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Biomedical subjects

F Müller

Publications and source records attributed to F Müller.

At least 73 records · Page 4Linked to original sources
PubMed2001

Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess--possible role in bone homeostasis.

OBJECTIVE: To investigate the possible role of osteoprotegerin (OPG) in bone metabolism in humans by measuring serum levels of OPG in five well-characterized patient populations with known or suspected pathology in bone homeostasis, but with differences in the pathogenesis of these disturbances. DESIGN: The study comprised 34 patients with Cushing's syndrome (CS), 24 acromegalic patients, 16 patients with growth hormone deficiency (GHD), 29 HIV-infected patients, 25 patients with common variable immunodeficiency (CVI) and 59 age- and sex-matched healthy controls (CTR). METHODS: Serum levels of tumor necrosis factor (TNF)-alpha, OPG, C-terminal telopeptides of Type-I collagen (CTX-I) and osteocalcin were determined in all study subjects as well as cortisol (CS and CTR) and IGF-I (acromegaly, GHD and CTR). RESULTS: OPG levels were significantly elevated in both CVI (median increase approximately 32%, P < 0.05) and HIV-infected patients with especially high levels in the latter group ( approximately 52%, P < 0.001), significantly correlated with increased TNFalpha levels (r = 0.47, P < 0.02). Also CS patients had elevated serum OPG ( approximately 24%, P < 0.01), significantly correlated with increased serum cortisol (r = 0.35, P < 0.05). In contrast, OPG levels in acromegalic and GHD patients were not different from healthy controls. No relationships were found between OPG levels and CTX-I or osteocalcin. CONCLUSIONS: These findings suggest that enhanced OPG levels may be a compensatory response to enhanced osteoclast activity or negative bone remodeling balance in some conditions, but may also be a parameter of enhanced activity in the OPG system possibly correlated to enhanced activity of other members of the TNF family.

Acromegaly↗
PubMed2001

[New therapeutic strategies in gastroenteropancreatic neuroendocrine tumours].

Neuroendocrine tumours are frequently malignant and have often reached an advanced stage by the time of diagnosis when they are inoperable, accompanied by severe symptoms, sometimes of an endocrine nature. Current therapeutic procedures include surgery, embolisation of hepatic metastases, local radiotherapy, biotherapy and chemotherapy. Over the years somatostatin analogs, of which octreotide is the first form, have become increasingly important in the treatment of patients with neuroendocrine tumours. A major step forward in analog treatment is represented by the development of slow-release formulas which do not require multiple daily injections and reduce the onset of resistance. The treatment of neuroendocrine tumours in the future will be based on the increased use of somatostatin analogs alone or in association with interferon or chemotherapy, and will also include surgery, radiometabolic therapy and targeted irradiation of the tumour.

Antineoplastic Agents, Hormonal↗
PubMed2000

Cloning and expression analysis of an inducible HSP70 gene from tilapia fish.

We isolated and characterized the tilapia (Oreochromis mossambicus) HSP70 gene, highly homologous to other HSP70 genes. A dramatic increase of tilapia HSP70 mRNA levels was observed after heat shock of whole animals in all organs tested. Reporter constructs were tested for transient expression in carp cells and in microinjected zebrafish embryos. The entire isolated regulatory region (-851/+157) was able to mediate heat shock inducible expression of the reporter gene, with no preference for a particular tissue. Our studies represent the first transcriptional analysis of a HSP70 promoter from fish, revealing a powerful tool to direct controlled, tissue-independent gene expression in fish.

Amino Acid Sequence↗
PubMed2000

Chromatin diminution in the parasitic nematodes ascaris suum and parascaris univalens.

Chromatin diminution in Parascaris univalens and Ascaris suum undoubtedly represents an interesting case of developmentally programmed DNA rearrangement in higher eukaryotes. It is a complex mechanism involving chromosomal breakage, new telomere addition and DNA degradation, and occurs in all presomatic cells. The process is rather specific with respect to its developmental timing and the chromosomal regions that are eliminated. The functional significance of chromatin diminution still remains an enigma. The fact, however, that single-copy, protein-coding genes are contained in the eliminated DNA demonstrates that in P. univalens and A. suum, there is a qualitative difference between germ-line and somatic genomes, and suggests that chromatin diminution may be used as a "throw-away" approach to gene regulation. We present a hypothesis as to how, during evolution, a partial genome duplication might have been linked to the process of chromatin diminution, in order to provide a selective advantage to parasitic DNA-eliminating nematodes.

