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Biomedical subjects

M J Bahr

Publications and source records attributed to M J Bahr.

At least 19 recordsLinked to original sources
PubMed2007

Induction of hepatitis C virus (HCV)-specific T cells by needle stick injury in the absence of HCV-viraemia.

BACKGROUND: The risk of hepatitis C virus (HCV) infection after occupational exposure is low with seroconversion rates between 0 and 5%. However, factors associated with natural resistance against HCV after needle stick injury are poorly defined. HCV-specific T-cell responses have been described in cross-sectional studies of exposed HCV-seronegative individuals. MATERIALS AND METHODS: In this study, we prospectively followed 10 healthcare professionals who experienced an injury with an HCV-contaminated needle. Blood samples were taken on the day or the day after the event and at different time points during follow-up for up to 32 months. HCV-specific T-cell responses were investigated directly ex vivo and in T-cell lines. RESULTS: None of the individuals became positive for HCV-RNA in serum tested with the highly sensitive transcription-mediated amplification (TMA)-assay or in peripheral blood mononuclear cells (PBMC). All of them remained anti-HCV negative throughout follow-up. At the time of injury, HCV-specific CD4+ T-cell responses were already detectable in two individuals and became detectable thereafter in three additional persons. Transient HCV-specific CD8+ T-cell responses developed in two HLA-A2 positive patients, which became negative until the most recent follow-up after 5 and 17 months, respectively. CONCLUSION: We demonstrate the development of HCV-specific T cells in HCV-exposed individuals after needle stick injury indicating subinfectious exposure to HCV. T-cell immunity against HCV may contribute to the low prevalence of HCV in medical healthcare professionals in Western countries.

Adult↗
PubMed2005

[Molecular therapy in gastroenterology and hepatology].

During recent years, molecular techniques have significantly impacted our understanding and therapeutic concepts in gastrointestinal and liver disease. In a number of diseases, diagnostic work-up includes molecular data that supplements the phenotypical evaluation. This includes monogenic diseases as well as the identification of genetic risk factors (e. g. NOD2/CARD15 mutation in Crohn's disease) and viral disease. Attempts to replace liver transplantation in hereditary liver disease by targeted molecular interventions (e. g. via viral vectors) are still experimental, but the associated techniques have improved considerably. The molecular identification of therapeutic targets was followed by the development of specifically tailored therapeutics. These agents are mainly used in the treatment of chronic inflammatory bowel disease and gastrointestinal tumors.

Animals↗
PubMed2005

Severe hearing loss after liver transplantation.

Little is known about hearing impairment in patients after organ transplantation. Few cases of hearing loss associated with different immunosuppressants have been published. To evaluate severe hearing impairment in patients after liver transplantation (OLT), all living adult patients in need of a hearing aid were analyzed. Out of 521 transplanted patients, 25 (5%) were identified with hearing aids. Nine (36%) of these patients either suffered from hearing loss prior to OLT or experienced risk factors such as ototoxic drugs. Of the remaining 16 patients who developed severe hearing loss after OLT (64%), half were men. Mean age was 42 +/- 18 years at OLT, which took place 8 +/- 4 years ago. Main transplantation indication was virus-induced cirrhosis (44%). In 14/16 (88%) patients, the hearing aid was bilateral. In 50% of patients, the hearing aid was necessary within 2 years post-OLT. Additional tinnitus was present in 9/16 patients (56%), otalgia in three patients (19%). Four patients (25%) reported a history of sudden deafness. In three of them, an association with high levels of calcineurin inhibitors was found. The proportion of patients receiving tacrolimus (50%) was relatively higher than those receiving cyclosporine (50%) compared to control patients (28% respectively 64%, P < .05). In conclusion, a high incidence of severe hearing loss was found in patients after liver transplantation. In most patients, onset of hearing loss is early and bilateral, suggesting a dose-dependent toxicity. The pathogenetic role of different immunosuppressants remains to be evaluated.

Adult↗
PubMed2005

Retrospective analysis of the impact of immunosuppression on the course of recurrent hepatitis C after liver transplantation.

