during virulent Escherichia coli infection and in lipopolysaccharide (LPS)-induced mortality. In this report we describe an increased susceptibility of IL-6-deficient mice to E. coli infection in terms of mortality and accumulation of viable bacteria in tissues, indicating a protective role for IL-6 during the immune response against E. coli. In contrast, mortality rates of IL-6-deficient mice and control animals undergoing LPS-induced shock did not differ, indicating that IL-6 was inconsequential for survival in this model. Furthermore, we have shown that neutrophils were crucial for resistance to E. coli in normal mice. IL-6-deficient mice were unable to efficiently induce neutrophilia in the bloodstream immediately following challenge with E. coli, in contrast to a characteristic neutrophilia induced in control animals. Prophylactic treatment of the mutant animals with recombinant IL-6 protein reverted both the deficit of neutrophilia and the accumulation of bacteria in tissues. These data clarify the role of IL-6 as protective in virulent E. coli infection and suggest that the protective effect may be at least partially mediated through neutrophils.

Animals↗
PubMed1996

Intraductal papillary mucinous neoplasm of the pancreas presenting as acute pancreatitis.

Intraductal papillary mucinous neoplasms are rare pancreatic exocrine tumors with distinct clinicopathologic features. They usually present with a long history of chronic pancreatitis-like symptoms, which are often associated with weight loss, diarrhea, and malabsorption. We report a case of benign intraductal papillary mucinous neoplasm with focal squamous metaplasia presenting as acute necrotizing pancreatitis. The clinicopathologic features are discussed in a brief review of the literature.

Acute Disease↗
PubMed1996

Immunohistochemical detection of bcl-2 protein in adenocarcinoma and non-neoplastic cellular compartments of the lung.

The expression of bcl-2 seems to influence the biologic activity of a variety of neoplasms. In this study, we examined bcl-2 protein expression in 47 surgically resected adenocarcinomas of the lung to determine its expression in the neoplastic and adjacent non-neoplastic cells. Seven squamous cell carcinomas, six small cell carcinomas, five non-neoplastic lung lesions, and five normal lungs were also studied. The bcl-2 protein was detected after antigen retrieval with bcl-2 monoclonal antibody using archival formalin-fixed, paraffin-embedded tissue material. Fifty-one of 52 cases had bronchioles that could be evaluated and all expressed bcl-2, and of these, 12 showed basal immunostaining, 17 showed luminal immunostaining, and 22 showed immunostaining in both cellular compartments. Thirty of the 47 adenocarcinomas expressed bcl-2, whereas four of seven squamous cell carcinomas and all six small cell carcinomas were bcl-2 positive. bcl-2 immunostaining was correlated with a survival using the Fisher exact test. There were no statistically significant differences in survival between patients with bcl-2-positive and bcl-2-negative adenocarcinomas (P = 0.332). Similar results were obtained using the Kaplan-Mier product limit survival analysis method (P = 0.356). Our study also showed that expression of bcl-2 is common in pulmonary adenocarcinomas and that bcl-2 expression may be found in the basal and the luminal surfaces of normal bronchioles.

Adenocarcinoma↗