Animals↗
PubMed2000

Prenatal ages and stages-measures and errors.

BACKGROUND: The confusing term "gestational age" is generally either not defined or is used for menstrual "age," postovulatory age, or postfertilizational age. The designation (post)menstrual weeks and/or days is very useful in obstetrics but, because prenatal age extends from fertilization to birth, menstrual "age" is a misnomer. The term "stage" has a specific morphological meaning in embryology and should not be used either for ages or for lengths. METHODS: Embryonic age is best assessed, when possible, from the 23 internationally recognized morphological stages. A morphological staging system is not available for the fetal period, and fetal age is assessed mainly from measurements. RESULTS: Among these, the unsatisfactory designation crown-rump length (CRL) should be replaced, in ultrasonic biometry as well as in embryology, by the greatest length (GL), exclusive of the lower limbs. These points are discussed in detail, and justification for the views expressed is provided. CONCLUSIONS: The continuing confusion concerning prenatal age is shown to be unnecessary once the ambiguous and superfluous term "gestational age" is abandoned.

Crown-Rump Length↗
PubMed2000

Self-assembly of beta-amyloid 42 is retarded by small molecular ligands at the stage of structural intermediates.

Assemblyof the amyloid-beta peptide (Abeta) into fibrils and its deposition in distinct brain areas is considered responsible for the pathogenesis of Alzheimer's disease (AD). Thus, inhibition of fibril assembly is a potential strategy for therapeutic intervention. Electron cryomicroscopy was used to monitor the initial, native assembly structure of Abeta42. In addition to the known fibrillar intermediates, a nonfibrillar, polymeric sheet-like structure was identified. A temporary sequence of supramolecular structures was revealed with (i) polymeric Abeta42 sheets during the onset of assembly, inversely related to the appearance of (ii) fibril intermediates, which again are time-dependently replaced by (iii) mature fibrils. A cell-based primary screening assay was used to identify compounds that decrease Abeta42-induced toxicity. Hit compounds were further assayed for binding to Abeta42, radical scavenger activity, and their influence on the assembly structure of Abeta42. One compound, Ro 90-7501, was found to efficiently retard mature fibril formation, while extended polymeric Abeta42 sheets and fibrillar intermediates are accumulated. Ro 90-7501 may serve as a prototypic inhibitor for Abeta42 fibril formation and as a tool for studying the molecular mechanism of fibril assembly.

Amyloid beta-Peptides↗
PubMed2000

[Familial myoclonus-dystonia syndrome associated with panic attacks].

We report a case of autosomal dominantly inherited dystonia and panic attacks to discuss successful treatment of a common serotonergic pathology with medication. The objective analysis of the movement disorder was done by Optotrak. First we demonstrate a reduction of the myoclonus by L-5-hydroxytryptophan, which inhibits after 11 months. After changing the medication to Nefadozone, the myoclonus and the frequency of panic attacks were reduced.

Adult↗
PubMed2000

Role of Na+/H+ exchange and HCO3- transport in pHi recovery from intracellular acid load in cultured epithelial cells of sheep rumen.

This study sought to investigate effects of short-chain fatty acids and CO2 on intracellular pH (pHi) and mechanisms that mediate pHi recovery from intracellular acidification in cultured ruminal epithelial cells of sheep. pHi was studied by spectrofluorometry using the pH-sensitive fluorescent indicator 2',7'-bis (carboxyethyl)-5(6')-carboxyfluorescein acetoxymethyl ester (BCECF/AM). The resting pHi in N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES)-buffered solution was 7.37 +/- 0.03. In HEPES-buffered solution, a NH4+/NH3-prepulse (20 mM) or addition of butyrate (20 mM) led to a rapid intracellular acidification (P < 0.05). Addition of 5-(N-ethyl-N-isopropyl)-amiloride (EIPA: 10 microM) or HOE-694 (200 microM) inhibited pHi recovery from an NH4+/NH3-induced acid load by 58% and 70%, respectively. pHi recovery from acidification by butyrate was reduced by 62% and 69% in the presence of EIPA (10 microM) and HOE-694 (200 microM), respectively. Changing from HEPES-(20 mM) to CO2/HCO3(-)-buffered (5%/20 mM) solution caused a rapid decrease of pHi (P < 0.01), followed by an effective counter-regulation. 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS; 100 microM) blocked the pHi recovery by 88%. The results indicate that intracellular acidification by butyrate and CO2 is effectively counter-regulated by an Na+/H+ exchanger and by DIDS-sensitive, HCO3(-)-dependent mechanism(s). Considering the large amount of intraruminal weak acids in vivo, both mechanisms are of major importance for maintaining the pHi homeostasis of ruminal epithelial cells.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2000

Phenotypic effects in Xenopus and zebrafish suggest that one-eyed pinhead functions as antagonist of BMP signalling.

