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Biomedical subjects

A Zimmermann

Publications and source records attributed to A Zimmermann.

At least 163 records · Page 9Linked to original sources
PubMed1996

Inosine monophosphate dehydrogenase expression: transcriptional regulation of the type I and type II genes.

Inosine 5'-monophosphate dehydrogenase (IMPDH) is an essential rate-limiting enzyme in the de novo guanine nucleotide synthetic pathway that catalyzes the conversion of IMP to XMP. Enzyme activity is accounted for by the expression of two distinct but closely related genes termed IMPDH I and II. Increased IMPDH activity has been linked to both cellular proliferation and neoplastic transformation and generally ascribed to an increase in the expression of the type II gene. We have characterized the type I and type II genes and identified elements important in the transcriptional regulation of both genes. The type II IMPDH gene contains a 466 bp 5' flanking region spanning the translation start site that contains several transcription factor binding sites and mediates increased transcription of a CAT reporter gene in peripheral blood T lymphocytes when these cells are induced to proliferate. The single functional IMPDH type I gene contains exon-intron boundaries and exon structures that are nearly identical to those in the type II gene. In contrast to the type II gene, however, it contains two putative promoter sites, each with the potential for transcriptional regulation. We conclude that these two genes most probably arose from an early gene duplication event and that their highly conserved structures and differential regulation at the transcriptional level argue strongly for a significant role for each gene in cellular metabolism, growth, and differentiation.

Chloramphenicol O-Acetyltransferase↗
PubMed1996

Analysis of sequence and pathogenic properties of two variants of encephalomyocarditis virus differing in a single amino acid in VP1.

The encephalomyocarditis (EMC) virus-induced diabetes-like syndrome in mouse inbred strains was used as a model to study the insulin-dependent diabetes mellitus (IDDM). Our investigations were performed with two EMC virus variants, PV2 and PV7. After infection of SJL mice with 10(5) PFU of PV2 about 70% of the animals developed a diabetes-like syndrome, whereas the PV7 infected mice appeared healthy. Histological examination and in situ experiments revealed that the islets of Langerhans are a main target of PV2, whereas PV7 infection leads to only modest changes of the islets. Sequence analysis of both variants revealed one amino acid exchange within the capsid protein VP1. Hence, we describe the first diabetogenic and non-diabetogenic EMCV variants differing in only one single amino acid.

Amino Acid Sequence↗
PubMed1996

Fixed versus titrated interferon-alpha 2B in chronic hepatitis C. A randomized controlled multicenter trial. The Swiss Association for the Study of the Liver.

BACKGROUND/AIM: Interferon has become the mainstay of treatment of chronic hepatitis C; however, duration of treatment and dose remain unresolved questions. The present study aimed to compare standard dose interferon with a titrated dose regimen carried out for 1 year. METHODS: This was a randomized, controlled multicenter trial. Patients with chronic hepatitis C were randomly allocated to a control group (n = 30), to a fixed dose group (n = 31) where interferon-alpha 2b 3 MU thrice weekly was given for 1 year or a titrated group (n = 34) where interferon was titrated starting at 5 MU thrice weekly to the lowest dose keeping the patient in remission as assessed by a normal ALT value. Liver biopsies were obtained before and at the end of treatment; in addition, galactose elimination capacity was measured as a measure of cytosolic function. RESULTS: In the control, fixed and titrated groups a complete response was achieved in 2/29, 10/28 and 15/31, respectively (p < 0.001 in favor of treatment, p = n.s. for the two treatments). The corresponding figure for sustained response was 1/29, 5/28 and 6/ 31 (p = n.s). In the titrated group, a complete (sustained) response was achieved with 5 MU in 2 (2), with 4 MU in 1 (0), with 3 MU in 4 (0), with 2 MU in 3 (0) and with 1 MU in 5 (4). Liver biopsy score and galactose elimination capacity improved significantly in responders but not in treatment failures. CONCLUSIONS: Both fixed and titrated dosing of interferon given for 1 year induced virus clearance in only a minority of treated patients. However, in a small number of patients, a complete and sustained response can be achieved with low doses of interferon. Dose titration could be an interesting approach to decreasing the cost and side effects in the treatment of chronic hepatitis C.

