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Biomedical subjects

G Gerken

Publications and source records attributed to G Gerken.

At least 55 records · Page 3Linked to original sources
PubMed2001

[AIDS and non-Hodgkin's lymphoma: initial cardiac manifestations of highly malignant B-cell lymphoma 18 years after HIV infection].

HISTORY AND FINDINGS: A 35-year-old man who, as a result of intravenous drug abuse, had become infected with HIV 18 years previously, was admitted with signs of right-heart failure. Three months earlier a systolic murmur had first been heard in the 5th intercostal space parasternally. INVESTIGATIONS: Transesophageal echocardiography (TEE) demonstrated a 3 x 2 cm right atrial tumour, moderate to severe tricuspid regurgitation and pulmonary hypertension. Blood cultures grew Streptococcus. DIAGNOSIS, TREATMENT AND COURSE: Endocarditis with atrial thrombi and recurrent pulmonary emboli was diagnosed and treated with antibiotics and anticoagulants. Three weeks later the TEE showed an increase in the atrial tumour. Computed tomography of skull, thorax and abdomen did not demonstrate any significantly enlarged lymph nodes. Exploratory thoracotomy revealed an infiltrating highly malignant centroblastic non-Hodgkin's lymphoma (NHL) of almost the entire free wall of the right atrium. After two courses of chemotherapy (CHOP protocol) the size of the tumour had significantly decreased. CONCLUSION: The differential diagnosis of a right atrial tumour can be difficult in patients with HIV or AIDS. Even if the site is atypical and there is no lymphadenopathy, a lymphoma should be considered. In case of doubt a histological diagnosis via an exploratory thoracotomy should be performed.

Adult↗
PubMed2001

Possible role of human interleukin-6 and soluble interleukin-6 receptor in hepatitis B virus infection.

Human interleukin-6 has been shown to promote hepatitis B virus (HBV) infection. However, it is not clear whether this influence is the result of a direct interaction between interleukin-6 (IL-6) and the HBV envelope proteins or of a rather indirect mechanism. A direct interaction of IL-6 and the preS region of the large envelope protein (L-protein) of HBV has been reported. In this study we assessed the binding of IL-6 and of the IL-6 receptor subunits to the preS region of the L-protein of HBV. Binding of IL-6 and IL-6 receptor subunits sIL-6R and gp130 to preS was assessed by immunoprecipitation with recombinant preS proteins. In patient sera IL-6 and sIL-6R concentrations were analysed with respect to the course of hepatitis B infection during and after interferon-alpha (IFN-alpha) therapy. The IL-6 and IL-6 receptor subunits could not be precipitated with recombinant preS proteins. In sera of patients who responded to IFN-alpha therapy by virus elimination, a significant increase in sIL-6R concentration was measured. No increase in sIL-6R levels was seen in patients who did not respond to IFN-alpha. Hence, IL-6 and IL-6 receptor subunits do not bind to preS directly. A possible role for sIL-6R in the elimination of HBV infection is discussed.

Animals↗
PubMed2001

Prediction of progressive liver fibrosis in hepatitis C infection by serum and tissue levels of transforming growth factor-beta.

Although many patients with chronic viral hepatitis C infection suffer from progressive liver disease, the rate of fibrosis progression is highly variable and some patients do not show any measurable progression. However, our ability to predict which patients progress is very limited. Since transforming growth factor-beta (TGF-beta) is a key mediator of liver fibrogenesis, we assessed the predictive role of TGF-beta for fibrogenesis in chronic hepatitis C. We studied 39 patients with chronic hepatitis C in whom two liver biopsies were taken at least 12 months apart, and who did not receive therapy during this period. TGF-beta was measured by bioassay and by ELISA in serum samples taken at the time of the first biopsies, and TGF-beta was determined semiquantitatively by immunostaining of liver biopsy sections. Fibrosis was scored blinded in the biopsy samples by two pathologists independently. There was a close correlation between TGF-beta serum levels and the rate of fibrosis progression. Patients with no progression of fibrosis had significantly lower (59 ng/mL +/- 22) TGF-beta serum levels than patients with progressive disease (115 ng/mL +/- 20), and a TGF-beta level below 75 ng/mL was predictive for stable disease. Immunohistology for TGF-beta in biopsy samples was also predictive for progressive liver disease with fibrosis progression found in those patients displaying staining of hepatocytes and sinusoidal cells. No such correlation was found with other markers such as procollagen III peptide, viral load or transaminase levels. These results further support the role of TGF-beta in liver fibrogenesis, and offer an opportunity to predict clinical disease progression, which may help in selecting patients who are in need of therapeutic interventions.