INTRODUCTION: In a substantial proportion of patients, recurrent hepatitis C after liver transplantation (OLT) rapidly progresses to graft cirrhosis. The role of different immunosuppressive schemes is not well evaluated. PATIENTS AND METHODS: The clinical course of 130 patients with recurrent hepatitis C after OLT was retrospectively analyzed. Mean trough levels of calcineurin inhibitors and cumulative doses of the remaining immunosuppressants were calculated. The results were compared with liver function tests, histological fibrosis progression, and survival. RESULTS: Survival and fibrosis progression were similar in patients with tacrolimus and cyclosporine and did not correlate with mean trough levels. In contrast, the application of azathioprine (mean dose of more than 25 mg/d during the first 3 months after OLT) was associated with significantly less progression of fibrosis (P = .01). Administration of azathioprine after the early postoperative phase was not related to the long-term outcome. The dose of prednisolone in the long-term course after OLT significantly correlated with the rate of fibrosis progression (P = .008). CONCLUSIONS: The clinical course of recurrent hepatitis C was variable. Survival and fibrosis progression did not correlate with the type or trough level of calcineurin inhibitors. Azathioprine early in the course after OLT and prolonged administration of prednisolone were associated with less fibrosis progression.

Female↗
PubMed2005

[Splenosis--important differential diagnosis in splenectomized patients presenting with abdominal masses of unknown origin].

A 40-year-old female patient was admitted for work-up of multiple abdominal masses. The lymphoma-mimicking tumors were detected accidentally during an ultrasound course. The past medical history was unremarkable besides a status post-traumatic splenic rupture and splenectomy. The patient was asymptomatic, especially there were no complaints of fever, night sweats or weight loss. Laboratory tests did not show pathological results. Ultrasound of the abdomen revealed multiple hypoechoic mesenterial and peritoneal enlarged tumors as well as a subhepatic mass (30 x 20 mm). Transmission computed tomography (CT) showed a normal chest, excluded abnormal thoracal masses and confirmed the multiple abdominal nodules. Microparticles were trapped only by tissue with phagocytosis function as cells of the reticulohistiocytary system in liver and spleen. Uptake of (99 m)Tc-labeled microparticles is specific for splenic tissue. All abdominal masses were detectable by single photon emission computed tomography (SPECT) after intravenous administration of this radiotracer. Ultrasound-guided biopsy proved the presence of spleen tissue with follicular hyperplasia. In conclusion, we report a case of post-traumatic splenosis. In 16 - 67 % of patients who experienced traumatic splenic rupture autotransplanted spleen tissue can be detected. Splenosis therefore is an important differential diagnosis of abdominal masses in splenectomized patients.

Abdomen↗
PubMed2004

[Liver transplantation for metabolic liver disease in adulthood].

The clinical presentation of metabolic liver disease is highly variable, covering acute liver failure, liver cirrhosis, hepatic cancer and various extrahepatic manifestations. Both natural course and prognosis after liver transplantation are substantially influenced by extrahepatic manifestations. In many types of metabolic liver disease, timely diagnosis allows for successful medical treatment. However, progressive liver failure and severe extrahepatic damage can be the indication for liver transplantation. In general, standard transplantation criteria also apply for metabolic liver disease. They have to be modified by disease-specific criteria, and extrahepatic damage may necessitate multiorgan transplantation. The overall prognosis after liver transplantation for metabolic liver disease is favorable. Furthermore, several metabolic defects are phenotypically cured by liver transplantation. Alternative treatments like hepatocyte transplantation or gene therapy are still in the experimental stage.

Adult↗
PubMed2003

[Acute liver failure].

Acute liver failure is characterized by a dynamic clinical course associated with high mortality. The main prognostic determinant is the development of extrahepatic complications. Close monitoring is mandatory, and prophylactic measures to avoid complications should be initiated. In case of complications, early and aggressive treatment is indicated. To date, artificial liver support devices are still in the experimental phase. Liver transplantation should be considered in patients with predictors of a poor spontaneous prognosis. Therefore, a transplant center should be contacted in every case of acute liver failure.

