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Biomedical subjects

F L Dumoulin

Publications and source records attributed to F L Dumoulin.

At least 19 recordsLinked to original sources
PubMed2006

Detection of human aspartyl (asparaginyl) beta-hydroxylase and homeobox B7 mRNA in brush cytology specimens from patients with bile duct cancer.

BACKGROUND AND STUDY AIMS: The diagnosis of bile duct cancer is hampered by the low sensitivity of intraductal brush cytology and forceps biopsy. In the present study real-time reverse transcription polymerase chain reaction (RT-PCR) assays for the detection of human aspartyl (asparaginyl) beta-hydroxylase (HAAH) and homeobox B7 (HoxB7) mRNA from intraductal brush cytology specimens were established. Both markers are overexpressed in biliary cancer cell lines and possibly involved in the pathogenesis of bile duct cancer. PATIENTS AND METHODS: RT-PCR assays were validated for detection limit, in-assay variability, and inter-assay variability. Target gene expression was determined in brush cytology specimens from 16 patients with biliary strictures (11 with histologically proven cholangiocarcinomas and five with benign biliary strictures). RESULTS: The assay was quick (about 3 h), highly sensitive (with detection limits between 3 and 106 molecules), and reproducible (maximum in-assay variability 10.3 %, maximum inter-assay variability 11.8 %). The sensitivity of routine brush cytology alone was 36 % (four of 11 cases), with 100 % specificity. A combination with detection of HoxB7 and HAAH mRNA increased the overall diagnostic sensitivity to 82 %. CONCLUSIONS: Detection of these markers using the RT-PCR assays from brush cytology specimens described here may prove to be a useful additional tool for the diagnosis of bile duct carcinoma.

Adult↗
PubMed2005

[Malaria in the emergency room. Results of the emergency treatment of 137 patients with symptomatic malaria].

OBJECTIVE: To assess characteristics and outcome of emergency patients with acute malaria. PATIENTS AND METHODS: We retrospectively assessed the clinical and laboratory parameters of 137 consecutive patients (87 males, 50 females; median age 37 years, range 17 - 67 years) presenting with acute malaria to our tertiary care center between 1992 and 2002. RESULTS: Falciparum malaria was diagnosed in 116/137 and tertian malaria in 19/137 patients; a single patient was infected with both parasites while in another case the type of parasite remained unclear. Infections were acquired in Africa (121), Asia , and in the Americas . One traveler visited multiple continents. Only 36 % (50/137) of patients had used malaria chemoprophylaxis. 128/137 patients were treated as in-patients; 22 of these had to be treated on an intensive care unit. According to the criteria of the German Society of Tropical Medicine, 44/137 (32 %; 95 % confidence interval (CI): 25 - 40 %) patients suffered from complicated malaria. The overall mortality rate was 2/137 (1.5 %; 95 % CI: 0,4 - 5.2 %); the mortality rate of complicated malaria tropica was 2/44 (4,5 %; 95 % CI 1,3 - 15 %). Patients with complicated malaria were significantly older than those with uncomplicated malaria. Median length of hospital stay was 4 days in uncomplicated and 9 days in complicated cases. Based on costs of EUR 2500 per case, an attack rate of > 3 % in East African travelers and a cost of EUR 55 for a chemoprophylaxis with mefloquine, chemoprophylaxis is cost-effective. CONCLUSION: In our retrospective analysis, complicated malaria tropica was associated with older age. Although malaria causes considerable morbidity, the overall mortality from severe malaria is low. Reinforcement of chemoprophylaxis especially in travelers to Africa could reduce malaria cases and is cost-effective.

Adolescent↗
PubMed2002

[Endemic celiac sprue and Hodgkin's disease in a 72-year-old patient].

