Search PubMed⌕ Search

Biomedical subjects

T J Layden

Publications and source records attributed to T J Layden.

At least 19 recordsLinked to original sources
PubMed1999

Is the presence of surgically treatable coronary artery disease a contraindication to liver transplantation?

Advanced coronary artery disease has been traditionally considered an absolute contraindication to orthotopic liver transplantation where chronic liver failure significantly increases the surgical risk for coronary artery bypass grafting. Performing a simultaneous coronary artery bypass grafting and liver transplant is a theoretically attractive strategy in liver transplant candidates with coronary artery disease in need of revascularization. In the present article, we report a successful simultaneous coronary artery bypass grafting and orthotopic liver transplant with 1-yr post-operative follow-up and we discuss the rationale for this approach. In selected cases, the presence of advanced coronary artery disease should not be considered an absolute contraindication to liver transplantation.

Carcinoma, Hepatocellular↗
PubMed1999

Molecular cloning, tissue distribution, and functional expression of the human Na(+)/H(+) exchanger NHE2.

In the present report, we describe the cloning of a human colonic cDNA that describes the full-length Na(+)/H(+) exchanger (NHE) 2 coding region. The human NHE2 (hNHE2) cDNA encodes for a polypeptide of 812 amino acids with a 90% overall identity to both rabbit and rat NHE2 isoforms. In comparison with SLC9A2, recently reported as the human NHE2, the hNHE2 polypeptide is 115 amino acids longer in the NH(2)-terminal end and shows only an 84% DNA nucleotide sequence identity. Northern blot analysis revealed that hNHE2 message has an uneven tissue distribution, with high levels in the skeletal muscle, colon, and kidney and lower levels in the testis, prostate, ovary, and small intestine. Protein expression studies with hNHE2 clone showed that a 75-kDa protein was expressed. Stable expression of transfected full-length hNHE2 cDNA in Na(+)/H(+) exchange-deficient LAP1 cells exhibited Na(+)-dependent pH recovery after an acid prepulse that was inhibited by 0.1 mM amiloride. These data indicate that this cDNA is the true human NHE2 cDNA and that the encoded protein is capable of catalyzing Na(+)/H(+) exchange activity.

Amino Acid Sequence↗
PubMed1998

Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy.

To better understand the dynamics of hepatitis C virus and the antiviral effect of interferon-alpha-2b (IFN), viral decline in 23 patients during therapy was analyzed with a mathematical model. The analysis indicates that the major initial effect of IFN is to block virion production or release, with blocking efficacies of 81, 95, and 96% for daily doses of 5, 10, and 15 million international units, respectively. The estimated virion half-life (t1/2) was, on average, 2.7 hours, with pretreatment production and clearance of 10(12) virions per day. The estimated infected cell death rate exhibited large interpatient variation (corresponding t1/2 = 1.7 to 70 days), was inversely correlated with baseline viral load, and was positively correlated with alanine aminotransferase levels. Fast death rates were predictive of virus being undetectable by polymerase chain reaction at 3 months. These findings show that infection with hepatitis C virus is highly dynamic and that early monitoring of viral load can help guide therapy.

Alanine Transaminase↗
PubMed1998

Impact of alcohol on the histological and clinical progression of hepatitis C infection.

In patients infected with the hepatitis C virus (HCV), 20% to 30% will progress to cirrhosis in over two to three decades. Viral and host factors that are important in the clinical and histologic progression of HCV infection are not entirely certain. It has been suggested that liver disease is worse in alcoholics infected with HCV. In the present retrospective study, we examined the effect of moderate alcohol intake on the histologic and clinical progression of HCV infection and assessed whether other variables such as gender, length of exposure, mode of exposure, HCV RNA levels, and ferritin levels also independently impacted disease progression. Liver biopsies were analyzed for the degree of fibrosis, presence of cirrhosis, and histologic activity by using the Histologic Activity Index of Knodell. Patients were divided into two groups based on whether their alcohol intake was significant or not significant. Significant alcohol intake was defined as > 40 g alcohol/day in women and > 60 g of alcohol/day in men for > 5 years. Groups were further divided based on the decades of exposure to HCV. There was no difference in the age or length of exposure to HCV in the alcohol and the alcohol-free group. HCV RNA serum levels, ferritin levels, and viral genotypes were similar in both groups. There was a two- to threefold greater risk of liver cirrhosis and decompensated liver disease in the alcohol group. Also, the rate to which subjects developed cirrhosis was faster in the alcohol group with 58% being cirrhotic by the second decade as opposed to 10% being cirrhotic in the nonalcohol group by the second decade. The histologic and clinical acceleration of liver disease was independent of the mode of exposure or sex. In summary, alcohol intake is an independent risk factor in the clinical and histologic progression of HCV infection.

