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Biomedical subjects

K N Khan

Publications and source records attributed to K N Khan.

At least 37 records · Page 2Linked to original sources
PubMed1998

Regulation of alkaline phosphatase gene expression in human hepatoma cells by bile acids.

Bile acid-dependent secretion and the translationally regulated synthesis of alkaline phosphatase (ALP) in rat liver cell culture and by bile duct ligation has already been demonstrated. With the advent of ALP cDNA cloned sequences, the mechanism of the effect of bile acids on ALP activity and the expression of the ALP gene in different hepatoma cells was investigated. The HuH7 and HepG2 cells were treated with taurine-conjugated cholic acid (CA), chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) at 0-1 mmol/L and the numbers of viable cells were counted at 24, 48 and 72 h after treatment. A [3H]-thymidine incorporation study was performed with different bile acids at a concentration of 1 mmol/L for 48 h. The cellular activity of ALP in HuH7 and HepG2 cells by bile acids was measured by a substrate-specific enzymatic assay. To elucidate the effects of bile acids on ALP gene expression, a northern blotting experiment using hybridization with mouse placental ALP cDNA was performed. Cellular ALP activity was time- and dose-dependently increased in both HuH7 and HepG2 cells treated by CA and CDCA; however, no change in ALP activity was observed following treatment with UDCA compared with controls. Induction of ALP activity was dominant in HepG2 cells and independent of cell growth and proliferation. The addition of UDCA synergistically reduced the increased activity of ALP produced by CA and CDCA in both HuH7 and HepG2 cells. By northern blot analysis, the level of ALP mRNA was elevated by CA and CDCA; however, levels of ALP mRNA were suppressed by UDCA. In conclusion, CA and CDCA cause up-regulation of ALP mRNA and UDCA leads to down-regulation of ALP mRNA by its interaction with either CA or CDCA. We assume that increased ALP synthesis in hepatoma cells after bile acid treatment results from an enhanced rate of transcription rather than translation of mRNA.

Alkaline Phosphatase↗
PubMed1997

Idiopathic myelofibrosis (agnogenic myeloid metaplasia) in a marmoset (Callithrix jacchus): hematologic and histopathologic changes.

Idiopathic myelofibrosis (IMF), or agnogenic myeloid metaplasia, was diagnosed in a sexually mature male marmoset (Callithrix jacchus) based on the results of hematology and histopathologic evaluation of the bone marrow. The hematologic changes included pancytopenia, leukoerythroblastosis, anisocytosis, poikilocytosis, and giant platelets. Histopathologic evaluation of the bone marrow showed marked widespread fibrosis replacing hematopoietic cells and the presence of atypical megakaryocytes. In addition, slight multifocal osteolysis with an increase in serum alkaline phosphatase activity was observed. We believe this is the first report of IMF in a nonhuman primate species.

Animals↗
PubMed1995

Systemic mastocytosis in a goat.

Systemic mastocytosis was diagnosed in a 4-year-old, female Nubian goat. Clinically, the animal was depressed and had severe macrocytic hypochromic anemia and leukopenia. Postmortem examination revealed neoplastic mast cells invading the heart, lung, liver, spleen, lymph nodes, and bone marrow. Eosinophils were frequently admixed with infiltrating mast cells in all organs. Using routine light microscopy, histochemistry, and transmission electron microscopy, metachromatic and periodic acid-Schiff-positive granules were identified within the cytoplasm of neoplastic mast cells. Erythrophagocytosis was observed in some neoplastic cells, although its contribution to the anemia was not clear. This report represents the first description of mast cell neoplasia in the goat.

Anemia, Hypochromic↗
PubMed1993

Systemic mycosis caused by Acremonium sp in a dog.