Emergencies↗
PubMed2001

Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study.

BACKGROUND: Renal dysfunction is a major complication of long-term immunosuppressive therapy with calcineurin inhibitors (CNI) in liver-transplant recipients. We undertook a randomised study to assess the safety and efficacy of CNI withdrawal and replacement by mycophenolate mofetil. METHODS: 28 people who had had renal dysfunction attributable to suspected CNI toxicity after liver transplantation participated in the study. We replaced CNI with mycophenolate mofetil in a stepwise pattern in half the group (study patients); the other half (controls) stayed on CNI immunosuppression. Renal function, blood pressure, uric acid, and blood lipids were measured before and 6 months after study entry. Side-effects of medication and graft function were recorded throughout the study. FINDINGS: At the end of the study, mean (SD) serum creatinine had fallen by 44.4 (48.7) micromol/L in study patients compared with 3.1 (14.3) micromol/L in controls; a mean difference of 41.3 micromol/L (95% CI 12.4-70.2). Moreover, systolic and diastolic blood pressure, and serum uric acid decreased significantly in the study group but not in the control group (mean [95% CI] between group differences 10.8 mm Hg [3.0-18.6], 5.0 mm Hg [0.9-9.2], and 83.1 micromol/L [12.7-153.6], respectively). There were no changes in cholesterol or triglyceride concentrations in either group. Side-effects were reported by eight of the study patients. Three reversible episodes of acute graft rejection occurred in study patients during mycophenolate mofetil monotherapy, whereas none occurred in the control group. INTERPRETATION: Substitution of CNI by mycophenolate mofetil can improve renal function, blood pressure, and uric acid concentration of liver-transplant patients, but there is an increased rejection risk with mycophenolate mofetil monotherapy.

Blood Pressure↗
PubMed2001

Lamivudine and low-dose hepatitis B immune globulin for prophylaxis of hepatitis B reinfection after liver transplantation possible role of mutations in the YMDD motif prior to transplantation as a risk factor for reinfection.

BACKGROUND/AIMS: Reinfection with hepatitis B virus (HBV) after liver transplantation (OLT) is associated with an unfavourable clinical course. Lamivudine/hepatitis B immune globulin (HBIG) combination treatment reduces reinfection rates. However, it is unclear at what time point lamivudine should be started and which HBIG doses are sufficient. METHODS: Twenty-one patients receiving combination treatment were studied. Lamivudine was started up to 16.5 months before OLT and continued thereafter. HBIG was started intraoperatively and continued according to anti-HBs-titers. Median follow-up after OLT was 20 months. RESULTS: Eleven patients received lamivudine pretreatment for >2 (median 6) months due to initial HBV-DNA-positivity (median 749 pg/ml). After initial lamivudine response HBV-DNA increased in two of them to concentrations above 10 pg/ml prior to OLT. Both had developed mutations in the YMDD motif and suffered from HBV reinfection 13 and 75 days postoperatively. Individual HBIG consumption was highly variable (range 787-4,766 lU/month). Twenty-two percent of anti-HBs titers measured before HBIG administration were below 100 IU/l. CONCLUSIONS: Combined reinfection prophylaxis with lamivudine and HBIG is effective in patients with controlled viral replication at the time of OLT. However, pretransplantation lamivudine resistance is a risk factor for reinfection. Low dose HBIG maintenance therapy individualized according to anti-HBs-titers appears to be tenable.

Adolescent↗
PubMed2001

Decreased splanchnic oxygen uptake and increased systemic oxygen uptake in cirrhosis are normalized after liver transplantation.

