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Biomedical subjects

J G Müller

Publications and source records attributed to J G Müller.

At least 19 recordsLinked to original sources
PubMed2004

Modulation of simian immunodeficiency virus neuropathology by dopaminergic drugs.

Drug abuse and human immunodeficiency virus (HIV) infection seem to cause cumulative damage in the central nervous system (CNS). Elevated extracellular dopamine is thought to be a prime mediator of the reinforcing effects of addictive substances. To investigate the possible role of increased dopamine availability in the pathogenesis of HIV dementia, simian immunodeficiency virus (SIV)-infected monkeys were treated with dopaminergic drugs (selegiline or L-DOPA). Both substances increased intracerebral SIV expression, combined with aggravation of infection-related neuropathology and ultrastructural alterations of dendrites in dopaminergic areas (spongiform polioencephalopathy) in asymptomatic animals. Moreover, this treatment resulted in enhanced TNF-alpha expression in the brains of SIV-infected animals. These findings indicate a synergistic interaction between dopamine and SIV infection on microglia activation, leading to increased viral replication and production of neurotoxic substances. Our results suggest that increased dopamine availability through dopaminergic medication or addictive substances may potentiate HIV dementia.

Animals↗
PubMed2004

[Isolated Rosai-Dorfman disease].

A case of extranodal sinus histiocytosis with massive lymphadenopathy (ENSHML; Rosai-Dorfman disease) is reported. The patient presented with a history of intracranial tumour and exophthalmus. Clinical examination found a large mass in the left orbit and paranasal sinuses. Excisional biopsy showed a dense fibrous tissue with an infiltrate rich in macrophages. Further evaluation revealed a retroperitoneal mass with consecutive ureteral stenosis. Further histological and immunohistochemical investigation of the orbital mass, now in suspicion of a systemic disease showed an infiltrate of S-100-positive histiocytes and emperipolesis allowing the diagnosis of extranodal sinus histiocytosis. The correct histologic diagnosis was delayed due to the unusual and isolated extranodal localisation of the disease. The literature concerning extranodal manifestations of Rosai-Dorfman disease is reviewed. We suggest the additional evaluation of such rare and unusual cases in experienced reference centers.

Biopsy↗
PubMed2003

Linewidth-limited energy transfer in single conjugated polymer molecules.

Using low temperature single molecule spectroscopy on rigid-rod conjugated polymers we are able to identify homogeneously broadened, strongly polarized emission from individual chromophore units on a single chain. Gated fluorescence spectroscopy allows real time imaging of intramolecular energy transfer as the chain behaves as a series of weakly interacting chromophores. Energy transfer is controlled by the chromophoric spectral linewidth, which depends on temperature. Linewidths exceeding intramolecular disorder lead to incoherent chromophore coupling and collective fluorescence phenomena.

Journal Article↗
PubMed2003

[Solid-pseudopapillary tumor of the pancreas as differential diagnosis in pancreatic tumors of the young].

AIM: The presentation of solid pseudopapillary tumors of the pancreas (SPTP) with examples of our own surgical department. SPTP occur typically in young women or in children and are for most of benign behavior. In about 5 % a malignant course with occurrence of metastases can develop. METHODS: Diagnosis, morphological and histological findings and therapeutic approach are described in three cases. The differential diagnosis of other tumors of the pancreas is discussed. FINDINGS: Three women (age 21, 33 and 43) with SPTP have been treated in the Department of Surgery at the University of Würzburg between 1997-1999. All tumors were resected curatively. No adjuvant treatment was performed. The follow up ranged from 31-56 months. No relapse of disease or occurrence of metastases were observed. All resected specimen revealed the typical character of SPTP with areas of solid parts and hemorrhage within the tumor. A panel of immunohistological markers (Vimentin, N-Cam, NSE, Chromogranin, Synaptophysin, Ck7, Ck19, Ck20, EMA) and expression of receptors were investigated. CONCLUSION: The diagnosis of this rare tumor can be made clinically and intraoperatively according to its typical morphology and occurrence, predominantly in young women or in children thus helping to perform adequate surgical therapy.

Adult↗
PubMed2002

Precursor states for charge carrier generation in conjugated polymers probed by ultrafast spectroscopy.

