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Biomedical subjects

D A Malatjalian

Publications and source records attributed to D A Malatjalian.

At least 19 recordsLinked to original sources
PubMed2001

Orthotopic liver transplantation using low-dose tacrolimus and sirolimus.

Although sirolimus (SRL) binds the immunophilin FK506-binding protein-12 (FKBP-12) with greater avidity than tacrolimus (TAC), animal studies have shown that SRL and TAC act synergistically to prevent rejection. Dose-related toxicity is more often the cause of TAC discontinuation than rejection. We hypothesized that SRL would allow for a substantial reduction in the concomitant dose of TAC after liver transplantation to levels less than the threshold for toxicity. A series of 56 liver transplant recipients were administered a combination of SRL and TAC (target trough levels, 7 and 5 ng/mL, respectively). Planned weaning of steroids commenced after 3 months. Pharmacokinetic (PK) studies were undertaken. Patient and graft survival were 52 patients (93%) and 51 grafts (91%), with a follow-up of 23 months (range, 6 to 35 months). One episode (1.8%) of hepatic artery thrombosis was seen. The rate of acute cellular rejection was 14%. No extra treatment was administered in 3 of 8 patients, and the other 5 episodes responded to a single course of steroids. Cytomegalovirus infection occurred in 4 patients (7%). Renal function, glucose control, and lipid metabolism are near normal in 47 patients (84%) without additional medication. Steroid elimination is completed in 51 patients (91%). Bioavailability of SRL and TAC varied between transplant recipients, but trough levels strongly correlated with the area under the curve (r(2) = 0.82 and r(2) = 0.84, respectively). Simultaneous administration did not affect the PK profile of the drugs at this dose. The ratio of trough level to daily dose correlated between SRL and TAC. The synergistic effect seen in animal models also occurs in clinical liver transplant recipients on SRL-TAC combination immunosuppression. A low-dose combination of SRL and TAC should be compared with conventional immunosuppression in a multicenter, randomized, controlled trial.

Adolescent↗
PubMed2000

Therapeutic role for bismuth compounds in TNBS-induced colitis in the rat.

The 2,4,6-trinitrobenzene sulfonic acid (TNBS) -induced model of chronic inflammation of the rat colon was used to determine the efficacy of bismuth subsalicylate (BSS), bismuth subcitrate (CBS), and 5-aminosalicylic acid (5-ASA) administered in enema form. A novel bismuth compound 1, 2-bis[2-(1,3-dithiobismolane)thio]ethane [Bi2(EDT)3] was also tested. On day 1 colitis was induced with 50 mg TNBS/50% ethanol in female Sprague-Dawley rats, while controls received a saline enema. On day 3, twice-daily treatment with enemas of either saline, BSS, CBS, Bi2(EDT)3, or 5-ASA were initiated in the colitis and control rats. All rats were killed on day 14, and the colons excised, weighed, rated macroscopically, and then fixed for hematoxylin and eosin staining. Blinded microscopic scoring was used to determine injury and healing in all groups. Colon mass and macroscopic scores were increased (P < 0.05) in the group of rats treated with TNBS (N = 16) compared to saline controls (N = 12). Colon mass and macroscopic scores in controls treated with BSS (N = 4), CBS (N = 4), Bi2(EDT)3 (N = 4), and 5-ASA (N = 4) alone did not differ from saline control animals. Macroscopic scoring showed a decrease (P < 0.05) in the degree of damage in the group of rats treated with TNBS plus BSS (N = 15), TNBS plus Bi2(EDT)3 (N = 10) and TNBS plus CBS (N = 4) compared to the group of rats treated with TNBS plus saline (N = 16). A decrease (P < 0.05) in injury and an increase (P < 0.05, Kruskal-Wallis) in healing was observed in the groups of rats treated with TNBS plus BSS, TNBS plus CBS, and TNBS plus 5-ASA compared to the group of rats treated with TNBS plus saline. It appeared that Bi2(EDT)3 was not protective against injury at the microscopic level but that the novel Bi2(EDT)3 has an effective healing capacity at the macroscopic level. We conclude that BSS and CBS decrease injury and/or promote healing as effectively as 5-ASA in this model.