A 4-year-old female German Shepherd Dog was examined to determine the cause of ataxia, progressive head tilt, anorexia, lethargy, and weight loss of 3 weeks' duration. A vestibular syndrome, generalized lymphadenopathy, bilateral uveitis, and chorioretinitis with complete detachment of the left retina were detected. Abnormal clinicopathologic findings were isosthenuria and hyperglobulinemia. The non-functional left eye was enucleated and fungal organisms resembling Aspergillus spp were identified on histologic examination. Microbial culture of a urine sample yielded Acremonium sp, which was initially considered a contaminant. The dog was considered to have systemic aspergillosis and was treated with itraconazole for 7 months, until it was euthanatized because of persistent vomiting and anorexia. Postmortem examination revealed multisystemic pyogranulomatous and necrotizing inflammation of the myocardium, pericardium, liver, and kidneys; and granulomatous splenitis, lymphadenitis, retinitis, endometritis, and meningoencephalitis. Fungal culture of affected organs yielded Acremonium sp. These findings indicated that Acremonium spp can be pathogenic and should not be ignored when cultured.

Acremonium↗
PubMed1993

Macrophage tropism of feline leukemia virus (FeLV) of subgroup-C and increased production of tumor necrosis factor-alpha by FeLV-infected macrophages.

Erythroid aplasia is induced in cats by feline leukemia virus (FeLV) of subgroup C but not by FeLV of subgroup A. In an investigation of the role of macrophages in FeLV-C-induced diseases, the concentrations of FeLV and tumor necrosis factor-alpha (TNF-alpha) were compared between feline peritoneal macrophages incubated with FeLV of subgroup A or C. FeLV of both subgroups infected macrophages, but expression of FeLV-C was 21-fold higher than FeLV-A in peritoneal macrophages (P = .004). The supernatants of FeLV-C-inoculated macrophage cultures contained significantly higher levels of TNF-alpha (70 +/- 14 U/mL) at 72 hours postincubation compared with FeLV-A-inoculated (38 +/- 8 U/mL) and uninoculated (31 +/- 8 U/mL) cultures. Moreover, a positive correlation was shown between cell-associated FeLV surface glycoprotein gp70 and TNF-alpha expression in FeLV-C-infected macrophages by immunofluorescence (r = .6; P = .001), measured with a computer-assisted, laser-based digital imaging system. The addition of TNF-alpha to a uniform population of FeLV-infected cells (feline embryonic fibroblasts) caused an enhancement of viral expression (P < .05). These results indicate that FeLV-C has tropism for macrophages, FeLV expression is positively correlated with TNF-alpha expression in macrophages, and TNF-alpha enhances FeLV replication in fibroblasts. We suggest that FeLV-C infection of macrophages and secretion of TNF-alpha may be important in hematopoietic suppression in FeLV-C-infected cats.

Animals↗
PubMed1993

Pancreatic tissue damage by transcatheter arterial embolization for hepatoma.

We analyzed the serial changes in serum pancreatic enzyme activities by transcatheter arterial embolization (TAE) in 20 hepatoma patients with liver cirrhosis in an attempt to evaluate the incidence of the pancreatic tissue damage by TAE. Serum amylase activities increased in two (10%) cases, elastase 1 levels in six (30%) cases, and trypsin and pancreatic secretory trypsin inhibitor (PSTI) levels in each of five (25%) cases. Consequently, TAE resulted in the elevation of at least more than one serum pancreatic enzyme in eight (40%) of 20 cases, although none had clinical symptoms related to pancreatitis. When the adverse effect on the pancreatic tissue was compared among 6 cases of the superselective TAE and 14 cases of the nonsuperselective TAE, which were performed from the segmental and the nonsegmental hepatic arteries, respectively, the elevation of serum pancreatic enzymes was caused only by nonsuperselective TAE, not by superselective TAE. The volumes of Spongel and Lipiodol used or the injected doses of the anticancer agent mitomycin C were not different between the two groups. These results indicate that TAE for the treatment of hepatoma frequently causes pancreatic tissue damage, and the position of the inserted catheter tip is very important to avoid the pancreatic tissue damage by TAE.

Adult↗
PubMed1993

A physiological role of epidermal growth factor in cell kinetics of gastric epithelium.