Adult↗
PubMed1996

The UL97 gene product of human cytomegalovirus is an early-late protein with a nuclear localization but is not a nucleoside kinase.

The temporal expression of the UL97 gene product during human cytomegalovirus (HCMV) infection of human foreskin fibroblasts (HFF) and subcellular localization of this protein were analyzed by using a polyclonal antiserum raised against a truncated UL97 protein of 47 kDa. The UL97 protein was detectable 16 h after infection by Western blot (immunoblot) analysis. Since only reduced UL97 expression occurred in the presence of two inhibitors of DNA replication, phosphonoacetic acid and ganciclovir, we conclude that UL97 is an early-late gene, requiring DNA replication for maximum expression. By indirect immunofluorescence, the protein could be visualized in the nuclei of virus-infected HFF 22 h after infection. Nuclear localization of the UL97 protein was also detected in thymidine kinase-deficient 143B cells infected with a recombinant vaccinia virus containing the entire UL97 open reading frame (ORF), as well as in HFF transiently expressing the entire UL97 ORF under the control of HCMV major immediate-early promoter. However, transiently expressed 5'-terminal deletion mutants of the UL97 ORF in addition showed a cytoplasmic localization of the UL97 protein, confirming the presence of a nuclear localization site in the N-terminal region of the protein. Our high-pressure liquid chromatography analyses confirmed the ganciclovir phosphorylation by the UL97 protein, but no specific phosphorylation of natural nucleosides was observed, indicating that the UL97 protein is not a nucleoside kinase. During plaque purification of recombinant UL97-deficient HCMV, this virus was growth defective; hence, we presume that UL97 may be essential for the viral life cycle.

Amino Acid Sequence↗
PubMed1996

[Bilateral coronary fistula: a case report and review].

A case is presented of an atypical arteriovenous coronary artery fistula which occurred in a young man who was admitted to hospital with constant stress-dependent dyspnea and a feeling of thoracic constriction. A continuous systolic-diastolic murmur above the 5th intercostal space to the left of the sternum was present. By means of transoesophageal echocardiography and heart catheterization a rather atypical bilateral coronary fistula was found. A bilateral coronary fistula had been formed from RCA and RCX which drained via a common intramural cavity into the right ventricle. The fistula was operatively closed. Bilateral coronary artery fistula are rare, being found with a frequency of 0.002-0.013% in heart catheterization. In 36 reported instances of bilateral fistulae it has been noted that drainage into the pulmonary artery is more common than is the case with single coronary artery fistulae. The therapeutic considerations correspond with those for single fistulae.

Adult↗
PubMed1996

[Diffuse bile duct papillomatosis: high rate of recurrence and risk of malignant transformation].

Bile duct papillomatosis is a rare disease. It is characterised by multicentric papillary lesions of the intra- and/or extrahepatic biliary epithelium. Because of its slow progression, its high rate of recurrence and significant risk of malignant transformation, it is an important cause of obstructive neoplastic bile duct diseases. We report one of these rare cases with the typical clinical signs and exceptional long survival time of eight years: After a history of fifteen years of recurrent epigastric pains the diagnosis of a diffuse biliary papillomatosis was made after surgery. Five years postoperatively a bile duct carcinoma has developed. After a R1-resection of the tumor, the patient was again free of complaints up to the appearances of multiple metastases two years later. He died a year later of metastasizing disease. We discuss the pathological and clinical aspects of this disease and review the literature.

Aged↗
PubMed1996

Tenascin and type IV collagen expression in liver cell dysplasia and in hepatocellular carcinoma.