Photocurrent experiments using two femtosecond laser pulses are performed on a photodiode using a ladder-type conjugated polymer as the active layer. With a photon energy of 3.1 eV the first pulse excites singlet excitons. A time-delayed second pulse with a photon energy of 2.49 eV leads to a decrease of the photocurrent by exciton depletion due to stimulated emission. S1 excitons being dissociated during their entire lifetime are identified as the only relevant channel for charge carrier generation. Intrachain polaron pairs are also formed on an ultrafast time scale with a yield of approximately 10%. They can be efficiently dissociated by reexcitation with photons of an energy of 1.9 eV.

Journal Article↗
PubMed2002

[Cylindrocarcinoma in a patient with Brooke-Spiegler syndrome].

BACKGROUND: Cutaneous cylindromas are benign adnexal tumors that may occur as a solitary lesion or in a multiple familiar pattern. Malignant change is rare. The association of multiple trichoepitheliomas and cylindromas, the so called Brooke-Spiegler Syndrome, is supposed to be inherited in an autosomal dominant manner. PATIENTS: A 55 year old woman presented with multiple skin tumors on the scalp, as well as the nasolabial and periauricular area since the age of 20 years. Her daughter and her nephew were also affected. Tumors were surgically removed for cosmetic reasons and showed histological signs of benign cylindromas and trichoepitheliomas. 35 years after diagnosis patient presented with a large exulceration on the right occipital area with intracranial invasion. Staging revealed multiple metastases in both lungs. Patient died 1 month later. RESULTS: Histological examination showed beside zones of massive necrosis multiple mitosis. The jigsaw puzzle pattern and the thick PAS positive basal layer, the striking characteristics of benign cylindromas, were lost. These histological findings and the clinical presentation led to the diagnosis of cylindrocarcinoma. CONCLUSIONS: Cylindrocarcinoma is an aggressive tumor with tendency to a local destructive growth and metastases. As malignant transformation of a benign cylindroma occurs more often in the multiple form a close follow-up of patients with multiple cylindromas is necessary. A family study is indicated.

Carcinoma, Adenoid Cystic↗
PubMed2002

Butyrate inhibits NF-kappaB activation in lamina propria macrophages of patients with ulcerative colitis.

BACKGROUND: In ulcerative colitis (UC) the activation (i.e. nuclear translocation) of nuclear factor kappa B (NF-kappaB) is an important step in the regulation of cytokines secreted by lamina propria macrophages. Clinical trials suggest anti-inflammatory effects of locally administered butyrate in UC. The potential effects of butyrate on NF-kappaB activation in lamina propria macrophages of UC patients were investigated. METHODS: Eleven patients with distal UC were treated for up to 8 weeks with butyrate at 100 mM (n = 6) or placebo (n = 5) enemas. At entry and after 4 and 8 weeks, clinical status was noted and intestinal inflammation was graded endoscopically and histologically. Double-staining with antibodies against NF-kappaB (p65) and CD68 was employed to detect NF-kappaB and macrophages, respectively. RESULTS: In untreated patients, nuclear translocation of NF-kappaB was detectable in virtually all macrophages. Butyrate treatment for 4 and 8 weeks resulted in a significant reduction in the number of macrophages being positive for nuclear translocated NF-kappaB. In addition, butyrate significantly reduced both the number of neutrophils in crypt and surface epithelia and of the lamina propria lymphocytes/plasma cells. These findings correlated with a significant decrease in the Disease Activity Index (DAI). CONCLUSIONS: The decrease in DAI and mucosal inflammation in butyrate-treated patients is associated with a reduction of NF-kappaB translocation in lamina propria macrophages. Since the inflammatory process in UC is mainly sustained by macrophage-derived cytokines, the known anti-inflammatory effects of butyrate may in part be mediated by an inhibition of NF-kappaB activation in these macrophages.

Adult↗
PubMed2001

Enhancement of central nervous system pathology in early simian immunodeficiency virus infection by dopaminergic drugs.

Human immunodeficiency virus infection (HIV) at late stages of the disease is accompanied by neurological complications, including motor, behavioral and cognitive impairment. Using simian immunodeficiency virus (SIV)-infected rhesus monkeys, an animal model of HIV infection, we found that during the asymptomatic SIV infection dopamine (DA) deficits are early components of central nervous system (CNS) dysfunction. To investigate the role of the DA system in SIV infection and to restore the DA deficiency, we administered selegiline, an agent with DAergic and neuroprotective properties, to SIV-infected monkeys. Selegiline increased DA availability but induced CNS vacuolization, SIV encephalitic lesions, and enhanced CNS viral replication during early SIV infection. The pathological changes seem to be mediated by DA, as treatment with L-DOPA, the precursor of DA, had similar effects. We propose that any natural or induced DAergic dysregulation which results in increased DA availability may potentiate HIV-associated neurological disease (ND). Our findings raise new questions regarding the pathogenesis of HIV-ND and generate concerns about the safety of dopaminergic drugs in the clinical management of HIV-infected patients.