Adult↗
PubMed1998

Combined coronary bypass and liver transplantation: technical considerations.

Combined coronary artery bypass grafting and orthotopic liver transplantation was carried out successfully in a 58-year-old man with angina pectoris and end-stage liver disease. To date, only 2 similar cases have been documented worldwide whereby the transplantation was performed either during cardiopulmonary bypass or with femoral-to-axillary venovenous bypass initiated at the termination of cardiopulmonary bypass. In this report we describe our experience with a simplified one-exposure approach for the combined operation using cardiopulmonary bypass in tandem with percutaneous femoral-to-right atrial venovenous bypass.

Angina Pectoris↗
PubMed1998

The inaccuracy of duplex ultrasonography in predicting patency of transjugular intrahepatic portosystemic shunts.

BACKGROUND & AIMS: A prospective double-blinded study with preset sonographic criteria has not been performed to assess the accuracy of duplex ultrasonography in determining the patency of transjugular intrahepatic portosystemic shunts (TIPS). The purpose of this study was to determine the sensitivity and specificity of duplex ultrasonography in predicting shunt malfunction using accepted preset sonographic criteria. METHODS: Sixty ultrasonographic and venographic follow-up comparisons were made on 38 cirrhotic patients who had undergone TIPS placement for variceal bleeding (n = 28) or intractable ascites (n = 10). Ultrasonographic results were analyzed by one of two board-certified ultrasonographers without knowledge of venographic findings. RESULTS: Of the 31 occluded (n = 8) and stenotic (n = 23) shunts, ultrasonography accurately predicted a shunt malfunction (occlusion or stenosis) in only 11 studies and incorrectly predicted patency in 20. Compared with venography, ultrasonography had a sensitivity of 35% and a specificity of 83% in predicting TIPS stenosis or occlusion. CONCLUSIONS: These results suggest that duplex sonography is not a sensitive test in predicting the presence of a hemodynamically significant stenosis and that shunt status should be assessed by venography and direct portal pressure measurements until a more reliable and proven noninvasive ultrasonographic criterion is devised.

Adult↗
PubMed1998

Acute acid exposure increases rabbit esophageal cell proliferation.

In the present study we examined whether an acute infusion of HCl into the esophagus of rabbits would cause an increase in esophageal cellular proliferation independent of morphologic evidence of cell injury. To examine this question, the distal two thirds of the rabbit esophagus was infused for 1 hour with either 40 mmol/L HCl or NSS (control), and cellular proliferation was studied 24 and 48 hours later by using bromodeoxyuridine (BrDu) to label the nuclei of dividing cells and ornithine decarboxylase (ODC) enzyme activity as a biochemical index of cell division. Although there was no gross or microscopic evidence of cell necrosis or mucosal inflammation 24 hours after H+ infusion, BrDu labeling of basal cell nuclei was significantly greater 24 hours after H+ infusion (31%+/-6%) as compared with that in control animals infused with NSS (15%+/-4%). This increase in labeling index was paralleled by a threefold greater ODC enzyme activity at 24 hours with H+ infusion. Rete pegs were infrequent in control tissues (4+/-4 rete pegs per 100 microm of esophageal length) or in animals examined 24 hours after acid exposure (4+/-2 rete pegs per 100 microm). However, rete pegs were very prominent 48 hours after acid infusion (22+/-6 rete pegs per 100 microm). A short exposure to acid can cause a significant increase in mucosal proliferation independent of injury, suggesting that esophageal cell acidification either directly or indirectly acts as a tissue mitogen.

Animals↗
PubMed1998

Early HCV RNA values after interferon predict response.