The aim of this study is to (1) characterize the impact of orthotopic liver transplantation (OLT) on splanchnic and systemic oxygen uptake (VO(2)) in patients with liver cirrhosis, and (2) investigate possible influencing factors, as well as metabolic consequences, of reduced splanchnic VO(2) in patients with cirrhosis. Therefore, we measured systemic VO(2) (indirect calorimetry), portal pressure (hepatic venous pressure gradient), hepatic blood flow (HBF; primed continuous infusion of indocyanine green), and hepatic turnover (arteriohepatic venous concentration differences multiplied by HBF) of oxygen, glucose, free fatty acids (FFAs), and aromatic amino acids (AAAs) in 52 patients with advanced cirrhosis and 16 patients with a clinically stable long-term course after OLT. Systemic VO(2) was significantly increased in patients with cirrhosis (261 +/- 7 mL/min) and normalized after OLT (216 +/- 8 mL/min; P < .001). Arterial and hepatic venous oxygen saturation and splanchnic oxygen extraction (in percent) were not different between patients with cirrhosis and after OLT. Splanchnic VO(2) was decreased in patients with cirrhosis (41 +/- 3 mL/min, representing 16% +/- 1% of systemic VO(2)) and normalized after OLT (69 +/- 6 mL/min; P < .001, representing 32% +/- 3% of systemic VO(2); P < .001). In patients with cirrhosis, a decrease in HBF was associated with decreased splanchnic VO(2) (r = 0.74; P < .001). Conversely, decreased splanchnic VO(2) reflected a decrease in hepatic glucose production (r = 0.34; P = .01) and hepatic extraction of FFAs (r = 0.40; P < .01) and AAAs (r = 0.30; P < .05). These results show that (1) splanchnic and systemic VO(2) normalize after OLT, indicating correction of hepatic and extrahepatic metabolic derangements; (2) in cirrhosis, HBF becomes limiting for hepatic oxygen supply; and (3) impaired splanchnic VO(2) reflects a decrease in metabolic liver function.

Adult↗
PubMed2001

Three quantitative approaches to the diagnosis of abdominal pain in children: practical applications of decision theory.

BACKGROUND/PURPOSE: The authors compared 3 quantitative methods for assisting clinicians in the differential diagnosis of abdominal pain in children, where the most common important endpoint is whether the patient has appendicitis. Pretest probability in different age and sex groups were determined to perform Bayesian analysis, binary logistic regression was used to determine which variables were statistically significantly likely to contribute to a diagnosis, and recursive partitioning was used to build decision trees with quantitative endpoints. METHODS: The records of all children (1,208) seen at a large urban emergency department (ED) with a chief complaint of abdominal pain were immediately reviewed retrospectively (24 to 72 hours after the encounter). Attempts were made to contact all the patients' families to determine an accurate final diagnosis. A total of 1,008 (83%) families were contacted. Data were analyzed by calculation of the posttest probability, recursive partitioning, and binary logistic regression. RESULTS: In all groups the most common diagnosis was abdominal pain (ICD-9 Code 789). After this, however, the order of the most common final diagnoses for abdominal pain varied significantly. The entire group had a pretest probability of appendicitis of 0.06. This varied with age and sex from 0.02 in boys 2 to 5 years old to 0.16 in boys older than 12 years. In boys age 5 to 12, recursive partitioning and binary logistic regression agreed on guarding and anorexia as important variables. Guarding and tenderness were important in girls age 5 to 12. In boys age greater than 12, both agreed on guarding and anorexia. Using sensitivities and specificities from the literature, computed tomography improved the posttest probability for the group from.06 to.33; ultrasound improved it from.06 to.48; and barium enema improved it from.06 to.58. CONCLUSIONS: Knowing the pretest probabilities in a specific population allows the physician to evaluate the likely diagnoses first. Other quantitative methods can help judge how much importance a certain criterion should have in the decision making and how much a particular test is likely to influence the probability of a correct diagnosis. It now should be possible to make these sophisticated quantitative methods readily available to clinicians via the computer.

Abdominal Pain↗
PubMed2001

[Function of the immune system in liver cirrhosis].