The extracellular matrix (ECM) located in and around tumors is different from normal organ stroma, and there is evidence that it is critically involved in carcinogenesis and malignant growth. Whereas an abnormal composition of ECM in hepatocellular carcinomas (HCC's) has previously been demonstrated, not much is known so far with respect to putative HCC precursor lesions. We have, therefore, systematically analyzed the immunohistochemical reactivity for two major ECM components, tenascin and type IV collagen, in three types of liver cell dysplasia (LCD), and compared the findings with patterns observed in HCC's of different types and grades. Tenascin reactivity was generally stronger in HCC's than in cirrhosis. In cirrhotic nodules harboring areas of LCD, tenascin expression was significantly lower in small cell LCD than in large cell LCD. Type IV collagen reactivity in and around HCC's decreased as a function of a lower differentiation grade. In both groups of cirrhosis, i.e. with or without HCC, cirrhotic nodules occupied by the small cell variant of LCD exhibited a significantly lower type IV collagen reactivity than those with large cell LCD or simple regenerative cells. Taken together these findings suggest that, similar to adenomatous hyperplasia, small cell LCD is characterized by an abnormal tenascin and type IV collagen expression, thus reflecting the defective ECM pattern observed in HCC's.

Carcinoma, Hepatocellular↗
PubMed1996

Copper/zinc and manganese superoxide dismutases in alcoholic liver disease: immunohistochemical quantitation.

Alcohol damage to the liver can, among other factors, be mediated through the action of toxic oxygen radicals generated by ethanol. Major antioxidants in the liver are copper/zinc and manganese superoxide dismutases (Cu/Zn- and Mn-SODs). In order to test whether SODs may be differentially expressed in alcoholic liver disease (ALD), biopsies from 45 patients with ALD were analyzed for qualitative and quantitative immunoreactivity of Cu/Zn- and Mn-SOD in hepatocytes. The overall amount of Cu/Zn-SOD reactivity was significantly lower in ALD than in control biopsies, whereas no difference was found for Mn-SOD. Staining for both enzymes was decreased in ballooned hepatocytes. Low Cu/Zn-SOD was correlated with advanced lattice-like perisinusoidal fibrosis. In hepatocytes forming cirrhotic nodules, SOD reactivity was similar to that of control cells. The results suggest that SODs may be differentially regulated in ALD, and that Mn-SOD, an inducible enzyme, may be involved in recovery and cell protection in ALD.

Adult↗
PubMed1995

[Demonstration of mesangial IgA deposits in kidney biopsies of pediatric patients: comparison with the clinical picture].

Clinical and morphological findings were evaluated in 25 children with mesangial IgA deposits. 19 patients had recurrent macroscopic hematuria (n = 10), chronic proteinuria > 40 mg/(m2.h) (n = 5), recurrent hematuria with chronic proteinuria (n = 3), or chronic nephrotic syndrome (n = 1). The glomerular involvement was similar in six patients with history of Schönlein-Henoch purpura and in 13 patients without such history: normal or nearly normal glomeruli (n = 3), focal and segmental glomerulonephritis (n = 11) and diffuse proliferative glomerulonephritis (n = 5). End-stage renal disease developed in two patients with proteinuria > 40 mg/(m2.h) and more than 50% of their glomeruli are affected by crescents. The common histopathological features in patients with and without history of Schönlein-Henoch purpura suggest a common pathogenesis. The risk of poor outcome appears, related to the severity of proteinuria and to the presence of crescents, in more than 50% of glomeruli. Mesangial IgA deposits were also demonstrated in six children with steroid-responsive idiopathic nephrotic syndrome: light microscopic studies revealed normal or nearly normal glomeruli in five and focal segmental glomerular sclerosis in one patient. The microscopic findings were clearly different in the six patients with idiopathic nephrotic syndrome as compared with the patient with chronic nephrotic syndrome, who presented with severe glomerular lesions and extensive crescent formation. The results indicate that the presence of mesangial IgA deposits in the clinical setting of idiopathic childhood nephrotic syndrome is incidental and that such patients should still be considered as having idiopathic nephrotic syndrome in spite of their immunopathological features.

Adolescent↗
PubMed1995

Histological features of glomerular immaturity in infants and small children with normal or altered tubular function.