Zebrafish one-eyed pinhead (oep) is essential for embryonic axis and dorsal midline formation by promoting Nodal signalling and is thought to act as a permissive factor. Here we describe that oep elicits profound phenotypic effects when overexpressed in Xenopus and zebrafish. In Xenopus, wild-type oep inhibits mesoderm induction, disrupts axis formation and neuralizes animal caps. A secreted Oep dorsoanteriorizes and neuralizes Xenopus embryos indicative of BMP inhibition. In zebrafish, misexpression of smad1 in oep mutant embryos also reveals an interaction of oep with BMP signalling. Furthermore, the phenotypic effect of nodal overexpression can be rescued by coexpression of oep both in Xenopus and zebrafish. Taken together, our results support an interaction between oep and nodal but they suggest also (1) that the role of oep in Nodal signalling may include negative as well as positive regulation, (2) that oep is able to function in an active fashion and (3) that oep exerts a regulatory effect on the BMP signalling pathway.

Animals↗
PubMed2000

Enhancement of lymphocyte proliferation induced by interleukin-12 and anti-interleukin-10 in HIV-infected patients during highly active antiretroviral therapy.

Based on the potentially important role of IL-10 and IL-12 in the pathogenesis of HIV infection, we have examined the effect of highly active antiretroviral therapy (HAART) on the production of these two cytokines, and whether addition of IL-12 or anti-IL-10 in vitro could improve the proliferative response in peripheral blood mononuclear cells (PBMC) from HIV-infected patients during such therapy. Our findings are: (i) After initiating HAART there were no significant changes in PHA- or MAC-PPD-stimulated IL-10 and IL-12 levels in PBMC supernatants in the patient group as a whole. (ii) However, while a decline in IL-10 synthesis was shown in patients with high baseline MAC-PPD- and PHA-stimulated IL-10 levels, IL-10 increased in patients with lower baseline levels. A similar pattern was seen for MAC-PPD-stimulated IL-12 levels. (iii) Exogenously added IL-12 and anti-IL-10 markedly and additively improved MAC-PPD-stimulated PBMC proliferation in vitro. Thus, a loss of cell-mediated immune response exists in HIV-infected patients also during apparently successful HAART and this can be significantly improved by addition of IL-12 and anti-IL-10, at least in vitro. These results suggest that further exploration of both IL-10 and IL-12 as targets for immunomodulating therapy in HIV-infected patients in addition to HAART might be important.

Adult↗
PubMed2000

Interferons and interferon (IFN)-inducible protein 10 during highly active anti-retroviral therapy (HAART)-possible immunosuppressive role of IFN-alpha in HIV infection.

Interferons play an important, but incompletely understood role in HIV-related disease. We investigated the effect of HAART on plasma levels of IFN-alpha, IFN-gamma, neopterin and interferon-inducible protein 10 (IP-10) in 41 HIV-infected patients during 78 weeks of therapy. At baseline HIV-infected patients had raised levels of both IP-10 and IFN-alpha compared with healthy controls (n = 19), with particularly high levels in advanced disease. HAART induced a marked decrease in levels of both IFN-alpha, neopterin and IP-10, though not to normal concentrations. In contrast, IFN-gamma levels were low throughout the study, and not different from controls. While neopterin and IP-10 remained significantly decreased compared with baseline levels throughout the study, IFN-alpha levels returned to baseline at the end of the study. Persistently high IP-10 and IFN-alpha levels were associated with immunological treatment failure and even high baseline levels of IFN-alpha appeared to predict immunological relapse. Furthermore, we found a markedly suppressive effect of exogenously added IFN-alpha on phytohaemagglutinin-stimulated lymphocyte proliferation in both patients and controls, and this suppressive effect seemed not to involve enhanced lymphocyte apoptosis. Our findings suggest a pathogenic role of IFN-alpha in HIV infection, which may be a potential target for immunomodulating therapy in combination with HAART.

Anti-HIV Agents↗
PubMed2000

Chemokines and soluble adhesion molecules in renal transplant recipients with cytomegalovirus infection.