Administration of epidermal growth factor (EGF) stimulates DNA synthesis in gut epithelial cells and inhibits gastric acid secretion. A physiological role of EGF in cell kinetics of gastric epithelium, however, has not been fully understood. In mature male mice, large amounts of EGF are produced in the submandibular glands, and sialoadenectomy (removal of the submandibular glands) causes a marked reduction of plasma EGF levels. For the evaluation of a biophysical function of EGF, sialoadenectomized mice and sham-operated mice were injected with 3H-thymidine to compare the proliferative activity and the cell-turnover of gastric epithelium between the two groups using the autoradiographic analysis. When mice were killed 90 min after a single injection of 3H-thymidine, the percentages of fundic gland mucosal cells radiolabeled in sialoadenectomized and sham-operated mice were 27.3 +/- 5.0% and 26.3 +/- 5.8% (mean +/- SD), respectively. The difference was not significant (p > 0.05). Similarly, the labeling indices of pyloric gland mucosal cells were not different between the two groups (26.7 +/- 4.3% vs 27.8 +/- 3.7%, p > 0.05). In contrast, when mice were given 17 repeated injections of 3H-thymidine at 6 hr intervals and killed 48 hr after the last injection, labeling indices in sialoadenectomized mice were significantly lower than those in sham-operated mice (35.3 +/- 4.3% vs 52.8 +/- 1.1% in the fundic gland area; 41.0 +/- 6.2% vs 55.1 +/- 5.9% in the pyloric gland area, p < 0.001, respectively). Treatment of sialoadenectomized mice with EGF (5 mg/mouse per day) completely restored the percentages of the radiolabeled cells to control levels. These findings suggest that endogenous EGF plays a major role in maintaining biological cell-turnover of the mouse gastric epithelium.

Animals↗
PubMed1992

Cytotoxicity in feline leukemia virus subgroup-C infected fibroblasts is mediated by adherent bone marrow mononuclear cells.

The pathogenesis of retrovirus-induced erythroid aplasia in cats is unknown. In studies to define mechanisms of cytotoxicity associated with retroviral infections, bone marrow mononuclear cells (BMMC) from healthy specific pathogen-free cats were co-cultured with uninfected feline embryonic fibroblasts (FEA cells) and FEA cells infected with feline leukemia virus (FeLV) of subgroup A (FEA-A) or subgroup C (FEA-C). Moderate to marked cytotoxicity (CPE) developed in co-cultures of BMMC and FEA-C cells on Days 5 to 7 of incubation but not in co-cultures of BMMC and FEA-A or BMMC and uninfected cells (FEA-CT). Cytotoxicity was associated with adherent cells of light density (1.056) from bone marrow and peripheral blood, which were positive for alpha naphthyl butyrate esterase activity. Stimulation of adherent cells with phorbol ester or addition of recombinant human tumor necrosis factor-alpha (rhTNF-alpha) caused similar CPE in FEA-CT cells. The TNF-alpha concentrations in the culture supernatants of BMMC+FEA-C were higher than those of BMMC+FEA-A or BMMC+FEA-CT, and addition of anti-TNF antibodies to the cultures blocked the CPE. These data support the hypothesis that macrophages exposed to FeLV-C cause CPE in co-cultures of BMMC and FEA cells by a mechanism involving TNF-alpha. It is suggested that TNF-alpha may be involved in the suppression of hematopoiesis in cats which develop FeLV-C induced erythroid aplasia.

Animals↗
PubMed1992

Effects of tumor necrosis factor-alpha on normal feline hematopoietic progenitor cells.

