Biomedical subjects

H P Fischer

Publications and source records attributed to H P Fischer.

At least 19 recordsLinked to original sources

PubMed2006

Podocalyxin-like protein 1 expression in primary hepatic tumours and tumour-like lesions.

AIMS: The differential diagnosis of benign hepatic lesions and well-differentiated hepatocellular carcinomas can be a challenge, especially in small biopsy specimens. Recently, novel proteins expressed by the neovasculature in hepatocellular carcinoma (HCC) have been identified. The aim of this study was to compare the expression of podocalyxin-like protein 1 (PODXL1), a CD34-related sialomucin, in HCC and benign liver tumours or tumour-like lesions. METHODS AND RESULTS: Vascular marker expression was examined using tissue microarrays as well as standard paraffin sections from formalin fixed paraffin-embedded liver tissue samples. Expression of PODXL1 was compared with anti-CD34, CD31 and von Willebrand factor VIII staining by immunohistochemistry. PODXL1 is expressed in tumour-associated microvasculature endothelial cells in HCC, as well as in capillarized sinusoidal endothelium of focal nodular hyperplasia (FNH) and hepatic adenoma. Expression in cirrhotic nodules correlates with CD34 and highlights endothelium in the inflow area. In dysplastic nodules CD34 and PODXL1 are not or only focally expressed. CONCLUSIONS: Expression patterns of CD34 and PODXL1 are almost identical in primary hepatic tumours and tumour-like lesions. The presence of CD34+ and PODXL1+ sinusoidal endothelial cells aids in the diagnosis of HCC. Sinusoidal expression of PODXL1 is also seen in a less diffuse pattern in FNH and adenoma.

Antigens, CD34↗

PubMed2005

Renal anemia aggravated by long-term parvovirus B19 and cytomegalovirus infection in a renal transplant patient: case report and evaluation of B19 seroprevalence in dialysis patients.

Due to viral replication in erythroid precursor cells, severe anemia represents a major complication of B19 infection. However, cytomegalovirus (CMV) is the leading cause of virus-induced complications with a significant impact on graft outcome of renal transplant patients. Herein, we present a long-term B19 infection in a 45-year-old female renal transplant patient, which aggravated the renal anemia associated with a concomitant CMV infection. Since no data were available on the seroprevalence of this virus in pretransplant patients, we determined the B19 serostatus of 90 dialyzed pretransplant adult subjects.

Adult↗

PubMed2005

Discovering the mechanism of action of novel antibacterial agents through transcriptional profiling of conditional mutants.

We present a new strategy for predicting novel antibiotic mechanisms of action based on the analysis of whole-genome microarray data. We first built up a reference compendium of Bacillus subtilis expression profiles induced by 14 different antibiotics. This data set was expanded by adding expression profiles from mutants that showed downregulation of genes coding for proven or emerging antibacterial targets. Here, we investigate conditional mutants underexpressing ileS, pheST, fabF, and accDA, each of which is essential for growth. Our proof-of-principle analyses reveal that conditional mutants can be used to mimic chemical inhibition of the corresponding gene products. Moreover, we show that a statistical data analysis combined with thorough pathway and regulon analysis can pinpoint the molecular target of uncharacterized antibiotics. We apply this approach to two novel antibiotics: a recently published phenyl-thiazolylurea derivative and the natural product moiramide B. Our results support recent findings suggesting that the phenyl-thiazolylurea derivative is a novel phenylalanyl-tRNA synthetase inhibitor. Finally, we propose a completely novel antibiotic mechanism of action for moiramide B based on inhibition of the bacterial acetyl coenzyme A carboxylase.

Algorithms↗

PubMed2004

Autoimmune hepatitis--sequel of a relapsing hepatitis A in a 75-year-old woman.