Malfunction of the immune system at different levels is typical for patients with liver cirrhosis. Both non-specific as well as antigen-specific functions may be compromised. The best studied and clinically most important problem is the diminished clearance capacity of the reticulo-endothelial system in liver cirrhosis. This transfers into a significantly higher rate of bacterial infections associated with a poorer prognosis in these patients. The clinical relevance of concomitant immune disorders like neutrophil dysfunction is less clear. An impaired activation of natural killer cells (NK) and lymphokine-activated killer cells (LAK) may have a role in the development of hepatocellular carcinoma but additional studies are needed. Clinically important is a moderately reduced efficacy of standard immunization protocols, which can be overcome by an increased dose in most vaccines.

Bacterial Infections↗
PubMed2000

Improvement of acute and chronic renal dysfunction in liver transplant patients after substitution of calcineurin inhibitors by mycophenolate mofetil.

BACKGROUND: Renal dysfunction caused by treatment with the calcineurin inhibitors (CNI) is a major problem in the long-term course after liver transplantation. PATIENTS: In 22 liver graft recipients with renal dysfunction and stable graft function between 3 weeks and 12 years after transplantation, CNI were substituted by MMF at a final dose of 1.5-3 g/day between October 1996 and October 1998. METHODS: In a prospective non-randomized study, the development of renal function, the side effects of MMF medication, and the stability of liver function were analyzed for a mean follow-up of 15 months. Results. (1) MMF was withdrawn in four patients for major side effects between 1 and 7 months after study entry; eight patients had minor side effects. (2) Six months after study entry, renal function had improved in 17 of the 22 study patients; mean serum creatinine +/-SD (micromol/L) was 201+/-77 at entry and 153+/-65 after 3 months (P<0.001). (3) Improvement occurred in 11 of 15 patients with creatinine elevation > or =12 months and in 6 of 6 patients with creatinine elevation < or =6 months. (4) One patient developed transient liver dysfunction and a second required retransplantation for progressive cholestasis but without signs of rejection. CONCLUSIONS: In patients who undergo liver transplantation, substitution of CNI by MMF leads to improvement of acute as well as chronic renal dysfunction in most cases. Side effects of MMF may be limiting in some patients, and the immunological consequences remain to be studied.

Adult↗
PubMed1999

Control of the tissue inhibitor of metalloproteinases-1 promoter in culture-activated rat hepatic stellate cells: regulation by activator protein-1 DNA binding proteins.

In the injured liver hepatic stellate cells (HSCs) undergo a dramatic phenotypic transformation known as "activation" in which they become myofibroblast-like and express high levels of the tissue inhibitor of metalloproteinase 1 (TIMP-1). HSC activation is accompanied by transactivation of the TIMP-1 promoter. Truncation mutagenesis studies delineated a minimal active promoter consisting of nucleotides -102 to +60 relative to the major start site for transcription. Removal of an AP-1 site located at nucleotides -93 to -87 caused almost a complete loss of promoter activity. Analysis of AP-1 DNA binding activities during culture activation of HSCs initially indicated transient expression of proteins capable of forming a low mobility AP-1 DNA binding complex (LMAP-1). LMAP-1 was maximally induced at 24 hours of culture and then fell to undetectable levels at 120 hours. Western blot studies showed that both c-Fos and c-Jun underwent similar transient inductions. These temporal changes in c-Fos and c-Jun activities were unexpected because TIMP-1 mRNA expression is not detected in HSCs until culture day 3 to 5 and is thereafter sustained at a high level. Previous work in other cell lineages has established a key role for Pea3 binding proteins (Ets-1) in AP-1 mediated transactivation of the TIMP-1 promoter. We show that HSCs express relatively low levels Ets-1 and Ets-2 and show that mutagenesis of the Pea3 DNA binding site in the TIMP-1 promoter has less than a twofold effect on its activity in activated HSCs. Further analysis of AP-1 DNA binding activities in 7- to 14-day culture activated HSCs led to the discovery of high mobility AP-1 complexes (HMAP-1). HMAP-1 DNA binding activities were sequence specific with respect to AP-1 and absent from freshly isolated HSCs. Supershift EMSA and Western blot studies identified JunD, Fra2, and FosB as potential components of the HMAP-1. Mutations of the AP-1 site of the TIMP-1 promoter that prevented formation of HMAP-1 caused a 70% loss of activity in transfected activated HSCs. Taken together the data indicate that sustained upregulation of TIMP-1 gene expression may be at least partially controlled by a novel AP-1 dependent regulation of TIMP-1 promoter activity.