The effects of tumor necrosis factor-alpha (TNF-alpha) on feline bone marrow hematopoietic progenitors were evaluated by exposing bone marrow mononuclear cells from specific pathogen-free cats to different concentrations of TNF-alpha (ranging from 50 to 800 pg/ml) for 2 h before plating for clonal assays of colony-forming units. TNF-alpha caused a dose-dependent suppression of feline erythroid colony-forming units (CFU-E) and erythroid burst-forming units (BFU-E), whereas granulocyte-macrophage colony-forming units (CFU-GM) were minimally affected. TNF-alpha concentrations as low as 200 pg/ml significantly inhibited growth of erythroid progenitors. Addition of polyclonal rabbit anti-TNF-alpha antibodies completely neutralized the suppressive effect of TNF-alpha on erythroid progenitors. At higher concentrations of TNF-alpha (800 pg/ml), 35% of CFU-E and 21% of BFU-E still survived, indicating that some erythroid progenitors are not sensitive to a single exposure of TNF-alpha in vitro. These results suggest that TNF-alpha may play a role in regulating hematopoiesis in cats and may be involved in the pathogenesis of erythroid aplasia in cats infected with feline leukemia virus.

Animals↗
PubMed1991

Evaluation of nontumorous tissue damage by transcatheter arterial embolization for hepatocellular carcinoma.

The serial changes in serum hepatic enzyme activities by transcatheter arterial embolization (TAE) were analyzed in 17 patients with hepatocellular carcinoma to estimate the contribution to the value by the damage of tumor or nontumorous hepatic cells. The serum levels of relatively tumor-specific fructose 1,6-diphosphate (FDP) aldolase were elevated after TAE in the cases of both superselective and nonsuperselective TAE that were performed from the segmental and the nonsegmental hepatic artery, respectively, but we found the marked elevation of FDP aldolase in the cases of the superselective TAE. In contrast, the non-tumor-specific fructose 1-phosphate (F1P) aldolase was markedly elevated only in the cases of nonsuperselective TAE. The total amount of FDP aldolase released by TAE correlated significantly with the integrated tumor tissue volume (P less than 0.005), whereas the total amount of F1P aldolase output correlated significantly with the integrated nontumorous tissue volume (P less than 0.005) as defined by lipiodol accumulation on computerized tomography scan. The consequent changes in the total nontumorous liver volumes after TAE were also analyzed by the follow-up computerized tomography scan. The nonsuperselective TAE caused the significant total nontumorous liver atrophy when compared with the superselective TAE. The progression of the total nontumorous liver atrophy correlated significantly with F1P aldolase output by TAE (P less than 0.001) but not with FDP aldolase output. These results suggest that the outputs of FDP and F1P aldolase are useful to estimate the degree of the tumorous and nontumorous tissue damage by TAE, respectively, and F1P aldolase output can be used to predict the progression of liver atrophy caused by TAE.

Adult↗
PubMed1989

Preliminary serological studies comparing immunofluorescence assay with radioimmunoassay.

We assayed serum from 12 patients with untreated cicatricial pemphigoid affecting the conjunctiva for circulating autoantibodies directed against the epithelial basement membrane zone. We employed a conventional indirect immunofluorescence assay, with monkey esophagus and human conjunctiva as substrates, and compared the results with those obtained employing a radioimmunoassay measuring antibasement membrane zone antibody binding to COLO-16 and to SCaBER tumor cell lines. The indirect immunofluorescence assay on normal human conjunctival substrate detected circulating antibodies to conjunctival epithelium in 6 of 12 CP patient serum specimens. Monkey esophagus failed to detect antibodies to the epithelial basement membrane zone. In contrast, autoantibodies were detected in all 12 specimens by the radioimmunoassay. Specificity, as demonstrated by appropriate controls and assay of normal human serum, was 100%. These results demonstrate that radioimmunoassay employing COLO-16 or SCaBER cells is an exquisitely sensitive and specific assay for detection of circulating antibasement membrane antibodies in patients with cicatricial pemphigoid affecting the conjunctiva.

Aged↗
PubMedDate not supplied

Cyclooxygenase-2 expression in the developing human kidney.