Acute hepatitis A virus (HAV) infection is a global cause of acute hepatitis. However, chronic HAV infection is unlikely. Nevertheless, there is some evidence that acute infection with HAV may trigger chronic active hepatitis which fulfils the criteria of autoimmune hepatitis (AIH). Whether AIH following HAV infection is virus specific remains unclear. Despite evidence that inherited factors may play a role in the development of autoimmunity after viral infection, the pathomechanism remains unclear. We describe a 75-year-old woman with a history of pulmonary sarcoidosis who developed AIH after acute HAV infection.

Acute Disease↗

PubMed2003

[Fatty liver and increased serum lactate in a woman with HIV].

HISTORY AND CLINICAL PRESENTATION: A 50-year-old woman with HIV who had undergone a 7-month course of antiretroviral treatment (stavudine, lamivudine, indinavir, ritonavir) was admitted to hospital with abdominal pain, nausea, vomiting and muscle pain. Physical examination revealed subfebrile body temperature and hepatomegaly. INVESTIGATIONS: Biochemical tests revealed moderate elevations of gamma GT, AST and ALT as well as marked hyperlactatemia. Abdominal computed tomography indicated pronounced hepatomegaly. Percutaneous liver biopsy was performed and demonstrated macro- and microvesicular hepatic steatosis on light microscopy. Electron microscopy showed mitochondrial damage. TREATMENT AND COURSE: Despite discontinuation of antiretroviral treatment serum lactate levels further increased initially and clinical symptoms were progressive. In the following weeks, a slow but steady recovery of laboratory values and physical condition was noted. CONCLUSION: Hyperlactataemia associated with abdominal pain can indicate the mitochondrial toxicity due to nucleoside reverse transcriptase inhibitors. After drug discontinuation, improvement of clinical symptoms and laboratory values is often delayed, frequently for several weeks.

Abdominal Pain↗

PubMed2003

Benign hepatic tumours.

Benign hepatic tumours include a broad spectrum of regenerative and true neoplastic processes. Due to advances in imaging procedures like MRI, Cf-scan and ultrasound as well as progress in immunohistochemistry, the appropriate diagnosis is made ina high percentage of patients without laparotomy and resection. Most important in clinical practice is the differential diagnosis of focal nodular hyperplasia and hepatocellular adenoma because of the risk of rupture and bleeding in the latter. Cavernous haemangioma, the most common benign hepatic tumour, rarely needs treatment. The diagnosis of nodular regenerative hyperplasia is often missed and patients present with secondary complications and signs of portal hypertension that necessitate treatment. The main problem in angiomyolipoma is to distinguish it from malignant processes which do require treatment. Because of its clinical presentation, inflammatory pseudotumour is also sometimes confused with a malignant tumour. Therapeutic options are drug therapy or surgical resection. Benign haemangioendothelioma of the infant is rare but may cause life-threatening complications. Bile duct adenoma is an incidental finding that is not known to cause any symptoms whereas biliary cystadenoma is often symptomatic and may progress to cystadenocarcinoma and therefore needs resection.

Adenoma, Liver Cell↗

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↗

PubMed2002

[Massive pulmonary capillary occlusion by microthrombi. Unexpected cause of fatal right heart failure during liver transplantation].

We report the case of a 46-year old man who developed an unexpected fatal cardiac failure during liver transplantation. Attempts at resuscitation were unsuccessful. At necropsy the lungs showed numerous microthrombi occluding small lung vessels and pulmonary capillaries. Thrombi were not found in other organs. The source of this extensive thrombus formation is not known. The thrombi could have been developed within the liver, the venous blood stream between liver and lungs or the pulmonary capillaries. In our experience, this complication is very rare, and a risk profile is not known.

Capillaries↗

PubMed2001

Association of CYP1B1 codon 432 mutant allele in head and neck squamous cell cancer is reflected by somatic mutations of p53 in tumor tissue.