Alanine Transaminase↗
PubMed2001

Diurnal variation of abdominal motor responses to colorectal distension and plasma cortisol levels in rats.

Most patients with functional bowel disorders complain of daytime symptoms while they remain asymptomatic at night. As symptoms are associated with heightened visceral sensitivity, we hypothesized that circadian fluctuations of the visceral sensory function occur. At four different timepoints (06.00, 12.00, 18.00 and 24.00 h), colorectal distensions (CRD) were performed in fasting conscious male Lewis rats using a balloon catheter and a barostat device. The abdominal wall contractions (behavioural pain response) were assessed during colorectal distension by abdominal wall electromyography (EMG). Plasma levels for endogenous cortisol were determined simultaneously at these timepoints. EMG responses to CRD were significantly (P < 0.05) higher at midnight and in the early morning. Plasma cortisol levels peaked in the evening. In night-active Lewis rats, the behavioural pain response to noxious visceral stimulation is augmented at night and fluctuations of visceral sensitivity are accompanied by circadian changes of plasma concentrations of endogenous cortisol. We conclude that there are marked circadian fluctuations in visceral sensory functions. Thresholds are low during time periods of normal behavioural activity. These findings suggest that fluctuation of the sensory functions may be linked to the circadian variability of symptoms in patients with functional GI disorders.

Abdomen↗
PubMed2001

Long-term management and prognosis of autoimmune hepatitis (AIH): a single center experience.

BACKGROUND: Controlled trials have firmly established the need for immunosuppressive therapy in autoimmune hepatitis. However, reports about long-term management and prognosis of the disease are scarce. PATIENTS AND METHODS: We reviewed the charts of 103 consecutive patients with a well-documented long-term course of autoimmune hepatitis who had been carefully managed over a mean observation period of 95 months (12-405 months). RESULTS: Under immunosuppressive therapy 94 patients (91.2%) reached complete remission after a mean treatment duration of 3 +/- 3 months. 28 of the 103 patients (27.2%) were eligible for a trial of treatment withdrawal after a mean treatment duration of 32.2 months (range: 12-81 months). 21 of these patients (75%) had a relapse following treatment withdrawal. 13.6% of patients had intolerance of or severe side effects to azathioprine. There was no increase in tumor risk during a cumulative observation period of 423 patient-years of azathioprine therapy. Corticosteroid side effects occurred mostly during induction therapy, but were usually minor and resolved upon dose reduction. During a cumulative observation period of 842 patient-years no liver related deaths occurred and no patient had to be referred to liver transplantation, even though 30 patients (29.1%) had histological evidence of cirrhosis at presentation. The overall 5- and 10-year survival of patients with autoimmune hepatitis was identical to an age- and sex-matched control population. CONCLUSION: Our study shows that the majority of patients with AIH do achieve a complete remission within 3 months, but require long-term or permanent immunosuppressive therapy that is usually well tolerated. Long-term survival in well-managed patients is excellent.

Adolescent↗
PubMed2001

Mycophenolate mofetil reduces tissue damage and inflammation in an experimental model of colitis in rats.