Animals↗
PubMed1996

Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up.

BACKGROUND AND DESIGN: Methotrexate (MTX) hepatotoxicity in psoriatic patients is well recognized, but there are discrepancies in the reported incidence and associated risk factors. This retrospective study describes 104 Nova Scotian patients with psoriasis seen between 1979 and 1990. Patients received MTX over one to 11 years (mean 3.38), with baseline and annual follow-up liver biopsies. Clinical data were obtained by chart review. Statistical analysis evaluated the risks associated with obesity, diabetes, alcohol consumption and duration of therapy, with the histological grade of liver biopsies. RESULTS: Of the 104 patients, 35 were obese, 10 were diabetic and 37 occasionally consumed alcohol. At the end of the study, 21 patients had developed severe hepatic fibrosis (grade IIIB), and three developed liver cirrhosis (grade IV). Significant risk of severe hepatotoxicity is related to diabetes (P = 0.02) but not to obesity (P = 0.12) or alcohol consumption (P = 0.12). All patients with cirrhosis took MTX for two years in standard doses of 20 to 25 mg/week. CONCLUSIONS: In this first Canadian study evaluating MTX hepatotoxicity in psoriatics, the incidence of severe hepatotoxicity is high: 23.1% (24 of 104 patients). This study shows that diabetic patients are particularly at increased risk of MTX hepatotoxicity. Occasional alcohol consumption is not associated with increased risk. Three patients who developed cirrhosis over two years of standard MTX therapy may represent a subset of psoriatics with increased hepatic susceptibility to MTX. Another three patients whose severe hepatic fibrosis had regressed upon discontinuation of MTX, but who developed accelerated recurrence of the severe hepatic fibrosis upon resumption of MTX therapy, also suggest the possibility of unusual sensitivity to the drug. These cases emphasize the need for continuing surveillance, with regular liver biopsies, of psoriatic patients on MTX.

Adolescent↗
PubMed1992

Serological detection of Helicobacter pylori by a flow microsphere immunofluorescence assay.

A flow cytometric immunofluorescence assay (FMIA) for the detection of immunoglobulin G antibodies to Helicobacter pylori was developed. A multicomponent antigen was prepared and used to coat carboxylated polystyrene microspheres for reaction with patient sera followed by fluorescein isothiocyanate-labelled goat anti-human immunoglobulin G. The reacted microspheres were collected with a flow cytometer, and fluorescence was quantitated relative to the cutoff value provided by pooled sera from patients in whom H. pylori could not be demonstrated by culture or histology. Serum samples from 28 H. pylori-positive patients and 27 H. pylori-negative patients were tested by FMIA. Additionally, an in-house enzyme-linked immunosorbent assay (ELISA) employing the same antigen preparation and a commercially available ELISA were used to assay the patient population. Both the FMIA and in-house ELISA were 100% sensitive and 89% specific with positive and negative predictive values of 90 and 100% and no equivocal results. The commercial ELISA was 96% sensitive and 89% specific with positive and negative predictive values of 90 and 96% and five equivocal results. FMIA provides a rapid, inexpensive, and easily performed means for serodiagnosis of H. pylori.

Adult↗
PubMed1991

Surfactant-potentiated increases in intracranial pressure in a mouse model of Reye's syndrome.

Severe encephalopathy, the usual cause of death in Reye's syndrome (RS), is characterized by cerebral edema with associated increases in intracranial pressure (ICP). In previous studies, we have shown that exposure of neonatal mice to nontoxic doses of an industrial surfactant and subsequent infection with mouse-adapted influenza B (Lee) virus result in a significant increase in mortality rate and that this is associated with several of the characteristic features of human RS. In the present study we have measured ICP in the young mice undergoing their version of the disease, and we now report that the animals treated with surfactant plus virus experience increases in intracranial pressure that are significantly in excess of those in any of the three control groups. These findings support our hypothesis that this and the other abnormal biochemical and morphological responses in RS are related in some manner to a chemically compromised host.