AIDS Dementia Complex↗
PubMed2001

Lovastatin blocks basic fibroblast growth factor-induced mitogen-activated protein kinase signaling in coronary smooth muscle cells via phosphatase inhibition.

We have recently reported that the activation of mitogen-activated protein kinase (MAPK) through specific protein kinase C (PKC) isoforms is required for basic fibroblast growth factor (bFGF)-induced proliferation of coronary smooth muscle cells (cSMC). In this study, we investigated the effects of the 3hydroxy-3-methyl glutaryl coenzyme A (HMG CoA) reductase inhibitor lovastatin on bFGF-induced signal transduction in cSMC. The present study shows that lovastatin inhibits bFGF-stimulated DNA synthesis in cSMC, and that this inhibition is reversed by mevalonate (50 micromol/l) and by geranylgeranyl-pyrophosphate (1-5 micromol/l). Although lovastatin prevented Ras farnesylation the amount of bFGF-stimulated MAPK phosphorylation decreased only partially after lovastatin treatment. In addition, lovastatin pretreatment resulted in a sustained phosphorylation of MAPK. We observed a dose-dependent lovastatin-dependent increase in PKC activity, which could be prevented by mevalonate. This increase was comparable to the one induced by calyculin A (2 nmol/l), an inhibitor of protein phosphatase PP-1 and PP-2A. Lovastatin inhibited the expression of the PP-1 protein, which is involved in bFGF-induced DNA synthesis in cSMC. Thus, our data suggest that, lovastatin possibly affects the dephosphorylation processes of PKC and MAPK by inhibition of PP-1/PP-2A protein phosphatases which are involved in the bFGF-induced mitogenesis in cSMC.

Animals↗
PubMed2000

Early activation and proliferation of T cells in simian immunodeficiency virus-infected rhesus monkeys.

To longitudinally determine T cell activation and turnover in early simian immunodeficiency virus (SIV) infection of macaques, immunological and virological parameters were monitored in 10 SIV-infected animals starting before infection until 40 weeks postinfection (wpi). Lymphocyte subsets in blood and lymph nodes (LNs) were characterized by three-color flow cytometry for expression of markers of activation, proliferation, and differentiation. As early as 1 wpi, CD69 expression was upregulated both on CD4+ and CD8+ T cells, indicative of an early activation of these cells. Whereas this activation led to increased proliferation, determined by expression of Ki-67, and absolute numbers of CD8+ T cells, CD4+ T cells showed a decreased expression of Ki-67 and reduced counts in blood at 2 wpi. Later, the percentage of Ki-67-expressing CD4+ T cells in blood and LNs increased again above preinfection levels in most animals but remained low in two monkeys progressing to AIDS. These findings suggest that T cells are activated after SIV infection, leading to increased T cell proliferation already in the early asymptomatic phase. In addition, we found a correlation between the capacity to regenerate CD4+ T cells by peripheral proliferation and the disease course. Moreover, our data indicate that the increased peripheral T cell proliferation during immunodeficiency virus infection is probably not caused by the effort of the immune system to maintain T cell homeostasis but may be a reflection of the ongoing immune response against the virus.

Animals↗
PubMed2000

Differences in the effects of HMG-CoA reductase inhibitors on proliferation and viability of smooth muscle cells in culture.

We investigated the influence of lovastatin, simvastatin and pravastatin on proliferation and viability of vascular smooth muscle cells (SMC) in vitro and studied the effects of lovastatin on a mouse SMC line transgenic for a temperature-sensitive mutant of SV40 large T antigen (TAg), known to inhibit the function of p53 and pRb family members. We found that lovastatin and simvastatin inhibited cell proliferation by provoking G0/G1 phase arrest with concomitant depression of the proliferation antigen Ki-67/MIB-1. Lovastatin at high concentrations of 20 micromol/l caused cell death in the presence of serum but not under serum starved conditions, which was verified on the basis of increased DNA strand breaks, decreased DNA content and morphological alterations seen by electron microscopy. Cell death was also found for simvastatin, whereas pravastatin did not exhibit antiproliferative or cytotoxic effects. Mouse SMC transgenic for TAg did not show any impaired sensitivity to the antiproliferative and cell death inducing effect of lovastatin, but both effects could be antagonized by the supplementation of mevalonate. The data indicate that antiproliferative and cytotoxic effects of lovastatin are caused by the using up of products of mevalonate metabolism and do not require the presence of p53 or pRb.