BACKGROUND: Lymphocytes are widely believed to be responsible for persistent intestinal inflammation in inflammatory bowel diseases. Mycophenolate mofetil (MMF) is a potent immunosuppressant that inhibits lymphocyte proliferation and has been shown to be effective in preventing allograft rejection after organ transplantation. The purpose of this study was to assess the modulating effects of MMF on intestinal inflammation in an experimental model of colitis in rats. METHODS: Colitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in ethanol in male Sprague-Dawley rats. One group of rats (n = 10) was treated with MMF i.p. (25 mg/kg b.w.) daily for 1 week starting 24 h after induction of colitis. A second group of rats (n = 10) was treated with MMF at the same dose 2 days, I day and 1 h prior to induction of colitis. Control animals (n = 10) received vehicle only. After being killed, colonic tissue was macroscopically evaluated for necrosis and microscopically for ulcerations. Sections were stained and examined for the presence of granulocytes. RESULTS: Administration of MMF after induction of TNBS colitis reduced macroscopic injury by 62% compared to control animals (P = 0.01). Microscopic ulcerations were reduced by 64% compared to controls (P = 0.009). In addition, posttreatment significantly reduced the number of granulocytes. MMF pretreatment did not significantly prevent macroscopic or microscopic tissue damage, or change the number of granulocytes. CONCLUSION: Systemic administration of MMF significantly ameliorates tissue damage in a model of experimental colitis in rats suggesting that this compound may play an important role as an immunosuppressant in the therapy of inflammatory bowel diseases.

Animals↗
PubMed2001

Expression of insulin-like growth factor binding proteins and collagen in experimental colitis in rats.

OBJECTIVES AND DESIGN: Crohn's disease is complicated by smooth muscle hyperplasia and stricture formation. Insulin-like growth factor (IGF)-1 and insulin-like growth factor binding proteins (IGFBPs) may be involved in stimulating intestinal smooth muscle growth and collagen synthesis. Therefore, we investigated the expression of IGFBPs, collagen and collagenase activity in rat colitis and the effects of IGF-1 on IGFBP and collagen expression in rat colonic smooth muscle cells. METHODS: Animals were sacrificed during a 4-week time course of 2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced colitis. RNA from the animals' colons was blotted and hybridized with collagen-1 and IGFBP mRNA probes. Tissue proteins were screened for IGFBPs by Western ligand blotting. Collagenase activity was measured by zymography. Rat colonic smooth muscle cells in primary culture were incubated with IGF-1 then collagen-1, and IGFBP mRNAs and proteins were measured. RESULTS: In the rat tissue, IGFBP-3 mRNA and protein were increased 2 h after induction of colitis. IGFBP-4 mRNA was elevated after 2 h and IGFBP-4 protein after 4 h. IGFBP-5 mRNA was upregulated after 2 h with a peak at 12 h. IGFBP-5 protein was upregulated after 1 h and reached a peak at 3 days. Collagen-1 mRNA was increased after 5 days. Collagenase levels were decreased after 1 h and returned to normal by 28 days. In rat colonic smooth muscle cells, IGF-1 increased collagen-1 and IGFBP-5 expression. CONCLUSION: We demonstrated an upregulation of IGFBP and collagen expression and a downregulation of collagenase in rat colitis. In colonic smooth muscle cells, we found an upregulation of collagen-1 and IGFBP-5 following IGF-1 incubation. These results suggest an important role of IGF-1 in the collagen synthesis in colitis, mediated by IGFBPs.

Animals↗
PubMed2001

Epithelial cell-derived components induce transforming growth factor-alpha mRNA expression and epithelial cell proliferation in vitro.