Tobacco use is causally associated with head and neck squamous cell cancer (HNSCC). Here, we present the results of a case-control study that investigated the effects that the genetic variants of the cytochrome (CYP)1A1, CYP1B1, glutathione-S-transferase (GST)M1, GSTT1, and GSTP1 genes have on modifying the risk of smoking-related HNSCC. Allelisms of the CYP1A1, GSTT1, GSTM1, and GSTT1 genes alone were not associated with an increased risk. CYP1B1 codon 432 polymorphism was found to be a putative susceptibility factor in smoking-related HNSCC. The frequency of CYP1B1 polymorphism was significantly higher (P < 0.001) in the group of smoking cases when compared with smoking controls. Additionally, an odds ratio (OR) of 4.53 (2.62-7.98) was discovered when investigating smoking and nonsmoking cases for the susceptible genotype CYP1B1*2/*2, when compared with the presence of the genotype wild type. In combination with polymorphic variants of the GST genes, a synergistic-effect OR was observed. The calculated OR for the combined genotype CYP1B1*2/*2 and GSTM1*2/*2 was 12.8 (4.09-49.7). The calculated OR for the combined genotype was 13.4 (2.92-97.7) for CYP1B1*2/*2 and GSTT1*2/*2, and 24.1 (9.36-70.5) for the combination of CYP1B1*2/*2 and GSTT1-expressors. The impact of the polymorphic variants of the CYP1B1 gene on HNSCC risk is reflected by the strong association with the frequency of somatic mutations of the p53 gene. Smokers with susceptible genotype CYP1B1*2/*2 were 20 times more likely to show evidence of p53 mutations than were those with CYP1B1 wild type. Combined genotype analysis of CYP1B1 and GSTM1 or GSTT1 revealed interactive effects on the occurrence of p53 gene mutations. The results of the present study indicate that polymorphic variants of CYP1B1 relate significantly to the individual susceptibility of smokers to HNSCC.

Alleles↗

PubMed2001

Immunohistochemical patterns of human liver sinusoids under different conditions of pathologic perfusion.

This study reports the effects of altered hepatic perfusion on the sinusoidal bed and the phenotypic characteristics of sinusoidal endothelial cells (SECs). Sinusoids were studied by the application of endothelial cell markers (CD31, CD34, CD105, and ATZ 11) in lesions with localized increased perfusion (liver cell adenoma, focal nodular hyperplasia, and macroregenerative nodule), in chronic congestion, in decreased portovenous inflow (portal vein thrombosis), and in decreased arteriohepatic perfusion (obliterative arteriopathy in chronic allograft rejection). SECs react in a sensitive and uniform way to all investigated conditions of different pathologic liver perfusion: expression of CD31, CD34, and ATZ 11 by SEC is found in inflow areas, CD105-positive SECs are found at the end of the sinusoidal blood stream. This blood flow-orientated phenotypic shift of SECs was accompanied by a perisinusoidal accumulation of activated hepatic stellate cells and collagen IV. These findings are helpful in liver biopsies and provide new insights into the angioarchitecture of benign nodular lesions.

Adenoma↗

PubMed2001

Antibodies against serotonin have no diagnostic relevance in patients with fibromyalgia syndrome.

OBJECTIVE: To determine the prevalence and potential diagnostic relevance of autoantibodies against serotonin, thromboplastin, and ganglioside Gm1 in patients with fibromyalgia syndrome (FM). METHODS: Sera from 203 patients with FM and 64 pain-free control subjects were analyzed with enzyme immunoassays. Clinical and psychometric data of the patients were analyzed for the presence or absence of autoantibodies. RESULTS: Compared with control subjects patients with FM had a significantly higher prevalence of autoantibodies against serotonin (20% vs 5%; p = 0.003) and thromboplastin (43% vs 9%; p < 0.001), but not against ganglioside Gm1 (15% vs 9%; p = 0.301). Differences in autoantibody prevalence between controls and FM patients were not related to age or sex. No association was found between autoantibody pattern and clinical or psychometric data, e.g., pain, depression, pain related anxiety, and activities of daily living. CONCLUSION: There is an elevated prevalence of antibodies against serotonin and thromboplastin in patients with FM. The pathophysiological significance of this finding is unknown. Calculation of positive predictive values of antiserotonin antibodies shows that measurement of these antibodies has no diagnostic relevance.