Animals↗
PubMed2000

Total numbers of lymphocyte subsets in different lymph node regions of uninfected and SIV-infected macaques.

Human immunodeficiency virus (HIV) infection leads to a decline of CD4+ T-cells in blood. Because blood represents only a small proportion of the total lymphocyte pool, it is important to investigate other lymphoid organs. So far, only relative proportions of lymphocyte subsets in single peripheral lymph node (LN) regions of HIV-infected patients and simian immunodeficiency virus (SIV)-infected macaques have been documented. We have therefore quantified the absolute numbers of lymphocyte subsets in blood and six different LN regions of 10 uninfected and 26 SIV-infected macaques. In addition, we have determined the expression of markers of activation and differentiation. Already, in uninfected monkeys, there were significant differences in the cellular composition of different LN regions. Infection with SIV resulted in drastic changes in the proportion as well as absolute numbers of different lymphocyte subsets. Moreover, the relative contribution of the single LN regions to the total lymphocyte pool was also altered.

Animals↗
PubMed1999

[Fatty liver in adult celiac disease].

HISTORY AND ADMISSION FINDINGS: A 31-year-old woman was admitted because of heptomegaly and abnormal liver functions. For years she had suffered from diarrhoea but its cause had never been elucidated. She was underweight and had mild ankle edema. The liver margin was palpable at 20 cm below the midcostal margin, but the abdominal examination was otherwise unremarkable. INVESTIGATIONS: Sonography revealed a very large fatty liver. Biopsy showed fatty infiltration of nearly all the hepatocytes, without significant inflammation and fibrosis. Small-intestinal biopsy showed the typical histology of coeliac disease. Laboratory tests indicated abnormal liver function with increased transaminases, alkaline phosphatase, GPT and LDH, but no sign of inflammatory aetiology. These findings suggested that the liver changes were due to the coeliac disease. TREATMENT AND COURSE: After the patient had been put on a gluten-free diet the diarrhoea stopped and she started to gain weight. The liver function tests briefly became worse, but over the following 6 weeks normalized completely. The patient gained 5 kg in the subsequent 18 months and the liver became sonographically normal. The small-intestinal biopsy now showed merely discrete villar atrophy. CONCLUSION: Coeliac disease should be considered in any case of fatty liver of unknown cause. Strict gluten-free dietary treatment of the underlying cause can quickly lead to complete regression of the hepatic changes.

Adult↗
PubMed1999

Protein kinase C mediates basic fibroblast growth factor-induced proliferation through mitogen-activated protein kinase in coronary smooth muscle cells.

Proliferation of coronary smooth muscle cells (cSMCs) contributes to the pathogenesis of arteriosclerosis and restenosis after angioplasty, and basic fibroblast growth factor (bFGF) is a powerful mitogen for cSMCs. In this study, we investigated the involvement of mitogen-activated protein kinase (MAPK), protein kinase C (PKC), and the transcription factor c-myc in bFGF-stimulated mitogenesis, as well as the functional relationship between these factors. cSMC stimulation with bFGF resulted in phosphorylation of p42 MAPK, as well as the phosphorylation and increased expression of c-myc. The MAPK kinase (MEK) inhibitor PD98059 blocked bFGF-stimulated MAPK phosphorylation and resulted in both a decrease of c-myc expression and inhibition of bFGF-stimulated DNA synthesis in cSMCs. bFGF also increased PKC activity in cSMCs in a time-dependent manner. The inhibition of PKC by chelerythrine or its downregulation by phorbol 12-myristate 13-acetate (PMA) inhibited bFGF-induced DNA synthesis and blocked the phosphorylation of MAPK and c-myc expression in response to bFGF. This indicates an involvement of phorbol ester-sensitive PKC isoforms in MAPK activation and mitogenic signaling by bFGF. Western blot analysis revealed the presence of the phorbol ester-sensitive isoforms PKC alpha, epsilon, and gamma as well as the PKC isoforms iota, lambda, micro, and zeta in cSMCs. In this study, we show that the MAPK cascade is required for bFGF-induced proliferation and that phorbol ester-sensitive PKC isoforms contribute to the bFGF-induced cSMC mitogenesis in cSMCs.