In children with renal tubular disorders the existence of retarded histological features of glomerular maturation has been suggested by our group. However, no valuable information is available on the frequency of histopathologically immature glomeruli in the normal kidney. For this reason we established a simple, semiquantitative definition of postnatal glomerular development: immature glomeruli (with at least half of the circumference of capillary loops densely lined with cuboidal epithelial cells), intermediate glomeruli (circumference of capillary loops lined with at least five adjoining cuboidal cells), and mature glomeruli. This definition was applied in a set of 71 normal kidneys from ages birth to 5 years. The relative frequency of the mentioned stages of glomerular maturation was strongly age dependent. In comparing the patients data with the normal findings it was possible to separate patients with the finding of disproportionately high fractions of immature glomeruli, provided the right age at biopsy is chosen. It is therefore concluded that the previous suspicion of late glomerular maturation may be validated in at least in some bioptic specimens.

Biopsy↗
PubMed1995

[Primary biliary cirrhosis. Localization of antigen-presenting cells in piecemeal necroses].

Liver tissue from 14 female patients with primary biliary cirrhosis (PBC; stages I-IV) was systematically investigated for the prevalence and distribution of dendritic antigen-presenting cells. Dendritic cells (DCs) were immunhistochemically identified by use of anti-S 100 protein and KiMlp antibodies. We confirm previous findings that, in early PBC, S 100 protein-positive DCs can be detected within the lining of bile duct epithelia. However, the present study disclosed that S 100 protein- and KiMlp-positive DCs regularly occur in piece-meal necroses (PMNs) developing in PBC-associated chronic hepatitis. DCs in PMNs were observed in all PBC stages, but were most prominent in late-stage PBC. These findings suggest that autoimmune tissue damage in PBC may not be limited to bile ducts, but may also ensue in hepatic parenchyma, producing the pattern of chronic hepatitis with signs of activity.

Aged↗
PubMed1995

Complete nucleotide sequence and biological properties of an infectious clone of prototype echovirus 9.

The prototype Hill of echovirus 9, a human enterovirus, exhibits no pathogenicity for newborn mice in contrast to some other echovirus 9 strains isolated subsequently during epidemics. In this communication we report the first complete nucleotide sequence and construction of an infectious clone of echovirus 9. Aside from the 3' poly(A)-tract, the RNA genome is 7420 nucleotides (nt) in length and encodes a single polyprotein of 2193 amino acids (aa). The open reading frame extends from position 740 to position 7318 of the genome. Sequence comparisons to other enteroviruses reveal a strong overall amino acid identity to echovirus types 11 and 12 (in each case 76%). The proteolytic cleavage sites of the three major capsid proteins were determined after purification by HPLC and protein sequencing. A full-length clone coding for an infectious RNA transcript was constructed, and recombinant echovirus 9 particles could be isolated from the supernatant of transfected cell culture. It is shown that the recombinant virus, like the original prototype, is non-pathogenic for newborn mice and does not multiply in skeletal muscles.

Amino Acid Sequence↗
PubMed1995

The overexpression of proliferating cell nuclear antigen in biliary cirrhosis in the rat and its relationship with epidermal growth factor receptor.

Chronic bile duct obstruction in the rat leads to biliary cirrhosis but maintained hepatocellular mass. We have previously demonstrated translocation of epidermal growth factor receptor to nuclei. It remained unclear, however, whether this was due to hepatocyte proliferation and/or altered handling of epidermal growth factor receptor. Therefore, in the present investigation we stereologically estimated expression of proliferating cell nuclear antigen, a marker of the S phase of teh cell cycle at 1, 2, 3, 7, 14, 21 and 28 days after bile duct ligation. Proliferating cell nuclear antigen positive hepatocytes averaged 2.1 +/- 3.6% in sham-operated control animals. This increased to 20.7 +/- 6.4, 26.8 +/- 18.7, 31.3 +/- 23.9, 42.3 +/- 16.6 and 24.7 +/- 28.0% 3, 7, 14, 21 and 28 days after bile duct ligation, respectively (p<0.005 by ANOVA). This was correlated with the number of epidermal growth factor receptor positive nuclei (rs = 0.737) and inversely with the maximal binding capacity of epidermal growth factor to a crude plasma membrane fraction (rs = 0.697) reported previously. We conclude that bile duct ligation in the rat induces a significant hepatocellular proliferation as assessed by proliferating cell nuclear antigen expression and that this process could, at least in part, be related to increased nuclear expression of the epidermal growth factor receptor.