Animals↗
PubMed1991

Monocyte aryl hydrocarbon hydroxylase (AHH) activity mimics Kupffer cell and hepatocyte AHH activity in an animal model of liver disease.

We have previously reported that monocyte aryl hydrocarbon hydroxylase (AHH) activity is depressed in patients with liver disease and is decreased more in cirrhosis than in early stage liver disease. To determine if monocyte AHH activity reflects liver AHH activity, we studied an animal model of cirrhosis, i.e., yellow phosphorus induced cirrhosis in the pig. AHH activity was detectable in monocytes isolated from peripheral blood of normal pigs (0.32 +/- 0.13 nmol.mg-1 P.h-1, n = 11) and was comparable to the level of AHH activity in hepatic Kupffer cells isolated from wedge or needle biopsies of livers of normal pigs (0.38 +/- 0.21, n = 7). The AHH level in pig Kupffer cells was approximately 10% of the AHH level in hepatocytes and microsomes. To induce liver disease, pigs were administered yellow phosphorus (0.6 mg/kg) 5 days per week for 16 weeks. At 4 weeks of treatment, monocyte AHH activity was not different from control and liver histology was normal. Depression of monocyte AHH activity was evident at 8 weeks of treatment when liver fibrosis was seen histologically. At 12 weeks of treatment when histology revealed extensive liver fibrosis and collagen levels were elevated, the level of monocyte AHH activity was decreased 67% compared with controls. Similar changes were observed at 12 weeks in Kupffer cell AHH activity (86% decrease) and hepatocyte AHH activity (70% decrease) compared with controls. These results suggest that monocyte AHH activity reflects liver AHH activity and may be a good indicator of change in liver enzyme function in liver disease in the pig model of cirrhosis.

Animals↗
PubMed1990

The microanatomy of the intrahepatic bile duct in polycystic disease: comparison of the cpk mouse and human.

The cpk mutation in mice produces a lethal recessive form of polycystic kidney disease (PKD) that, like human forms of the condition, is associated with an age-related incidence of hepatic cysts. Injection of plastic into the biliary tree of affected animals revealed that these cysts arise from focal dilatations of the epithelial lining that may enlarge to the point that they obstruct the bile ducts. This concept was supported by histological and scanning and electron microscopic studies. No evidence could be found of primary obstruction of the biliary tree. The same techniques were then employed in specimens of human liver from patients with both recessive (ARPKD) and dominantly inherited PKD (ADPKD). Similar abnormalities of the biliary tree were identified. These abnormalities were not found in control liver samples from patients without PKD. The liver of the patient with ADPKD also demonstrated many von Meyenburg complexes. These were related to some cyst development, but these complexes freely communicated with bile ducts, contrary to currently held opinion. We conclude that hepatic abnormalities in the cpk mouse and human PKD arise from changes in bile ducts that are analogous to the renal lesions.

Animals↗
PubMed1987

Pathology of inflammatory bowel disease in colorectal mucosal biopsies.

The importance of colorectal biopsies in the diagnosis and management of inflammatory bowel disease (IBD) is reviewed and the histologic criteria for identifying the different types of colitis are outlined. While most of the histopathologic features of the various forms of colitis are characteristic, none is pathognomonic. Accordingly, emphasis is placed on considering all clinical and investigational data in evaluating histopathologic changes found in colorectal mucosal biopsies.

Biopsy↗
PubMed1987

Hepatic lipid abnormalities in a chemical/viral mouse model for Reye's syndrome.