Animals↗
PubMed1999

Effects of Selegiline in a retroviral rat model for neurodegenerative disease.

Upon inoculation into neonatal rats, murine leukemia virus (MuLV) NT40 causes a non-inflammatory degeneration of the central nervous system. While microglia cells appear to be the major target cells within the brain parenchyma for neurovirulent MuLV, degenerating neurons do not express retroviral gene products. In order to protect rats from neuronal damage we treated retrovirally infected rats once with monoamine oxidase (MAO) B inhibitor Selegiline which--under different conditions--exerts neuroprotective effects. Unexpectedly, when administered at 17 days post-infection (d.p.i.) a single intraperitoneal dose of Selegilin (1 mg/kg bodyweight) significantly shortened the incubation period for neurological disease. In contrast, Selegiline given in a lower dosage (0.05 mg/kg bodyweight) and/or at a different time point (13 d.p.i.) at the low (0.05 mg/kg bodyweight) and the high dose (1.0 mg/kg bodyweight) had no effect on the outcome of neurological disease. Animals treated with Selegiline (1.0 mg/kg bodyweight at 17 d.p.i.) contained higher amounts of viral loads in the CNS, higher numbers of brain cells expressing major histocompatibility complex class II molecules, and exhibited inhibition of MAO-B in comparison to untreated yet infected (control) animals. Supposedly, Selegiline activated the major target cell population of the CNS for MuLV-NT40, microglia, with the consequence of enhanced susceptibility for retroviral infection and triggered endogenous mechanism(s) involved in the pathogenesis of retroviral neurodegeneration.

Animals↗
PubMed1998

Suppression of rat bone marrow cells by Friend murine leukemia virus envelope proteins.

In a retroviral rat model, we have investigated the nontransforming effects of murine leukemia virus FB29 on the bone marrow. Upon intraperitoneal inoculation with murine leukemia virus FB29 of either neonatal or adult rats, bone marrow cells became massively infected within the first 12 days postinoculation. In neonatally inoculated rats, a persistent productive bone marrow infection was established, whereas in rats inoculated as adults, no infected bone marrow cells could be detected beyond 12 days postinoculation. Retroviral infection was most likely cleared by an antiviral immune response (Hein et al., 1995, Virology 211, 408-417). Exposure to virus irreversibly decreased numbers of bone marrow cells staining with monoclonal antibody OX7 by 10-30%. Reduction of OX7+ bone marrow cells by 20% was also observed in vitro, after bone marrow cells from uninfected adult rats had been co-incubated with virus. FB29-envelope proteins were sufficient alone to reduce numbers of OX7+ bone marrow cells, both in vivo and in vitro. According to results on incorporation of propidium iodide, decreased numbers of OX7+ cells were due to cell death. By flow cytometric analyses OX7+ bone marrow cells as well as monocytes/macrophages were identified to be major target cells for infection with FB29 within the bone marrow. Thus, the mechanism(s) responsible for death of OX7+ bone marrow cells might be due to direct toxicity of viral envelope proteins and/or to interactions of viral envelope proteins with cells of the monocytic lineage.

Animals↗
PubMed1998

Foamy virus particle formation.

Subgenomic expression plasmids for the so-called human foamy virus (HFV) structural gag, gag/pol, and env genes were constructed and used to analyze foamy virus particle formation by electron microscopy. Expression of an R-U5-gag-pol construct under control of the human cytomegalovirus immediate-early enhancer-promoter resulted in the formation of viral cores with a homogeneous size of approximately 50 nm located in the cytoplasm. Upon coexpression of an envelope construct, particles were observed budding into cytoplasmic vesicles and from the plasma membrane. Expression of the Gag protein precursor pr74 alone led to aberrantly formed viral particles of heterogeneous size and with open cores. Normal-shaped cores were seen after transfection of a construct expressing the p70gag cleavage product, indicating that p70gag is able to assemble into capsids. Coexpression of p70gag and Env resulted in budding virions, ruling out a requirement of the reverse transcriptase for capsid or virion formation. In sharp contrast to other retroviruses, the HFV cores did not spontaneously bud from cellular membranes. Radiochemical labeling followed by protein gel electrophoresis also revealed the intracellular retention of Env-deprived HFV capsids.

Humans↗