BACKGROUND: Epidermal growth factor (EGF) and transforming growth factor (TGF)-alpha protect the gastrointestinal mucosa against injury. In response to mucosal injury TGF-alpha, but not EGF, is locally increasingly expressed in the mucosa of the rat colon and stomach 4-8 h after injury. The aim of our present study was to characterize the possible signal for the induction of TGF-alpha expression. METHODS: Monolayers of the non-transformed intestinal epithelial cell (IEC)-6 and IEC-18 lines were harvested, homogenized and shock-frozen at -80 degrees C for 1 h. Cell cultures of intact IEC-6 or IEC-18 cells were exposed to these cell homogenates and modulation of epithelial cell migration and proliferation was evaluated using standardized procedures as described previously. TGF-alpha mRNA expression in the exposed epithelial cell monolayers was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR) and normalized to the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). RESULTS: The proliferation of IEC-6 and IEC-18 epithelial cell monolayers was significantly inhibited if epithelial cell homogenates of 2000 cells/ml or more, and significantly induced if homogenates of less than 2000 cells/ml, were applied to the medium of the monolayers in vitro. In proliferating epithelial cells, a significant two-fold increase in TGF-alpha mRNA expression was obtained at 48 h and 72 h after application of the cell homogenates. The homogenate-induced epithelial cell proliferation was completely abolished after preincubation of the epithelial cell homogenates with neutralizing monoclonal anti-TGF-alpha antibodies. No effect on epithelial cell migration was noticed after application of epithelial-cell homogenates to the cell cultures. CONCLUSIONS: Epithelial cell-derived components induce TGF-alpha mRNA expression and TGF-alpha-dependent cell proliferation of intact epithelial cells. We hypothesize that epithelial cell interaction bears one of the possible signals for the increased TGF-alpha mRNA expression after mucosal injury.

Animals↗
PubMed2001

Minimal protection of the liver by ischemic preconditioning in pigs.

Ischemic preconditioning (IP) protects the rat liver. In pigs, in which hepatic tolerance to ischemia is similar to that in humans, information on IP is lacking. Therefore, in enflurane-anesthetized pigs, hepatic vessels were occluded for 120 min (protocol 1) or 200 min (protocol 2) without (control) and with IP (3 times 10 min ischemia-reperfusion each). In protocol 1, cumulative bile flow (CBF) during reperfusion was greater in IP (47.3 +/- 5.2 ml/8 h) than in control (17.1 +/- 7.8 ml/8 h, P < 0.05). ATP content tended to recover toward normal during reperfusion in IP, whereas it remained at ischemic levels in control. Serum enzyme concentrations increased similarly during reperfusion, and <1% hepatocytes were necrotic or stained terminal deosynucleotidyl transferase-mediated dUTP nick-end labeling-positive in control and IP groups. In protocol 2, no differences in CBF, ATP, or serum enzyme concentrations during reperfusion were measured between control and IP groups, except for a somewhat reduced lactate dehydrogenase in IP. The number of necrotic or terminal deosynucleotidyl transferase-mediated dUTP nick-end labeling-positive hepatocytes tended to be greater in the IP than the control group. Thus IP provides some functional protection against reversible ischemia but no protection during prolonged ischemia in pigs.

Adenosine Triphosphate↗
PubMed2000

[Standard hepatitis B therapy].

Standard treatment of chronic hepatitis B virus infection includes the use of interferon-a and antiviral nucleoside analogues, alternatively. In general, in patients with hepatic inflammatory activity, low viral titers and HBe positive wild-type infection interferon leads to a long-term seroconversion rate of about 30-50%. However in patients with advanced liver disease, in interferon non-responders and HBe minus mutants HBV carriers nucleoside analogues like lamivudine represents a new and clinically proven therapeutical option. However, the longterm outcome and the problem of the emergence of HBV polymerase gene mutants has not been completely understood.

Antiviral Agents↗
PubMed2000

Liver sinusoidal endothelial cells are not permissive for adenovirus type 5.