The aim of this study is to determine in patients infected with hepatitis C virus (HCV) whether early HCV RNA measurements at 48 hr following standard doses of interferon-alpha (IFN-alpha) (3 million IU) would predict response during six months of therapy. Twenty-three patients with HCV were treated with IFN-alpha 3 million IU three times a week and HCV RNA levels were quantified by branched-chain (b-)DNA analysis at baseline and 24 and 48 hr following IFN-alpha and at one, three, and six months. Mean baseline HCV RNA levels significantly declined from 6.0 +/- 1.6 Meq/ml at baseline to 2.4 +/- 0.7 Meq/ml 24 hr after IFN-alpha. However, HCV RNA values increased to 4.3 +/- 1.1 Meq/ml by 48 hr. Mean HCV RNA values at one and six months were not significantly lower than 48-hr values. In six patients in whom HCV RNA was negative by bDNA at 48 hr, three were negative by polymerase chain reaction at six months. Of the 17 patients who were positive by bDNA at 48 hr, all were positive at one and three months; and in the nine of nine who continued therapy for six months, there was no further decrease in HCV RNA levels. In patients receiving standard doses of IFN-alpha (3 million IU), serum RNA values 48 hr after the first injection predict long-term response.

Female↗
PubMed1998

Cl- transport in an immortalized human epithelial cell line (NCM460) derived from the normal transverse colon.

Cells of a newly described, immortalized, epithelial, human transverse colonic cell line, NCM460, reach approximately 90% confluence on plastic and develop transepithelial resistances of 120-250 Omega . cm2 on porous substrates. Its utility as a model for the transverse human colon was validated by comparing second messenger-mediated Cl- transport, using the fluorescent probe 6-methoxy-quinolyl acetoethyl ester, in NCM460 cells and colonocytes isolated from human transverse crypts. Basal Cl- influx was increased (P < 0.01) by PGE1 (1 microM), forskolin (1 microM), 8-bromoadenosine 3'5'-cyclic monophosphate (100 microM), heat-stable Escherichia coli enterotoxin (STa; 1 microM), 8-bromoguanosine 3'5'-cyclic monophosphate (100 microM), histamine (1 microM), and phorbol 12,13-dibutyrate (1 microM) in both cell types. The Cl- channel blocker diphenylamine 2-carboxylic acid (50 microM) and the Na+-K+-2Cl- cotransport inhibitor furosemide (1 microM), but not the K+ channel blocker Ba2+ (3 mM), inhibited these Cl- permeabilities. These cells possess transcripts for cystic fibrosis transmembrane conductance regulator, Na+-K+-2Cl- cotransporter, STa receptor, and intestine-specific cGMP-dependent protein kinase II. Thus cAMP-, cGMP-, and Ca2+-dependent secretagogues act on NCM460 and primary colonocytes to stimulate Cl- transport. This validates the utility of NCM460 as a model for transverse colonic crypts and is the first demonstration of a colonic cell line whose origin is known.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1997

Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa.

To determine if the clearance of hepatitis C genotype 1 virus (HCV) is dependent on the dose of interferon alfa-2b (IFN-alpha2b), the acute clearance of HCV after a single dose of either 3, 5, or 10 mIU of IFN-alpha was compared in patients with chronic hepatitis C. HCV-RNA levels following IFN-alpha administration were measured. At 24 hours, mean percentage serum viral reduction was 41.4%, 63.7%, and 85.5% for 3, 5, and 10 mIU, respectively (P < .001). At 48 hours, the mean viral reduction was consistently less than the reduction at 24 hours, averaging 22.9%, 61.9%, and 74.3%, respectively (P < .001), indicating that the drug effect diminishes before 48 hours. Regression analysis showed a positive correlation between dose and percent reduction of HCV-RNA levels (r = .6; P < .001). A mathematical model showed that such dose dependence is expected if IFN-alpha partially blocks viral production. Minimum clearance and production rates of HCV were estimated from measurements of HCV-RNA levels after the 10-mIU dose. HCV decay followed an exponential decline with a minimum estimate of the viral clearance rate constant of 2.8 per day, corresponding to a virion half-life of 0.3 days or less. A minimal estimate of the daily HCV production and clearance is 3.7 x 10(11) virions per day, indicating a high rate of replication and turnover. These results indicate that there is a dose-dependent effect of IFN-alpha in clearance of HCV genotype 1. Because the virion production rate is very rapid and because the current recommended dose of IFN-alpha (3 mIU) is often ineffective, larger doses should be considered to treat genotype 1-infected patients.

Adult↗
PubMed1997

Effect of obesity on pharmacokinetics and biologic effect of interferon-alpha in hepatitis C.