Cyclooxygenase (COX) exists in two related but unique isoforms, COX-1 and COX-2, and is suggested to have specific functions in different segments of the nephron. COX-2 knockout mice develop fatal nephropathy, which implies that this isoform is important during nephrogenesis. The histologic changes seen in the COX-2 knockout mice are similar to those observed in the kidneys of human fetuses exposed to non-steroidal anti-inflammatory drugs (NSAIDs) in the third trimester of pregnancy. However, only minimal amounts of COX-2 mRNA or protein have been reported in the adult human kidney. We hypothesized that expression of COX-2 is significant in the fetal human kidney and that it is involved in the development of the nephron. To characterize the presence of COX-2 in the human fetal kidney, we used immunohistochemistry to evaluate its expression in 23 fetal kidneys ranging between 15 and 23 weeks of gestational age. Strong expression of COX-2 was localized primarily in the macula densa and the thick ascending limb of the loop of Henle, and in rare glomerular podocytes and vascular endothelial cells. There was a progressive decrease in COX-2 immunoreactivity from the most immature nephrons adjacent to the metanephric regions to the well-developed nephrons in the middle to inner cortex. In contrast to the adult human kidney, this temporal and spatial expression of COX-2 in the fetal kidney suggests that this enzyme may be involved in nephrogenesis, and its inhibition by NSAIDs during the third trimester may be responsible for fetal renal syndromes.

Cyclooxygenase 2↗
PubMedDate not supplied

Expression of cyclooxygenase-2 in the macula densa of human kidney in hypertension, congestive heart failure, and diabetic nephropathy.

Cyclooxygenase-2 (COX-2) is constitutively expressed in the macula densa of several laboratory animal species where it is considered to play a physiologic role in the regulation of basal renal function. Pertubations to normal homeostasis is shown to be associated with the upregulation of COX-2 in the macula densa of rats and dogs. In contrast, COX-2 has not been detected in the macula densa of normal adult human and non-human primate kidneys, suggesting a less prominent role of this isoform in normal renal function in these species. In this study, we characterized COX-2 expression in human kidneys collected from subjects with a clinical history indicative of compromised renal function associated with diabetic nephropathy (DN), hypertension, and congestive heart failure (CHF). COX-2 expression was evaluated by immunohistochemistry using isoform-specific antibodies and in situ hybridization. No COX-2 protein or mRNA was observed in the macula densa of normal kidneys (n= 11), whereas slight to moderate COX-2 expression was present in the macula densa of 7/15 subjects (46%) with DN, 5/11 (46%) subjects with hypertension, and 3/10 subjects (30%) with CHF. These results indicate that COX-2 is variably induced in the macula densa of the human kidney in compromised renal conditions and that COX-2-mediated prostaglandins may be involved in maintaining adequate renal functions in some patients with DN, hypertension, and CHF. This variability may be related to individual clinical status or synthesis of vasodilatory prostaglandins by cyclooxygenase-1 (COX-1).

Cyclooxygenase 2↗
PubMedDate not supplied

Effect of alcohol consumption on the progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients.

Chronic hepatitis C virus (HCV) infection is associated with a spectrum of liver diseases and a proportion of chronic cases progress through cirrhosis to hepatocellular carcinoma (HCC). The viral and host factors that are important in the clinical and histological progression of HCV infection are unclear. We investigated the effect of moderate (<80 g/day) and heavy (>80 g/day) alcohol intake on the histological and clinical progression of HCV infection and their associated risk of hepatic cancer in a group of Japanese patients. A number of other variables were assessed to evaluate their impact on disease progression. We recruited 120 patients with HCV infection and categorized them into four groups, based on alcohol consumption pattern. All clinical and biochemical profiles were collected from recorded files. Liver biopsies were analysed for the degree of fibrosis, presence of cirrhosis and histological activity of necroinflammation. Hepatic tumours were detected by the follow-up imaging analysis. There was no difference in the age, length of exposure to HCV infection and HCV RNA serum levels in the alcohol and alcohol-free groups. The histological grading of necroinflammation, serum levels of alanine aminotransferase and HCV RNA did not have any correlation with each other in the alcohol and alcohol-free group. There was a 1.5-2. 5-fold greater risk of liver cirrhosis and hepatocellular carcinoma in the alcohol intake group compared to the alcohol-free group. Kruskal-Wallis analysis among four groups demonstrated a significant transition to fibrosis (P < 0.05) for alcoholics with HCV infection. The increased risk of liver cancer in the alcohol group is independent of size and growth of tumours. The clinical manifestations of gastro-oesophageal variceal bleeding, ascites, and encephalopathy were also higher in the alcohol intake group. Alcohol consumption is an important risk factor in the histological and clinical progression of HCV infection and has no relation with HCV replication. Chronic HCV carriers should avoid excessive alcohol intake to reduce the acceleration of liver disease and risk of liver cancer.