Adenoviral vectors are known to transduce hepatocytes in normal liver tissue with high efficiency. The aim of this study was to investigate whether sinusoidal endothelial cells, which separate hepatocytes from the bloodstream in the sinusoidal lumen, are permissive for infection by adenoviruses. We show here that microvascular liver sinusoidal endothelial cells are not infected by adenovirus type 5 in vivo or in vitro unless high MOIs are used. In contrast, macrovascular endothelial cells from aorta are efficiently infected by adenovirus type 5. In addition, Kupffer cells, similar to sinusoidal endothelial cells, are not infected by adenovirus type 5. Liver sinusoidal endothelial cells do not express the integrin receptor alpha(v)beta3, which is required for efficient infection by adenoviruses. Our results demonstrate that hepatocytes are the main cell population of the liver that is infected by adenovirus type 5.

Adenoviridae↗
PubMed2000

Serological pattern "anti-HBc alone": report on a workshop.

In areas with low hepatitis B virus (HBV) endemicity such as most parts of Europe and the United States "anti-HBc alone" is found in 10-20% of all individuals with HBV markers, i.e., 1-4% of the population. In about 10% of these individuals HBV DNA is detected by PCR, the proportions varying greatly depending on the population studied, being highest in individuals coinfected with hepatitis C virus (HCV) (above 35%) and HIV (above 85%). A small proportion of individuals with "anti-HBc alone" are in the window phase of an HBV infection or in a stage of late HBV immunity. For the large proportion of these individuals this is not the case and they are thought to have an unresolved HBV-infection or a chronic infection in a late or "low grade" productive state. Currently, limited studies have been performed concerning the clinical aspects of individuals with "anti-HBc alone" and suspected chronic HBV infection. The majority of these individuals seem to be healthy. Some chronic carriers with "anti-HBc alone," however, do present signs of chronic hepatitis. Individuals with "anti-HBc alone" are potentially infectious. This is exemplified by a few case reports of HBV transmission to sexual contacts, perinatal transmission between mother and newborns and in blood recipients. Recommendations are given in relation to both the diagnostic and therapeutic procedures in the individuals with "anti-HBc alone" and in the blood banking and transplantation services.

Blood Banks↗
PubMed2000

Selection of hepatitis B virus variants with aminoacid substitutions inside the core antigen during interferon-alpha therapy.

The hepatitis B virus (HBV) core antigen carries many epitopes relevant for B and T cell response that show aminoacid variation during viral infection. In a longitudinal analysis, sequential serum samples of 15 patients that suffered from chronic HBV infection were collected before, during, and after high-dose IFN-alpha treatment. The HBV preCore/Core (preC/C) sequence of the selected samples in each patient was determined and analysed for sequence variations compared to the pretreatment sample. The positions of HBV core aminoacid substitutions were assigned to immunodominant B, CD4(+) and CD8(+) cell epitopes. Seventy-five percent of all aminoacid substitutions were found within immunodominant T and B cell epitopes (12.5% were inside known HBV core mutation cluster regions) that show an increased number of clustered aminoacid substitutions during chronic HBV infection and overlap partially with the immunodominant epitopes. Only 12.5% of the detected core antigen aminoacid substitutions could not be assigned to any epitope or mutation cluster region. Stable HBV core antigen aminoacid substitutions, which were found between pretreatment sequence and the last sequence analysed during therapy, were found most frequently inside T helper cell epitopes. This longitudinal analysis of aminoacid substitutions inside the HBV core antigen in patients with chronic HBV infection shows that core aminoacid variations occur most frequently inside immunodominant HBV core epitopes, possibly due to an immuneselective pressure of the host against the virus. The data also suggest that stable HBV variants with aminoacid substitutions in immunodominant core epitopes can be selected during high-dose IFN-alpha therapy and persist after the end of treatment.

Adult↗
PubMed2000

Interaction of Hypericum perforatum (St. John's wort) with cyclosporin A metabolism in a patient after liver transplantation.