Analysis of Variance↗
PubMed1995

Experimental atrophy/hypertrophy complex (AHC) of the liver: portal vein, but not bile duct obstruction, is the main driving force for the development of AHC in the rat.

BACKGROUND/AIMS: Patients with lobar or segmental impairment of bile flow or of portal venous blood flow frequently develop considerable atrophy of the area involved, followed by compensatory hypertrophy/hyperplasia of the non-affected parts. This configuration is termed atrophy/hypertrophy complex of the liver. METHODS: In order to analyze the relative contributions of bile duct and portal vein obstruction in the pathogenesis of atrophy/hypertrophy complex, we developed a rat model with selective bile duct and/or portal vein ligation of the anterior liver lobes, representing about two thirds of the liver mass. Evolution of total body weights and weights of the different liver lobes were determined, and morphometry and functional scintigraphy (hepatoiodida scanning) were performed immediately after ligation and at 30 h, 4, 8 and 28 days postoperatively. RESULTS: The major findings were: 28 days after biliary and/or portal ligation there was no difference between the body weights of all animals, all ligated animals having compensated an initial body weight loss. Total liver weight remained constant during the whole observation period, while atrophy of the anterior and hypertrophy/hyperplasia of the posterior lobes occurred. A significant atrophy/hypertrophy complex developed only after selective portal ligation, but not after selective biliary ligation. Morphometrically analyzed histologic changes after selective biliary ligation were reversible, whereas in portally ligated liver lobes a progressive parenchymal destruction and involution with subsequent impairment of hepatic function of the concerned lobe were observed. CONCLUSIONS: The present findings indicate that impairment of portal venous flow is the major driving force for the development of lobar atrophy in the rat and that atrophy/hypertrophy complex can be produced in a rodent model.

Animals↗
PubMed1995

Renal pathology after arterial yttrium-90 microsphere administration in pigs. A model for superselective radioembolization therapy.

RATIONALE AND OBJECTIVES: To test the selectivity of tissue damage in radioembolization, the authors performed an experimental study using superselective administration of yttrium-90 particles to deliver up to 100 Gy to the porcine kidney. Patterns and severity of damage in test organs were compared with controls, and the feasibility of this model is discussed. METHODS: Eight sows were included in the study. Bio-Rex 70 particles were applied via selective catheterization of the renal artery. Four pigs received inactive particles and four pigs received active particles. Organ distribution and shunting of yttrium-90 were determined, and kidney damage patterns were histologically analyzed. RESULTS AND CONCLUSIONS: The model demonstrates that yttrium-90-labeled resin particles can superselectively be applied. Retention of beta activity in the target organ was more than 95%. In addition to tissue shrinkage from mechanical obstruction, considerable damage ensued mainly by radiation-induced arterial necrosis and arteritis.

Animals↗
PubMed1995

Anaerobic activation of the entire denitrification pathway in Pseudomonas aeruginosa requires Anr, an analog of Fnr.

The Pseudomonas aeruginosa gene anr, which encodes a structural and functional analog of the anaerobic regulator Fnr in Escherichia coli, was mapped to the SpeI fragment R, which is at about 59 min on the genomic map of P. aeruginosa PAO1. Wild-type P. aeruginosa PAO1 grew under anaerobic conditions with nitrate, nitrite, and nitrous oxide as alternative electron acceptors. An anr deletion mutant, PAO6261, was constructed. It was unable to grow with these alternative electron acceptors; however, its ability to denitrify was restored upon the introduction of the wild-type anr gene. In addition, the activities of two enzymes in the denitrification pathway, nitrite reductase and nitric oxide reductase, were not detectable under oxygen-limiting conditions in strain PAO6261 but were restored when complemented with the anr+ gene. These results indicate that the anr gene product plays a key role in anaerobically activating the entire denitrification pathway.

Anaerobiosis↗