Cytomegalovirus (CMV) infection is associated with leucocyte infiltration in various organs, which supports a role for chemokines and adhesion molecules in the pathogenesis of CMV infection. In a prospectively conducted study of renal transplant recipients, 10 patients with CMV disease, five patients with asymptomatic CMV infection and 10 patients who did not have any CMV infection were included. During CMV infection, and in particular during CMV disease, plasma levels of the chemokines IL-8, macrophage inflammatory protein-1alpha (MIP-1alpha) and monocyte chemotactic protein-1 (MCP-1) and the soluble adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and L-selectin increased and were positively correlated with the degree of CMV pp65 antigenaemia. Furthermore, a decrease in plasma levels of these chemokines and adhesion molecules was observed following ganciclovir therapy in the patients with CMV disease. This could suggest a role for these molecules in the pathogenesis of CMV infection.

Adult↗
PubMed2000

Decreased vitamin A levels in common variable immunodeficiency: vitamin A supplementation in vivo enhances immunoglobulin production and downregulates inflammatory responses.

BACKGROUND: Vitamin A has a broad range of immunological effects, and vitamin A deficiency is associated with recurrent infections. Common variable immunodeficiency (CVI) is a group of B-cell deficiency syndromes with impaired antibody production and recurrent bacterial infections as the major manifestations, but the immunological dysfunctions may also include T cells and macrophages. In the present study we examined the possible role of vitamin A deficiency in CVI. PATIENTS AND METHODS: We analysed plasma vitamin A levels in 20 CVI patients and 16 controls, and examined the relationships between vitamin A and clinical, immunological and metabolic parameters in CVI. In the six CVI patients with the lowest vitamin A levels we also studied the effect of vitamin A supplementation in vivo on several immunological functions in these patients. RESULTS: (i) The majority of CVI patients had decreased vitamin A levels compared with healthy controls, as found in both cross-sectional and longitudinal testing. (ii) Low vitamin A levels were associated with the occurrence of chronic bacterial infections and splenomegaly as well as high neopterin levels. Decreased levels of carrier protein and malabsorption were not observed. (iii) Vitamin A supplementation in patients with low vitamin A levels resulted in increased interleukin-10 (IL-10) and decreased tumour necrosis factor-alpha (TNFalpha) levels, as found in both plasma and monocyte supernatants, possibly favouring anti-inflammatory net effects. (iv) Vitamin A supplementation in vivo also enhanced anti-CD40-stimulated IgG production, serum IgA levels and phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cell (PBMC) proliferation. CONCLUSION: A considerable subgroup of CVI patients appears to be characterized by low vitamin A levels. Our findings support a possible role for vitamin A supplementation in CVI, perhaps resulting in enhanced immunoglobulin synthesis and downregulated inflammatory responses.

Adult↗
PubMed2000

Virological and immunological effects of antioxidant treatment in patients with HIV infection.

BACKGROUND: Intracellular oxidative stress in CD4+ lymphocytes due to disturbed glutathione homeostasis may lead to impaired lymphocyte functions and enhanced HIV replication in patients with HIV infection, especially in those with advanced immunodeficiency. The aim of the present study was to assess whether short-term, high-dose antioxidant treatment might have effects on immunological and virological parameters in patients with HIV infection. MATERIALS AND METHODS: In this pilot study, we examined virological and immunological effects of antioxidant combination treatment for 6 days with high doses of N-acetylcysteine (NAC) and vitamin C in 8 patients with HIV infection. The following were assayed before, during and after antioxidant treatment: HIV RNA plasma levels; numbers of CD4+, CD8+, and CD14+ leukocytes in blood; plasma thiols; intracellular glutathione redox status in CD4+ lymphocytes and CD14+ monocytes; lymphocyte proliferation; lymphocyte apoptosis and plasma levels of tumour necrosis factor (TNF)alpha; soluble TNF receptors and neopterin in plasma. RESULTS: No significant changes in HIV RNA plasma levels or CD4+ lymphocyte counts in blood were noted during antioxidant treatment in the patient group. However, in the 5 patients with the most advanced immunodeficiency (CD4+ lymphocyte counts < 200 x 106 L(-1)), a significant rise in CD4+ lymphocyte count, a reduction in HIV RNA plasma level of 0.8 log, an enhanced lymphocyte proliferation and an increased level of intracellular glutathione in CD4+ lymphocytes were found. No change in lymphocyte apoptosis was noted. CONCLUSIONS: Short-term, high-dose combination treatment with NAC and vitamin C in patients with HIV infection and advanced immunodeficiency lead to immunological and virological effects that might be of therapeutic value.