Immunosuppressive therapy in patients after liver transplantation requires careful monitoring of blood levels for immunosuppressive agents such as cyclosporin A. A variety of drugs are capable of interfering with the metabolism of cyclosporin A. We observed a 63-year-old patient who received a liver allograft for cryptogenic liver cirrhosis in 1998. This patient developed severe acute rejection 14 months after transplantation which was associated with a sudden drop in cyclosporin A levels. Two weeks previously, he had started taking the herbal drug Hypericum perforatum (2 x 900 mg/day) for increasing episodes of depression. The cyclosporin A dosage later had to be doubled, which caused some side effects. Finally, an assessment of oral cyclosporin A resorption suggested an enhanced cyclosporin A metabolism. Hypericum perforatum was stopped. Both cyclosporin A dosage and blood levels immediately returned to normal. The liver function recovered completely. In conclusion, this observation is a previously undescribed drug interaction of a widely used herbal drug (Hypericum perforatum, i.e. St. John's wort) in a patient after liver transplantation.

Antidepressive Agents↗
PubMed2000

Local control of the immune response in the liver.

The physiological function of the liver--such as removal of pathogens and antigens from the blood, protein synthesis and metabolism--requires an immune response that is adapted to these tasks and is locally regulated. Pathogenic microorganisms must be efficiently eliminated while the large number of antigens derived from the gastrointestinal tract must be tolerized. From experimental observations it is evident that the liver favours the induction of tolerance rather than the induction of immunity. The liver probably not only is involved in transplantation tolerance but contributes as well to tolerance to orally ingested antigens (entering the liver with portal-venous blood) and to containment of systemic immune responses (antigen from the systemic circulation entering the liver with arterial blood). This review summarizes the experimental data that shed light on the molecular mechanisms and the cell populations of the liver involved in local immune regulation in the liver. Although hepatocytes constitute the major cell population of the liver, direct interaction of hepatocytes with leukocytes in the blood is unlikely. Sinusoidal endothelial cells, which line the hepatic sinusoids and separate hepatocytes from leukocytes in the sinusoidal lumen, and Kupffer cells, the resident macrophage population of the liver, can directly interact with passenger leukocytes. In the liver, clearance of antigen from the blood occurs mainly by sinusoidal endothelial cells through very efficient receptor-mediated endocytosis. Liver sinusoidal endothelial cells constitutively express all molecules necessary for antigen presentation (CD54, CD80, CD86, MHC class I and class II and CD40) and can function as antigen-presenting cells for CD4+ and CD8+ T cells. Thus, these cells probably contribute to hepatic immune surveillance by activation of effector T cells. Antigen-specific T-cell activation is influenced by the local microenvironment. This microenvironment is characterized by the physiological presence of bacterial constituents such as endotoxin and by the local release of immunosuppressive mediators such as interleukin-10, prostaglandin E2 and transforming growth factor-beta. Different hepatic cell populations may contribute in different ways to tolerance induction in the liver. In vitro experiments revealed that naive T cells are activated by resident sinusoidal endothelial cells but do not differentiate into effector T cells. These T cells show a cytokine profile and a functional phenotype that is compatible with the induction of tolerance. Besides sinusoidal endothelial cells, other cell populations of the liver, such as dendritic cells, Kupffer cells and perhaps also hepatocytes, may contribute to tolerance induction by deletion of T cells through induction of apoptosis.

Animals↗
PubMed2000

Campylobacter jejuni-induced severe colitis--a rare cause of toxic megacolon.

The development of toxic megacolon as a sequel of infectious colitis is rare. We have observed the very rare case of a campylobacter jejuni-induced toxic megacolon. A 28-year-old man was admitted with severe enterocolitis and appearance of blood in stools. He had been treated with loperamide without success. Two days after admission stool cultures revealed campylobacter jejuni and then an oral antibiotic therapy was started. On the fifth day clinical performance deteriorated again with development of toxic megacolon and consecutive subtotal colectomy. Rectoscopy before discharge after 13 days showed a normal mucosa. The unusual course with first improvement and then rapid deterioration despite adequate therapy was observed in 4 other cases, which may also be a hint of ensuing megacolon. Even in usually harmless enterocolitis like campylobacter infection, predisposing factors such as loperamide are known to precipitate toxic megacolon and should be considered in clinical practice.

Adult↗