Animals↗
PubMed1999

Persistent activation of nuclear factor-kappaB in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of IkappaB family proteins.

Rat hepatic stellate cells (HSC) cultured in serum-containing medium underwent a rapid (3-hour) classical induction of p50:p65 and p65:p65 nuclear factor-kappaB (NF-kappaB) dimers. Subsequent culturing was associated with prolonged expression of active p50:p65 and persistent induction of a high-mobility NF-kappaB DNA binding complex consisting of potentially novel Rel-like protein(s). Formation of the latter complex was competed for by specific double-stranded oligonucleotides, was up-regulated by treatment of HSCs with tumor necrosis factor alpha (TNF-alpha), and was maintained at basal levels of expression by a soluble HSC-derived factor. An NF-kappaB-responsive CAT reporter gene was highly active in early cultured HSCs but was also trans-activated at a lower but significant level in longer-term cultured cells and could be completely suppressed by expression of dominant negative IkappaB-alpha. Physiological significance of the lower persistent NF-kappaB activities was also demonstrated by the ability of long-term cultured HSCs to support the activity of the NF-kappaB-dependent human intercellular adhesion molecule-1 (ICAM-1) promoter. Freshly isolated HSCs expressed high levels of IkappaB-alpha and IkappaB-beta. Culture activation was accompanied by a long-term reduction in levels of IkappaB-alpha with no detectable expression in the nuclear fraction of cells, under these conditions p50:p65 was detected in the nucleus. IkappaB-beta expression was transiently reduced and, upon replenishment, was associated with appearance of a lower-mobility IkappaB-beta antibody-reactive species. Bcl3 expression was absent in freshly isolated HSC but was induced during culturing and became a persistent feature of the activated HSC. Inhibition of NF-kappaB DNA binding activity by gliotoxin was associated with increased numbers of apoptotic cells. We suggest that activation of NF-kappaB in cultured HSC is required for expression of specific genes associated with the activated phenotype such as ICAM-1 and may be antiapoptotic for rat HSCs.

Adipocytes↗
PubMed1999

Differential regulation of extracellular matrix synthesis during liver regeneration after partial hepatectomy in rats.

Little is known about the modulation of the extracellular matrix (ECM) during liver regeneration. We studied the temporospatial expression of procollagens and of matrix metalloproteinases (MMPs) and their physiological antagonists, the tissue inhibitors of metalloproteinases (TIMPs) after two-thirds partial hepatectomy (PH) by Northern blot analysis and in situ hybridization. The entry of hepatocytes into the S-phase at 24 hours after PH was accompanied by a peak (sixfold induction) of hepatic TIMP-1 RNA levels that steadily declined thereafter to reach normal levels 144 hours after PH. Moderate MMP-2 and TIMP-2 RNA levels remained constant up to 144 hours after PH, and MMP-1 and -13 RNA were always undetectable. In situ hybridization showed a dramatic upregulation of TIMP-1 RNA transcripts in mesenchymal cells of portal, perisinusoidal and, to a lesser extent, pericentral areas. In contrast, scattered hepatocytes represented only a minor fraction (below 10%) of TIMP-1 RNA positive cells. When hepatocytes stopped DNA synthesis at 72 hours after PH, an upregulation of procollagen alpha1(I) and alpha2(III) transcripts was observed paralleled by threefold increased PIIINP levels in the sera. Our data reveal a tightly regulated program of de novo matrix synthesis after PH. Whereas interstitial procollagens appear to participate in the induction and maintenance of the quiescent hepatocyte phenotype, the early and localized expression of TIMP-1 indicates a role unrelated to its function as a general MMP-antagonist, e.g., as a growth promoting agent for hepatocytes.

Animals↗