Adult↗
PubMedDate not supplied

Recombinant human interleukin-3 induces extramedullary hematopoiesis at subcutaneous injection sites in cynomolgus monkeys.

Parenteral administration of recombinant hematopoietic growth factors has been sporadically associated with cutaneous complications, including injection site reactions in humans and nonhuman primates. In this study, subcutaneous injection sites were evaluated from 12 cynomolgus monkeys administered a recombinant human interleukin-3 (rhIL-3) at dose levels of 0, 70, or 700 micrograms/kg daily for 18 days. Monkeys administered rhIL-3 developed small (0.5-1-cm-diameter), firm nodules at the subcutaneous injection sites. Histologically, these nodules from 4 of 8 rhIL-3-treated monkeys contained trilineage extramedullary hematopoiesis (EMH) represented by precursors of myeloid, erythroid, and megakaryocytic series cells. The lineage of hematopoietic cells was confirmed by histochemical and immunohistochemical methods. Hematopoietic cells of myeloid and megakaryocytic lineages were more common than erythroid cells. Of myeloid cells, immature eosinophils were more common, which usually formed small sheets or clusters in the panniculus and deep dermis. This report describes, for the first time, the occurrence of cutaneous EMH at the injection sites of recombinant hematopoietic growth factors, which should be differentiated from inflammation. We believe the cutaneous EMH was the exaggerated pharmacologic effect of rhIL-3.

Animals↗
PubMedDate not supplied

Pathology of perbutylated-N-butyl-1-deoxynojiromycin (an alpha-glucosidase-1 inhibitor) in Sprague-Dawley rats.

Perbutylated-N-butyl-1-deoxynojiromycin (p-N-butyl-DNJ, SC-49483), an alpha-glucosidase-1 inhibitor, is a candidate anti-HIV agent targeted against viral glycoprotein processing in host cell endoplasmic reticulum. The potential toxicity of this compound was evaluated in Sprague-Dawley rats after 4, 13, or 26 wk of oral administration at doses ranging from 300 to 3,670 mg/kg/day. In these studies, the target organs of p-N-butyl-DNJ effects were thyroid gland, salivary gland, stomach, and pancreas. The most prominent histologic change in these organs was the presence of clear or lightly eosinophilic vacuoles in the cytoplasm of thyroid follicular cells, gastric chief cells, salivary gland acinar cells, and exocrine pancreatic acinar cells. Ultrastructurally, these vacuoles were consistent with dilated rough endoplasmic reticulum, which sometimes contained homogeneously stained, moderately electron-dense material. The vacuoles in thyroid follicular cells contained pale eosinophilic colloidlike material consistent with accumulated thyroglobulin, as shown by immunohistochemical staining methods. The biological functions of these organs were not adversely affected as evidenced by the absence of clinical signs and the results of selected hormonal analyses. The morphologic changes were completely reversed after a 4-wk recovery period. The incidence and severity of histologic changes were decreased after 13 and 26 wk of treatment compared to 4 wk of treatment, indicating an attenuation of the host response or adaptation to the prolonged p-N-butyl-DNJ administration. We believe that morphologic changes in thyroid follicular cells, salivary gland acinar cells, pancreatic acinar cells, and gastric chief cells were the result of nonspecific inhibition of host alpha-glucosidase(s) by p-N-butyl-DNJ, causing clinically silent perturbation in host cell glycoprotein processing and/or glycoprotein transport.

Animals↗