To examine potential adverse effects of obesity in reducing the response to interferon-alpha (IFN-alpha) in chronic hepatitis C (HCV), IFN-alpha and HCV RNA levels in serum and the 2',5'-oligoadenylate synthetase (2-5 OAS) levels in peripheral blood mononuclear cells (PBMC) were compared between six obese and five nonobese patients before and after a single, 10 mIU dose of IFN-alpha2b. There were no differences in the mean histologic activity index between the two groups. The maximal IFN concentration and the area under the serum IFN concentration-time curve were higher in nonobese patients. These two parameters were inversely correlated with body weight and body surface area. No differences were found in the mean reduction in HCV RNA levels between the two groups following IFN-alpha. The maximal 2-5 OAS level after treatment divided by the pretreatment 2-5 OAS level (2-5 OAS response ratio) was greater in the nonobese patients, suggesting stronger biologic response upon exposure to exogenous IFN-alpha in nonobese patients.

2',5'-Oligoadenylate Synthetase↗
PubMed1996

Calcium regulated chloride permeabilities in primary cultures of rabbit colonocytes.

To determine if calcium-dependent secretagogues directly act on epithelial cells to elicit Cl- secretion, their effects on Cl- transport and intracellular Ca(2+) concentrations ([Ca2+]i) were determined in primary cultures of rabbit distal colonic crypt cells. The Cl- sensitive fluorescent probe, 6-methoxyquinolyl acetoethyl ester, MQAE and the Ca(2+)-sensitive fluorescent probe, fura-2AM were used to assess Cl- transport and [Ca2+]i, respectively. Basal Cl- transport (0.274 +/- 0.09 mM/sec) was inhibited significantly by the Cl- channel blocker diphenylamine-2-carboxylate (DPC, 50 microM, 0.068 +/- 0.02 mM/sec; P < 0.001) and the Na+/K+/ 2Cl- cotransport inhibitor furosemide (1 microM, 0.137 +/- 0.04 mM/sec; P < 0.01). Ion substitution studies using different halides revealed the basal influx to be l- > F- > or = Cl- > Br-. DPC inhibited l- influx by approximately 50%, F- influx by 80%, Cl-influx by 85%, and Br- influx by 90%. Furosemide significantly inhibited influx of Br- (84%) and Cl- (81%) but not of F- and l-. The effects of agents known to alter biological response by increasing [Ca2+]i in other epithelial systems were used to stimulate Cl- transport. Cl- influx in mM/second was stimulated by 1 microM histamine (0.58 +/- 0.05), 10 microM neurotensin (2.07 +/- 0.32), 1 microM serotonin (1.63 +/- 0.28), and 0.1 microM of the Ca2+ ionophore A23187 (2.05 +/- 0.40). The Cl- permeability stimulated by neurotensin, serotonin, and A23187 was partially blocked by DPC or furosemide added alone or in combination. Histamine-induced Cl- influx was significantly inhibited by only furosemide. Indomethacin blocked histamine-stimulated Cl- permeability but had no effect on the actions of the other agents. These studies, focusing on isolated colonocytes without the contribution of submucosal elements, reveal that (1) histamine stimulates Cl- transport by activating the Na+/K+/2Cl- cotransporter via a cyclooxygenase-dependent pathway; (2) neurotensin, serotonin, and A23187 activate both Cl- channels and the cotransporter, and their actions are cyclooxygenase-independent.

Animals↗
PubMed1996

Intestinal distribution of human Na+/H+ exchanger isoforms NHE-1, NHE-2, and NHE-3 mRNA.

The identity of Na+/H+ exchanger (NHE) isoforms in the human small intestine and colon and their role in vectorial Na+ absorption are not known. The present studies were undertaken to examine the regional and vertical axis distribution of NHE-1, NHE-2, and NHE-3 mRNA in the human intestine. Ribonuclease protection assays were used to quantitate the levels of mRNA of these isoforms in various regions of the human intestine. In situ hybridization technique was used to localize NHE-2 and NHE-3 mRNA in the colon. The NHE-1 isoform message was present uniformly throughout the length of the human intestine. In contrast, mRNA levels for human NHE-2 and NHE-3 isoforms demonstrated significant regional differences. The NHE-3 abundance was found in decreasing order: ileum > jejunum > proximal colon = distal colon. The NHE-2 message level in the distal colon was significantly higher than in the proximal colon but was evenly distributed in the small intestine. In addition, NHE-2 mRNA was present in surface epithelial cells as well as in cells of the crypt region, suggesting the presence of NHE-2 message throughout the vertical axis of the colonic crypts. In contrast, NHE-3 mRNA was localized to surface colonocytes in the proximal colon. On the basis of this tissue-specific localization of NHE-2 and NHE-3 mRNA, it can be speculated that the relative contribution of NHE-2 and NHE-3 isoforms in Na+ absorption in the human intestine may be region specific, and these putative apical isoforms may be differentially regulated.