HISTORY AND CLINICAL FINDINGS: A 72-year-old man was admitted with diarrhea, loss of weight and anemia. The diarrhea started after antibiotic treatment of a pneumonia and persisted for 6 months at admission. Monoclonal gammopathy was found on external examination. INVESTIGATIONS AND DIAGNOSIS: The work-up yielded iron deficiency anemia, monoclonal gammopathy (IgG kappa) and elevated polyclonal IgA due to Gliadin- and endomysium-antibodies. Duodenal mucosa biopsies showed villous atrophy and increased intraepithelial lymphocytes. Celiac disease was diagnosed. Unexpectedly, mediastinal lymphomas were found and the concomitant diagnosis of Hodgkin's disease was made. TREATMENT AND COURSE: On gluten free diet all symptoms of malabsorption resolved. Therapy for the Hodgkin lymphoma with chemotherapy was initiated. As Bleomycin associated lung disease occurred during therapy, radiotherapy was not administered. A complete remission could be achieved. CONCLUSIONS: The association of celiac disease and malignancy is well known. The pathogenesis is not fully understood, but a correlation between the duration of gluten exposure and the rate of malignancy was found. Thus, the chronic immunologic stimulation might also have contributed to the development of Hodgkin's disease in our patient, which to date has been reported only anecdotally.

Aged↗
PubMed2001

Intrahepatic MxA expression is correlated with interferon-alpha expression in chronic and fulminant hepatitis.

Interferon-alpha (IFN-alpha) has potent pro-inflammatory and anti-viral functions. It exerts its effects by inducing intracellular proteins such as MxA. To analyse the role of intrahepatic interferon activation, IFN-alpha and MxA expression was studied by immunohistochemistry in explant livers of 20 patients with fulminant hepatic failure (FHF), 41 patients with chronic liver disease (CLD), and ten normal controls (NCs). In NCs only small numbers of Kupffer cells, but no hepatocytes, showed IFN-alpha and MxA expression. In contrast, significantly enhanced numbers of IFN-alpha- and MxA-positive Kupffer cells, along with small numbers of MxA-positive and larger numbers of IFN-alpha-positive lymphocytes, were found in CLD and in FHF. MxA protein was also expressed on hepatocytes and bile ducts in the vicinity of IFN-alpha-positive inflammatory infiltrates (hepatocytes: NCs: 0%, CLD: 8%, FHF: 68%; bile ducts: NCs: 19%, CLD: 46%, FHF: 83%). A significant correlation was found between the numbers of IFN-alpha- and MxA-positive cells (r=0.67, p<0.001). Thus, large amounts of IFN-alpha are released in the livers of patients with FHF, which is likely to contribute to immune-mediated liver cell damage. Intrahepatic MxA expression corresponds to IFN-alpha produced particularly by infiltrating inflammatory cells, rather than by hepatocytes themselves.

Antiviral Agents↗
PubMed2000

Semi-quantification of human C-C chemokine mRNAs with reverse transcription/real-time PCR using multi-specific standards.

A reverse transcription/real-time polymerase chain reaction (PCR) assay was established to semi-quantify the mRNA levels of the human C-C chemokines RANTES, MIP-1beta and MCP-1 relative to the housekeeping gene beta-actin. The assay showed a high sensitivity (below 60 cDNA molecules/10 microl reaction) and dynamic range (8 log units); both within-assay and inter-assay variability were below 0.06 log units and the accuracy was +/-0.06 log units for all four chemokines. Moreover, it is demonstrated that a multi-specific DNA fragment, which had previously been constructed for competitive PCR, can be used as a reliable external standard. This allows a direct semi-quantitative comparison of different chemokine mRNA levels and is a convenient alternative to the use of different sets of homologous external standards. The method was successfully applied to the semi-quantification of chemokines in human liver specimens and should be useful in further studies on steady state mRNA levels of C-C chemokines from low cell numbers or small tissue specimens.

Chemokine CCL2↗
PubMed2000

T(H)1 to T(H)2 shift of cytokines in peripheral blood of HIV-infected patients is detectable by reverse transcriptase polymerase chain reaction but not by enzyme-linked immunosorbent assay under nonstimulated conditions.

BACKGROUND: Dysregulation of cytokines has been implicated in the pathogenesis of HIV infection. Therefore, we determined tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-4, IL-10, and interferon-gamma (IFN-gamma) mRNA and serum levels in HIV-infected patients under nonstimulated conditions. MATERIAL AND METHODS: Blood samples of 32 HIV-infected patients and 10 healthy HIV-negative controls were analyzed. Cytokine serum levels were quantified by enzyme-linked immunosorbent assay (ELISA). Cytokine mRNA levels were determined semiquantitatively by competitive reverse transcriptase polymerase chain reaction (RT-PCR) and expressed as ratios relative to those of beta-actin. RESULTS: Competitive RT-PCR was shown to be more sensitive than protein ELISA in analyzing cytokine production. We found a significant correlation between steady-state mRNA ratios and serum protein levels for TNF-alpha. Significantly higher cytokine mRNA ratios were found in those patients with IL-10 and IFN-gamma levels detectable by ELISA. Steady-state mRNA ratios of TNF-alpha, IL-4, and IL-10 were significantly increased in patients with highly replicative HIV-infection. Furthermore, elevated IL-4:IFN-gamma ratios were related to both high viral load and loss of CD4 cells. DISCUSSION: Determination of steady-state mRNA ratios by semiquantitative RT-PCR represents a sensitive method to analyze cytokines in peripheral blood of HIV-infected patients under nonstimulated conditions. The data obtained with this technique provide further evidence for a T(H)1 to T(H)2 cytokine shift with progressive HIV disease.