We have examined hepatic lipid profiles in a mouse model for Reye's Syndrome (RS) in which young animals are exposed to nontoxic doses of an industrial pesticide emulsifier and subsequently are infected with sublethal doses of mouse-adapted human Influenza B (Lee) virus (FluB). The purpose of this study was to determine whether liver lipid content was altered in the mice, the time course of any changes, and whether lipid changes were consistent with liver pathology. Neonatal mice exposed dermally to the emulsifier, Toximul MP8 (Tox), had significantly elevated levels of hepatic cholesterol, with otherwise normal lipid composition. Subsequent inoculation of the mice with FluB significantly increased mortality rate. The combined Tox + FluB treatment had several significant effects on liver lipids, including a transient increase in phospholipid (PL) content, a reduction in neutral glycerides and persistently high cholesterol levels. Abnormalities in fatty acid profiles included an apparent elevation in medium chain fatty acids and increased ratios of PL arachidonic to docosahexaenoic acids. Histologically, there was no evidence of fat accumulation in the liver; however, hepatic mitochondria had severe structural abnormalities characteristic of RS. These studies demonstrate that chemical-dependent enhancement of viral virulence is associated with significant alterations of hepatic lipids. We believe that these abnormalities are related to mitochondrial structural damage in RS despite the absence of hepatic steatosis.

Animals↗
PubMed1987

The aminopyrine breath test, an inadequate early indicator of methotrexate-induced liver disease in patients with psoriasis.

The aminopyrine breath test has been shown to be a sensitive noninvasive indicator of liver cell dysfunction. In a search for a noninvasive method of monitoring the effects of methotrexate therapy, we have investigated the use of the aminopyrine breath test in patients receiving methotrexate for the treatment of severe psoriasis. The [14C]-aminopyrine breath test was performed in 20 normal control subjects, 32 patients with psoriasis receiving methotrexate therapy, and 8 patients with histologically confirmed cirrhosis of differing etiology. Eighteen patients on methotrexate had liver biopsies classified as grade I changes, 6 patients as grade II, and 8 patients as grade III. The normal value for the breath test was 11.0 +/- 1.6% (mean +/- 1 SD). The mean [14C]-CO2 excretion (8.3 +/- 4.4%) of the 8 patients with grade III liver disease was significantly different from the control subjects (p less than 0.02), and those with grade I liver changes (p less than 0.04). The aminopyrine breath test was only able to detect the later severe stages of methotrexate hepatotoxicity, grade III, when fibrosis occurs, before established cirrhosis was present. Our data suggests that the aminopyrine breath test is not a sensitive indicator for the detection of early methotrexate-induced hepatotoxicity, (stages I and II), but will detect the precirrhotic stage III change. Consequently, we recommend that a liver biopsy should be performed annually in all psoriatic patients receiving methotrexate, to detect histological damage, especially when the aminopyrine breath test score falls below the 95% confidence limits of normal.

Aminopyrine↗
PubMed1986

Biochemical and morphological characteristics of a mouse model of Reye's syndrome induced by the interaction of influenza B virus and a chemical emulsifier.

One theory of the etiology of Reye's syndrome is that environmental toxins predispose the child to react abnormally to virus infection. Influenza B is the most commonly implicated virus. Suckling mice were exposed to a surfactant, Toximul MP8, either by a single intraperitoneal injection or by repeated applications to the skin. At various times after exposure, the mice were infected intranasally with influenza B virus. Mice exposed to a combination of chemical and virus had a higher mortality rate than that of the control groups. Serum ammonia levels were elevated and the mitochondrial urea cycle enzyme, ornithine transcarbamylase, had reduced activity in the livers of mice exposed to Toximul and infected with virus. The hepatocyte cytoplasmic urea cycle enzyme concentrations were variable. Livers of the animals with "chronic" skin application of Toximul followed by virus infection showed mitochondrial swelling and breakdown of cristae. Those animals who received one intraperitoneal injection of Toximul and those infected with virus alone showed either negative or mild morphologic changes in the liver. We conclude that young mice exposed to a chemical emulsifier and subsequently to influenza B develop histomorphic and urea cycle changes, as well as hyperammonemia analogous to human Reye's syndrome.

Ammonia↗
PubMed1984

Model systems demonstrating the volatile mutagenicity and carcinogenicity of sodium nitrite in rats.

Volatile mutagens derived from sodium nitrite buffered at various pH values or in the presence of human feces were detected using Ames Salmonella tester strain TA 1535 on petrie plates inverted over samples. Volatile mutagenicity increased as the pH decreased and was primarily a function of the nitrous acid produced from sodium nitrite and hydrogen ions. Sodium nitrite administered intracecally to 3 Wistar rats through surgically implanted cannula caused tumors (fibrosarcoma: 1/3 and squamous cell, 2/3). The possible role of nitrite-derived mutagens in GI cancer is discussed.