Amino Acid Sequence↗
PubMed1995

NHE-1 isoform of the Na+/H+ antiport is expressed in the rat and rabbit esophagus.

BACKGROUND & AIMS: Rabbit esophageal cells show an amiloride-sensitive Na+/H+ antiporter activity. Several distinct molecular isoforms of the Na+/H+ exchanger family (NHE) are reported to be present in the gastrointestinal tract of rats and rabbits. The aim of this study was to examine which isoforms are present in rabbit and rat esophageal cells and whether this isoform could be up-regulated by serum factors. METHODS: Specific primers designed from the rat NHE-1-4 and the rabbit NHE-1-3 isoform sequences were used for reverse-transcription polymerase chain reaction analysis with RNA from rabbit and rat esophageal cells. Ribonuclease protection assay was used to determine the serum-induced up-regulation of NHE-1. Antibodies raised against the NHE-1 C-terminal fragment were used for Western blotting with rabbit esophageal membranes. RESULTS: In both the rat and rabbit esophagus, only the NHE-1 isoform messenger RNA could be detected. The NHE-1 messenger RNA, detected in rabbit esophageal cells grown from tissue explants, was up-regulated by serum factors. The antibody detected a 95-kilodalton protein in esophageal cell membranes. CONCLUSIONS: The rabbit and rat esophagus exclusively express the NHE-1 isoform, hypothesized to be involved in cytoplasmic pH regulation. Therefore, the results of this study suggest a role for NHE-1 in protecting cells against gastric acid that is refluxed into the esophagus.

Animals↗
PubMed1995

Diagnosis and management of fulminant hepatic failure.

Fulminant hepatic failure is defined as the development of hepatic encephalopathy within 8 weeks of the onset of illness. While there are many causes of FHF, viral hepatitis, particularly hepatitis B, remains the most common etiology. Several drugs and toxins can also lead to FHF, most notably acetaminophen. Even with improvements in ICU care, mortality remains very high for these patients. Conservative management focuses on invasive monitoring and the prevention and treatment of complications like cerebral edema, infection, renal failure, and coagulopathy. Only orthotopic liver transplantation has reduced mortality from 80% to 30% to 50%. Therefore, the goals of management and treatment now include determining which patients are appropriate for liver transplant and finding a donor in a timely fashion.

Acetylcysteine↗
PubMed1994

Hepatitis C infection in potential recipients with normal liver biochemistry does not preclude renal transplantation.

The hepatitis C virus (HCV) may be an important cause of chronic liver disease in renal transplant recipients. We investigated retrospectively the incidence and outcome of HCV infection in long-term renal transplant recipients and patients on hemodialysis. Stored, pretransplant sera of transplant recipients with normal liver biochemistry at surgery were tested for hepatitis C by a second-generation enzyme immunoassay. Hemodialysis patients were tested by a first-generation enzyme-linked immunosorbent assay (ELISA) against c100-3. We studied 252 renal transplant recipients and 58 hemodialysis patients followed for 65 +/- 10 months and 26 +/- 6 months, respectively. Fifteen percent (38/252) of the transplant recipients were HCV positive as were 3/58 (5%) of the hemodialysis patients. Overt liver disease occurred in 22/252 (8.7%) transplant recipients and none in the hemodialysis group. Thirty-six percent (8/22) of transplant recipients with overt liver disease were HCV positive. No HCV-positive patients died of liver failure. Of six biopsies in the HCV-positive transplant group, two had histological evidence of CAH. CAH was seen in six of eight biopsies in the HCV-negative transplants and two of these latter patients progressed to cirrhosis. No hemodialysis patients had clinical or histological evidence of chronic liver disease. Two HCV-negative transplant patients died of liver failure, while no deaths related to liver disease occurred in hemodialysis patients regardless of HCV status. We conclude that hepatitis C may cause chronic hepatitis in renal transplant patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