Adult↗

PubMed2000

Is heterozygous alpha-1-antitrypsin deficiency type PIZ a risk factor for primary liver carcinoma?

BACKGROUND: It is well known that homozygotes with alpha-1-antitrypsin deficiency type PiZ are associated with an increased risk of chronic liver disease and liver carcinoma. The aim of this study was to determine whether heterozygous PiZ status is a risk factor for liver carcinoma development. METHODS: Three hundred seventeen consecutive primary liver carcinomas and the tumor-bearing liver tissue (tumor series) from adult patients were screened immunohistochemically for hepatocellular PiZ deposits. Liver specimens from 1663 consecutive adult patients (biopsy series) and liver tissue from 1030 consecutive adult autopsies (autopsy series) served as controls. The zygosity status of alpha-1-antitrypsin was verified by analysis of single strand conformational polymorphism and by sequencing DNA extracted from paraffin embedded tissue. RESULTS: The PiZ frequency in the tumor series (5.99%) was significantly higher than in the biopsy series (3.43%) or the autopsy series (1.84%). Cholangiocarcinomas and/or combined hepatocholangiocarcinomas were seen significantly more frequently in PiZ-associated liver carcinomas (57.9%) than in non-PiZ-associated carcinomas (27.2%). Cirrhosis was found in only 3 of the 19 PiZ-associated carcinomas. The remaining 16 livers showed varying stages of fibrosis or normal tissue. All nine cases with PiZ-associated liver carcinoma suitable for genetic analysis showed heterozygous PiZ mutations. CONCLUSIONS: Heterozygotes of type PiZ are associated with an increased risk of primary liver carcinoma. PiZ-associated carcinoma may develop in noncirrhotic liver tissue and without concurrent liver disease, and is frequently characterized by cholangiocellular differentiation. The site specific antibody ATZ11 is a reliable morphologic tool for detecting PiZ individuals.

Aged↗

PubMed2000

Primary central nervous system lymphoma: a clinicopathological study of 28 cases.

A group of 28 consecutive patients (mean age 59 years) with primary central nervous system lymphoma (PCNSL) was treated with different regimens, including steroids only, radiotherapy (RT), chemotherapy or combinations of all. Lymphoma was classified as high grade malignant B-cell non-Hodgkin's lymphoma of the diffuse large cell type in each of these cases. RT alone led to tumour remission in more than 70 per cent, survival could be prolonged with additional chemotherapy. Thirteen patients were treated with chemotherapy alone; nine of them received a novel combined intraventricular and systemic polychemotherapy protocol based on high dose methotrexate (MTX) and high dose cytarabine (ara-C). The response rate was 90 per cent with 80 per cent complete responses. Neurotoxicity, i.e. white matter lesions associated with severe cognitive dysfunction affected both patients surviving RT more than a year and patients treated with combination RT/chemotherapy. Confluent white matter hyperintense lesions were detectable on MRI in three out of 13 patients treated with chemotherapy alone, however, cognitive dysfunction has not been detected in these patients.

Adult↗

PubMed2000

Rapid analysis of alpha1-antitrypsin PiZ genotype by a real-time PCR approach.

alpha1-Antitrypsin (AAT) deficiency is a common inherited cause of emphysema and cirrhotic liver disease. Current laboratory diagnosis of Pi (proteinase inhibitor) status by protein analysis depends on the availability of blood samples and has a limited accuracy. Single-strand conformational polymorphism (SSCP) analysis and direct DNA sequencing can be performed from blood cells or from tissue samples, but it is a time-consuming procedure not suitable for screening purposes. We used a Light-Cycler assisted PCR approach to identify the PiZ mutation and to determine hetero- and homozygous carrier status from whole blood and from paraffin-embedded archival tissue specimens. The results were compared to those obtained by standard PCR amplification followed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR identified heterozygous PiZ mutations in 16 samples, a homozygous PiZ status in three cases, and wild-type PiM in five control samples. In all cases the results were confirmed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR has a high detection rate for the PiZ mutation. It can be performed from blood or from fixed archival tissues, requires only small amounts of DNA, and allows a rapid diagnosis on a high output level.