CD4 Lymphocyte Count↗
PubMed1999

Semiquantitation of human chemokine mRNA levels with a newly constructed multispecific competitor fragment.

Chemokines are a group of inducible, locally acting proinflammatory cytokines which have been implicated in the pathogenesis of a variety of diseases. Important members of the group include monocyte chemoattractant protein (MCP)-1, -2, -3, macrophage inhibitory protein (MIP)-1alpha, -1beta and RANTES (regulated upon activation, normal T expressed and secreted). To facilitate further investigation of the human chemokines, we have constructed a novel multispecific competitor fragment containing primer binding sites for the CC-chemokines MCP-1, MCP-2, MCP-3, MIP-1alpha, MIP-1beta and RANTES, the CXC-chemokines MIP-2alpha, MIP-2beta as well as for the housekeeping gene beta-actin. Using this competitor fragment we can demonstrate reliable semiquantitation of reverse transcribed chemokine mRNAs. The assay should be useful for further studies, in particular for the semiquantitation of chemokine mRNA species from small cell or tissue specimens.

Actins↗
PubMed1999

Enhanced expression of CD80 (B7-1), CD86 (B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure.

To define a possible role for changes in the regulation of antigen presentation in fulminant hepatic failure (FHF), we studied the expression of co-stimulatory molecules CD80 (B7-1), CD86 (B7-2), and CD40 along with their ligands CD28 and CD154. We analyzed the liver tissue from patients with FHF (n = 18), chronic liver disease (n = 30), and acute hepatitis (n = 3) and from normal controls (n = 9) by immunohistochemistry and examined the temporal relationship between CD80/CD86 and CD40 expression and disease in the mouse models of galactosamine-lipopolysaccharide and galactosamine-tumor-necrosis-factor-induced FHF. In human controls, faint CD80/CD86 immunoreactivity was restricted to Kupffer cells, and CD40 expression was expressed on bile ducts, macrophages, and sinusoidal endothelial cells (SECs). In FHF, immunoreactivity for CD80 and CD86 was observed on significantly higher numbers of cells, including SECs. Increased CD80/CD86 expression corresponded to increased numbers of CD28-positive lymphocytes. The expression of CD40 was also clearly elevated on virtually all cell types in FHF. In both murine models, CD40 and CD80/CD86 expression was up-regulated before tissue damage could be detected. Our data suggest that up-regulated expression of co-stimulatory molecules might lead to an excessive antigen presentation in FHF as an early step in the pathogenesis before the onset of tissue damage.

Animals↗
PubMed1999

Autoimmunity induced by interferon-alpha therapy for chronic viral hepatitis.

Type I interferons, which are mostly alpha-interferons (either as single agents or in combination with antiviral drugs), are currently the standard therapy for chronic viral hepatitis B, B/D, and C. Side-effects are not uncommon and include exacerbation of pre-existing autoimmune disorders or the de novo induction of autoimmunity. These adverse effects are attributed to the immunomodulatory properties of type I interferons, and should be distinguished from autoimmunity associated with chronic viral hepatitis in which interferon treatment may indeed be beneficial. The major autoimmune side-effects of interferon therapy for chronic viral hepatitis are thyroid or liver disease. Therefore, screening for thyroid antibodies and auto-antibodies indicative of autoimmune hepatitis both before, during, and after interferon therapy is strongly recommended. The presence of high concentrations of thyroid auto-antibodies or antibodies associated with autoimmune hepatitis can be contraindicative to interferon therapy. However, treatment is not contraindicated in viral hepatitis (in particular chronic hepatitis C) associated with autoimmune phenomena--including low-titer thyroid antibodies or other non-organ specific auto-antibodies. If interferon-induced autoimmunity occurs, the necessity of therapy has to be balanced carefully against the risks of autoimmune disease. Further research is needed to identify the factors which determine susceptibility to interferon-associated autoimmunity in individual patients.