Animals↗
PubMed1982

Acute fatty liver of pregnancy.

Acute fatty liver of pregnancy (AFLP) is rare and is peculiar to the latter half of pregnancy. Despite the high rates of death among affected mothers and their fetuses, early recognition of the disease and immediate delivery of the infant may improve the chances of survival. This paper describes a case of AFLP, characterized by a rapid decrease in the size of the liver, a greatly prolonged prothrombin time and minimal increases in the serum transaminase levels, in which an immediate cesarean section followed by vigorous supportive care led to survival of both mother and infant. It is clear that guidelines on treatment are necessary if the management of such cases is to be successful.

Acute Disease↗
PubMed1982

Liver adenoma with granulomas. The appearance of granulomas in oral contraceptive-related hepatocellular adenoma and in the surrounding nontumorous liver.

A 31-year-old woman who had taken oral contraceptives regularly for seven years was found to have a hepatocellular adenoma in the left lobe of her liver. An unusual microscopic feature of the resected specimen was the presence of numerous noncaseating, epithelioid granulomas in both the adenoma and the surrounding nontumorous liver. The literature contains brief mentions of granulomas occurring within an occasional hepatocellular adenoma, but a search uncovered no reports of granulomas occurring in both the tumor and the surrounding nontumorous liver. This further evidence of the occurrence of epithelioid granulomas with hepatocellular adenomas suggests a possible relationship between tumor antigens and the granulomatous response.

Adenoma↗
PubMed1981

Severe penicillin-induced cholestasis in a 91-year-old woman.

An elderly woman was admitted for treatment of severe stasis ulceration, associated with varicose veins. One course of cloxacillin was given orally followed by a second course of penicillin-G to eradicate persistant hemolytic streptococcal skin infection. Deep progressive jaundice subsequently developed due to intrahepatic cholestasis and persisted for several weeks before resolution. Having excluded a progressive extrahepatic malignant lesion by appropriate investigations, the diagnosis was substantiated by classical changes present in a percutaneous liver biopsy.

Acute Disease↗
PubMed1980

Colorectal cancer in Jordan and Nova Scotia: a comparative epidemiologic and histopathologic study.

A comparative study of colorectal adenocarcinoma was undertaken among the populations of Jordan and Nova Scotia, Canada. The incidence of this cancer was 13 (colon 6, rectum 7) and 53 (colon 31, rectum 22) per 100,000 males aged 35--64 years, respectively. Colonic tumors (excluding rectosigmoid) showed left-sided preponderance in Jordanians and right-sided preponderance in Nova Scotians. Age average at diagnosis was 49 years in Jordanians (colon 47 years and rectum 50 years) and 66 years in Nova Scotians (colon 67 years and rectum 63 years), with peaks in the fifth and seventh decades and a male to female ratio of 1.3:1 and 1:1, respectively. The mucinous type accounted for 31 and 13% of colorectal adenocarcinomas in Jordanians and Nova Scotians, respectively, of which the signet-cell type accounted for 14 and 2% of the total number, respectively. The actual incidence rate of mucinous carcinoma, however, was higher among Nova Scotians. In both groups, mucinous carcinoma showed predilection for females and rectal signet-cell carcinoma showed bias toward younger females. The authors believe that the significantly different epidemiologic and morphologic features of colorectal cancer demonstrated in these two communities could shed light on possible etiologic influences, such as dietary habits or other environmental factors.

Adenocarcinoma↗
PubMed1979

A chylous mesenteric cyst and a study of its contents.

A case of a patient with a large chylous cyst in the mesentery of the small intestine is presented. After excision of the cyst, the chyle was analyzed with special reference to its protein and lipid content. The composition of the chyle compared with that of intestinal lymph of experimental animals suggests that the fluid in the cyst has undergone concentration in terms of protein.

Adult↗