DNA↗

PubMed2000

[Liver changes in heterozygote alpha 1-antitrypsin deficiency PiZ].

Whether heterozygotes with alpha-1-antitrypsin (AAT) deficiency type PiZ bear an increased risk for chronic liver disease is controversial. On the basis of liver tissue from 1,030 autopsies (autopsy series), 1,847 biopsies (biopsy series) and 317 primary liver carcinomas (tumor series), we analysed the effect of heterozygous state PiZ for the development of liver diseases. The PiZ status was screened immunohistochemically and verified in selected cases by SSCP analysis and by sequencing DNA extracted from paraffin embedded tissue. The PiZ frequency in the biopsy series (3.4%) and tumor series (5.99%) was significantly higher than in the autopsy series (1.8%). Hepatic PiZ deposits in heterozygotes sometimes were as extensive as in homozygotes. The amount of PiZ deposits correlated positively with the inflammatory activity and stage of fibrosis, as well as with the age of patients. Patients with concurrent liver disease such as hepatitis and alcoholic liver disease showed significantly higher scores of inflammatory activity, stage of fibrosis and amount of PiZ deposits than those without additional liver disease. Cholangiocarcinomas and combined hepato-cholangiocarcinomas were seen significantly more frequently in patients with PiZ-associated liver carcinoma than in genetic healthy individuals (p = 0.004). Three out of 19 PiZ-associated liver carcinomas had developed in cirrhotic liver tissue. Heterozygotes of type PiZ have an enhanced risk for chronic liver disease including primary liver carcinoma. PiZ-associated liver diseases will become clinically manifest in middle or old aged adults. Rarely this genetic defect causes liver cirrhosis even without concurrent liver disease. PiZ-associated liver carcinomas are frequently characterized by cholangiocellular differentiation and may develop often in non-cirrhotic liver tissue. Immunohistochemistry is a specific method to detect hepatic PiZ deposits.

Adult↗

PubMed2000

Chronic liver disease in heterozygous alpha1-antitrypsin deficiency PiZ.

BACKGROUND/AIMS: The contribution of the heterozygous state PiZ of alpha1-antitrypsin deficiency (AATD) to the pathogenesis of chronic liver disease is debated. We analyzed whether patients with this genetic defect carrying a single PiZ gene are at increased risk for developing chronic liver disease. METHODS: 1847 consecutive biopsy cases and 1030 autopsy cases of Caucasian adults were screened immunohistochemically for PiZ deposits. The zygosity status was analyzed by single-strand conformational polymorphism (SSCP) and by sequencing DNA extracted from paraffin-embedded tissue. RESULTS: All analyzed biopsy cases were heterozygous for the PiZ mutation. The biopsy group revealed a significantly higher rate of PiZ-positive cases (3.4%) than the autopsy group (1.8%) (p=0.019). PiZ deposits ranged from scarce granules to extensive globular inclusions as in homozygous AATD of PiZ type. The extent of PiZ deposits correlated well with the inflammatory activity and stage of fibrosis. Cirrhotic livers contained globular PiZ deposits significantly more often than the biopsies with minor fibrosis. PiZ-positive biopsies from patients without concurrent liver disease (n= 26) revealed only minor fibrosis in the age group between 20 and 39 years, but significantly more severe fibrosis and significantly more PiZ deposits in the older age groups. Biopsies with concurrent liver disease (n=28) presented with significantly more severe inflammation and fibrosis, and more PiZ deposits than the cases without concurrent liver disease. CONCLUSIONS: Patients with heterozygous AATD of PiZ type bear an increased risk for chronic liver disease. If at all, this genetic defect will become clinically relevant only in middle-aged or old adults. It rarely causes liver cirrhosis even without concurrent liver disease. It can aggravate or can be aggravated by advanced coexistent chronic liver diseases. PiZ immunohistochemistry is an easy, highly specific method to detect this metabolic defect on liver biopsies.