Autoimmunity↗
PubMed1999

Increased frequency of the HLA-DR15 (B1*15011) allele in German patients with self-limited hepatitis C virus infection.

BACKGROUND: A genetically determined resistance or susceptibility to chronic hepatitis C virus infection (HCV) may make an important contribution to the course of liver disease and may be linked to the human major histocompatibility complex. DESIGN: Twenty-one subjects with self-limited HCV infection as assessed by the presence of HCV antibodies, absence of HCV-RNA and normal levels of aminotransferases for 2 years were identified from a large pool of blood donors. The frequency of HLA serotypes of these individuals was compared with 49 consecutive patients with chronic hepatitis C. RESULTS: We detected a significantly higher prevalence of HLA-DR15 in patients with self-limited HCV infection than in patients with chronic hepatitis C (10/21 vs. 6/49; relative risk 6.5; P = 0.02; corrected for multiple comparisons). To confirm HLA assignments by serotyping we also performed sequencing of HLA-DR types in the 27 patients (9 with self-limited infection, 18 with chronic hepatitis C) who had been enrolled during 1995-96. This analysis confirmed the predominance of HLA-DR15 (HLA-DRB1*15011) in self-limited HCV infection (4/9 vs. 1/18; relative risk 13.6; P = 0.03). CONCLUSIONS: Our data suggest that HLA-DR15 (B1*15011) might constitute an important genetic factor for the elimination of the hepatitis C virus in Germany.

Adolescent↗
PubMed1999

Hepatitis C virus core protein does not inhibit apoptosis in human hepatoma cells.

BACKGROUND: Viral persistence is a major problem after infection with the hepatitis C virus. Recently, it has been reported that hepatitis C virus core protein inhibits cis-platin induced apoptosis in human cervical carcinoma cells and apoptosis induced by overexpression of c-myc in Chinese hamster ovary cells. MATERIALS AND METHODS: This study investigated whether different variants of hepatitis C virus core or E2 protein interfere with tumour necrosis factor alpha or Fas (CD95/ APO-1) antibody-induced programmed cell death in transiently transfected human hepatoma (HepG2) cells. RESULTS: While neither full length or C-terminally truncated variants of hepatitis C virus core protein nor hepatitis C virus E2 protein inhibited tumour necrosis factor alpha- or Fas antibody-induced apoptosis, a strong inhibition was observed with the cowpox virus cytokine response modifier A protein. CONCLUSIONS: Thus, it is unlikely that hepatitis C virus core or E2 protein inhibit apoptosis mediated by apoptosis-signalling pathways sensitive to cytokine response modifier A protein. Discrepancies to previous reports probably reflect specific effects of hepatitis C virus core protein on different apoptotic pathways and/ or cell lines.

Animals↗
PubMed1999

Intrahepatic expression of interleukin-1beta and tumor necrosis factor-alpha in chronic hepatitis C.

The intrahepatic expression of interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha was studied in liver specimens from patients with chronic hepatitis C (n=29) and primary biliary cirrhosis (PBC; n=12) and from normal controls (n=19). IL-1beta and TNF-alpha immunoreactivity was predominantly localized in sinusoidal cells, with IL-1beta immunoreactivity being weaker in chronic hepatitis C samples than in PBC or control samples, whereas no difference in staining intensity could be observed for TNF-alpha. On semiquantitation by reverse transcription/competitive polymerase chain reaction, IL-1beta mRNA levels were significantly lower in chronic hepatitis C than in PBC or control samples (chronic hepatitis C, 0.87+/-0.77; PBC, 7.96+/-3.32; control, 3.78+/-2.56 amole IL-1beta mRNA/fmole beta-actin mRNA; P<.001). In contrast, no significant differences in TNF-alpha mRNA levels were observed between the groups. The data suggest insufficient IL-1beta production by sinusoidal cells in chronic hepatitis C, which might facilitate viral persistence.

Hepatitis C, Chronic↗
PubMed1997

Anomalous expression of costimulatory molecules B7-1, B7-2 and CD28 in primary biliary cirrhosis.