Acetylcysteine↗
PubMed2000

Flavin-protein interactions in flavocytochrome b2 as studied by NMR after reconstitution of the enzyme with 13C- and 15N-labelled flavin.

A new procedure was devised for reversibly removing the flavin from flavocytochrome b2. It allowed reconstitution with selectively enriched 13C- and 15N-labelled FMN for an NMR analysis of the chemical shifts of the enriched positions as well as that of 31P. From these measurements, it was possible to deduce information about the hydrogen-bonding pattern of FMN in the protein, the hybridization states of the nitrogen atoms and (in part) the pi-electron distribution. The carbonyl groups at C(2) and C(4) and the nitrogen atoms N(1) and N(5) form hydrogen bonds to the apoenzyme in both redox states. Nevertheless, according to 15N-chemical shifts, the bond from the protein to N(3) is very weak in both redox states, whereas that to N(5) is strong for the oxidized state, and is weakened upon flavin reduction. On the other hand, the 13C-NMR results indicate that the C(2) and C(4) carbonyl oxygens form stronger hydrogen bonds with the enzyme than most other flavoproteins in both redox states. From coupling constant measurements it is shown that the N(3) proton is not solvent accessible. Although no N-H coupling constant could be measured for N(5) in the reduced state due to lack of resolution, N(5) is clearly protonated in flavocytochrome b2 as in all other known flavoproteins. With respect to N(10), it is more sp3-hybridized in the oxidized state than in free FMN, whereas the other nitrogen atoms show a nearly planar structure. In the reduced state, N(5) and N(10) in bound FMN are both more sp3-hybridized than in free FMN, but N(5) exhibits a higher degree of sp3-hybridization than N(10), which is only slightly shifted out of the isoalloxazine plane. In addition, two-electron reduction of the enzyme leads to anion formation on N(1), as indicated by its 15N-chemical shift of N(1) and characteristic upfield shifts of the resonances of C(2), C(4) and C(4a) compared to the oxidized state, as observed for most flavoproteins. 31P-NMR measurements show that the phosphate geometry has changed in enzyme bound FMN compared to the free flavin in water, indicating a strong interaction of the phosphate group with the apoenzyme.

Binding Sites↗
PubMed2000

The role of the tumor necrosis factor system and interleukin-10 during cytomegalovirus infection in renal transplant recipients.

The effects of cytomegalovirus (CMV) infection on monocyte and T cell activation and the role of the tumor necrosis factor (TNF) system and interleukin (IL)-10 were studied in a prospective study of 25 renal transplant recipients. Ten patients developed CMV disease (group A), 5 developed asymptomatic infection (group B), and 10 did not have CMV infection (group C). During CMV disease (group A), there was evidence of both monocyte and T cell activation. All patients with CMV infection (groups A and B) showed increased activation of the TNF system, concomitant with an increase in plasma levels of IL-10. Patients with CMV disease (group A) had more marked manifestations of TNF activation and more moderate IL-10 increase than patients with asymptomatic CMV infection (group B), reflected in a higher plasma IL-10/TNF-alpha ratio in asymptomatic patients. Thus, the balance between TNF-alpha and IL-10 may be important in the development of CMV infection and CMV-related disease.

Adult↗
PubMed2000

Amalgam fillings and cognitive abilities in a representative sample of the elderly population.

OBJECTIVES: The ongoing controversial discussion about a possible negative effect of amalgam fillings on the cognitive abilities and the pathogenesis dementia was the objective of the present study. SAMPLE: A total of 300 patients aged from 70 to 103 years were selected from the multidisciplinary 'Berlin Aging Study' (BASE). The sample was heterogeneous concerning lifestyle, education and social prestige. According to their dental state subjects were allocated into three groups: edentate > or = 20 years (I) and residual teeth without (II) or with (III) amalgam restorations. All groups were matched for age and gender. DESIGN: Dental examinations and various psychiatric as well as psychological assessments were carried out by professionals within the protocol of the BASE. Tests were chosen to reveal the presence and degree of dementia and assess cognitive abilities such as 'perceptual speed', 'reasoning', 'memory', 'fluency' and 'knowledge'. RESULTS: The present findings negate a correlation between the dental state and the pathogenesis of dementia and the physiological age-related decline in cognitive abilities. Thus the presence of amalgam fillings did neither correlate to a demented mental condition nor an impaired cognitive performance.

Age Distribution↗