Adult↗

PubMed2000

Detection of alpha-1-antitrypsin PiZ individuals by SSCP and DNA sequencing in formalin-fixed and paraffin-embedded tissue: a comparison with immunohistochemical analysis.

BACKGROUND/AIM: The role of alpha-1-antitrypsin (AAT) deficiency in the development of cirrhosis and carcinoma of the liver can be investigated from the analysis of archival biopsy specimens. Immunohistochemistry can visualize the storage of defective protease inhibitor (Pi) variant Z, but does not allow differentation between homozygous and heterozygous patients. The aim of the study was to establish a method for the detection of the PiZ mutation on the gene level. METHODS: Liver biopsy and autopsy samples in which AAT deficiency was detected immunohistochemically by a monoclonal PiZ-antibody were analyzed by single-strand conformational polymorphism (SSCP) to reliably determine hetero- and homozygote carrier state in the absence of blood samples and to confirm the histological diagnosis. The accuracy of SSCP was verified by direct DNA sequencing. RESULTS: Tissue slices (>0.8 cm2) from 29 consecutive cases with immunohistochemically detected PiZ depositions and from ten PiZ-negative control cases were provided for extraction and amplification of DNA. In comparison to wild-type sequence of AAT exon V, all 29 cases showed band shifts on SSCP analysis, with a heterozygous pattern in 28 patients and a homozygous pattern in one patient. DNA sequence analysis revealed the same single-base mutation at position 342 of AAT exon V. CONCLUSIONS: SSCP analysis proved a sensitive and specific technique for the detection of the PiZ mutation at the gene level, which allowed unequivocal differentiation between heterozygous and homozygous PiZ status from paraffin-embedded archival tissue specimens. Besides a use in diagnostic pathology, this technique could be valuable for prenatal diagnosis and population screening purposes.

Base Sequence↗

PubMed1999

Interferon/antioxidant combination therapy for chronic hepatitis C--a controlled pilot trial.

The effects of two forms of antioxidative co-therapy were analyzed in 24 interferon-alpha (IFN)-naive patients with chronic hepatitis C who were randomized to either receive IFN monotherapy (3 x 4.5 million units IFN-alpha 2a per week), (group A), or IFN and N-acetylcysteine (N-acetylcysteine (NAC) 1.800 mg/day) plus sodium selenite (400 microg/day) supplementation (group B), or treatment as in group B plus vitamin E (544 IU/day) (group C), over 24 weeks. Changes in histology, normalization of ALT, reduction of viral RNA, serum levels of glutathione, selenium, vitamin E, erythrocyte glutathione peroxidase, trolox equivalent antioxidative capacity (TEAC), thiobarbituric acid reactive substances (TBARS) and protein carbonyl groups were measured. Low baseline TEAC and elevated TBARS indicated increased oxidative stress before therapy, which was not affected by antioxidant supplementation. At the end of treatment complete responses were found in 3/8, 2/8 and 6/8 patients in groups A, B and C, respectively, but liver histology had not significantly improved. Vitamin E treated patients had a 2.4 greater chance (95% CI: 1.05-5.5) of obtaining a complete response and had significantly greater reduction in viral load (P = 0.028) than patients without vitamin E. Relapses, i.e. re-appearance of detectable hepatitis C virus (HCV) RNA and/or re-elevation of ALT-activity occurred in 7 out of the 11 responders within 6 months after termination of therapy (group A: 2/3, group B: 1/2 and group C: 4/6). Thus, no overall beneficial effect of antioxidant/IFN therapy was detected. However, the apparent trend towards a more favorable outcome with vitamin E supplementation warrants to further study this substance as an adjuvant to IFN therapy in chronic hepatitis C.

Acetylcysteine↗