BACKGROUND: T lymphocytes require two important signals for efficient activation: 1) recognition of antigens bound to self major histocompatibility complex antigens, and 2) simultaneous stimulation via so-called costimulatory molecules. Interaction of the costimulatory B7 molecules on antigen presenting cells with CD28 on T lymphocytes appears to be particularly important, as it modifies secretion of cytokines, especially interleukin 2. In primary biliary cirrhosis biliary epithelial cells aberrantly express major histocompatibility complex class II antigens and may function as antigen presenting cells. METHODS: We studied expression of HLA-DR, B7-1, B7-2 and CD28 on cryostat liver sections in 16 patients with primary biliary cirrhosis, three patients each with autoimmune hepatitis and primary sclerosing cholangitis and nine patients with chronic viral hepatitis (five hepatitis B, four hepatitis C) using mouse monoclonal antibodies in an indirect immunoperoxidase technique. RESULTS: In advanced primary biliary cirrhosis, HLA-DR was found on 57% of bile ducts, B7-2 on 5% of bile ducts, and B7-1 could not be detected on any bile duct. Neither B7-1 nor B7-2 was seen on bile ducts in the four patients with early primary biliary cirrhosis. HLA-DR+ bile ducts also lacked expression of B7 molecules in autoimmune hepatitis. In contrast, HLA-DR, B7-1 and B7-2 were expressed simultaneously on professional antigen presenting cells such as macrophages in epitheloid granulomas. CONCLUSION: HLA-DR+ biliary epithelial cells in primary biliary cirrhosis insufficiently co-express B7-1 or B7-2 molecules. Therefore, they must either use different costimulatory molecules, or otherwise are deficient in lymphocyte activation. Since recognition of antigen in the absence of B7-CD28 interaction may lead to anergy of lymphocytes, this might contribute to the impaired cytokine secretion found in primary biliary cirrhosis.

Antigens, CD↗
PubMed1997

Semiquantitation of intrahepatic MDR3 mRNA levels by reverse transcription/competitive polymerase chain reaction.

BACKGROUND/AIMS: Knockout mice lacking mdr2, the murine analogue of human MDR3 P-glycoprotein, develop chronic non-suppurative cholangitis. Recently, a deficiency in MDR3 messenger RNA (mRNA) has been reported in a subtype of progressive familial intrahepatic cholestasis. Thus, reduced MDR3 gene expression could be involved in human cholestatic liver diseases. METHODS: We developed a sensitive and specific reverse transcription/competitive polymerase chain reaction for the semiquantitation of intrahepatic MDR3 mRNA levels. Using this method we determined the MDR3 mRNA levels in 52 liver specimens from primary biliary cirrhosis (n=11), chronic hepatitis B (n=5), chronic hepatitis C (n=14), non-cholestatic cirrhosis (n=9) and controls (n=13). RESULTS: MDR3 mRNA was detected in all specimens with some variation in mRNA levels. No significant differences in the mean MDR3 mRNA levels were present between the groups studied, including normal controls. CONCLUSIONS: We found no evidence for deficient or severely reduced intrahepatic MDR3 mRNA in primary biliary cirrhosis, nor were mRNA levels altered significantly by virus-induced inflammation or by cirrhosis. The reverse transcription/competitive polymerase chain reaction assay described here should be a useful tool in the semiquantitative study of MDR3 mRNA levels in small tissue specimens.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1997

Treatment of Barrett's esophagus by endoscopic argon plasma coagulation.

Barrett's esophagus is a premalignant condition characterized by the presence of specialized columnar epithelium in the distal esophagus. Conventional medical or surgical treatments do not consistently lead to a regression of Barrett's epithelium. However, restoration of squamous mucosa can occur in an anacid environment after endoscopic ablation of metaplastic epithelium. We report here on two patients with long-standing history of Barrett's esophagus who were treated with endoscopic argon plasma coagulation. By six months of endoscopic treatment, Barrett's epithelium had regressed by more than 50%, being replaced by apparently normal squamous epithelium in both patients. Extensive histological sampling confirmed the presence of squamous epithelium indistinguishable from normal esophageal mucosa. Both patients were asymptomatic under concomitant therapy with proton pump inhibitors with the exception of slight retrosternal discomfort the day after treatment. This demonstrates that endoscopic argon plasma coagulation may be considered for the treatment of Barrett's esophagus.

Adult↗