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Biomedical subjects

F Winkler

Publications and source records attributed to F Winkler.

At least 19 recordsLinked to original sources
PubMed2006

Structural and functional insights into the AmtB/Mep/Rh protein family.

X-ray crystallography revealed a similar architecture of the ammonium transport protein AmtB from Escherichia coli and the homologous protein Amt-1 from Archaeoglobus fulgidus. Furthermore, the atomic structures suggest that the proteins conduct ammonia (NH3) rather than ammonium ions (NH4+). These findings indicate that the more than 350 members of the ammonium transporter/methylamine permease/Rhesus (Amt/Mep/Rh) protein family found in archaea, bacteria, fungi, plants and animals are ammonia-conducting channels rather than ammonium ion transporters. The essential part of these proteins is the narrow hydrophobic ammonia-conducting pore with two highly conserved histidine residues located in the middle of the pore. A specific ammonium ion binding site is found at the extracellular entry site of E. coli AmtB. E. coli AmtB and its regulator GlnK form an effective ammonium sensory system that couples intracellular gene regulation by the nitrogen control system to external changes in ammonium availability. Based on structural and functional analysis of various mutants, two conserved histidine residues were found to be essential for substrate conductance also in the functional eukaryotic ammonium transporters. The next big challenge in the field surely is to determine the atomic structure of Rh proteins.

Ammonia↗
PubMed2006

[Complexities of "reversible posterior leukoencephalopathy syndrome"].

We report a case of reversible posterior leukoencephalopathy syndrome in a 50-year-old patient with severe untreated hypertension. Recent advances in magnetic resonance imaging (especially diffusion-weighted imaging) allow new pathopysiological insight: it was found that the resulting vasogenic edema was restricted neither to the posterior vascular territories nor to white matter. The apparent diffusion coefficient helps to differentiate between reversible vasogenic edema and cytotoxic edema, the latter indicating irreversible neuronal death.

Antihypertensive Agents↗
PubMed2004

Pamidronate increases bone mineral density in women with postmenopausal or steroid-induced osteoporosis.

INTRODUCTION: We aimed to determine the efficacy and safety of a cyclic intravenous therapy with pamidronate in patients with postmenopausal or glucocorticoid-induced osteoporosis. METHODS: We enrolled 86 Austrian female patients with postmenopausal (n = 69, mean age 68.13 +/- 1.14) or glucocorticoid-induced (n = 17, mean age 66.89 +/- 2.03) osteoporosis defined as a T-score of < -2.5 for bone mineral density (BMD) of the lumbar spine L1-L4. Patients received a single intravenous dose of 30 mg pamidronate at 3 months intervals. The per cent change in BMD was primary, whereas the safety and the biological response were secondary endpoints. RESULTS: Seventy-six female patients (88%) completed study. Sixty patients received pamidronate therapy for the treatment of late postmenopausal osteoporosis and 16 patients received the same treatment for glucocorticoid-induced osteoporosis. At the end of the trial, lumbar spine (L1-L4) BMD increased significantly in patients with postmenopausal osteoporosis (P = 0.000067), whereas in patients with glucocorticoid-induced osteoporosis no significant change was observed (P = 0.724). The increase in the Ward's triangle BMD did not reach significance level in postmenopausal women receiving pamidronate (P = 0.0740). However, pamidronate treatment for glucocorticoid-induced osteoporosis resulted in a significant increase in Ward's triangle BMD (P = 0.0029). The efficacy of pamidronate treatment for postmenopausal osteoporosis was also reflected in a decrease in circulating biochemical markers for bone formation, including alkaline phosphatase and osteocalcin. In addition, pamidronate was well tolerated with no incidence of severe gastrointestinal events. CONCLUSION: Cyclic intravenous administration of pamidronate is well-tolerated therapy in postmenopausal osteoporosis, and increases spinal BMD. Randomized controlled studies with adequate number of patients are needed to test the efficacy of the compound in the treatment of glucocorticoid-induced osteoporosis.

Aged↗
PubMed2003

Prospective multicentre trial comparing the efficacy of, and compliance with, glimepiride or acarbose treatment in patients with type 2 diabetes not controlled with diet alone.

AIM: To determine the efficacy of, and compliance with, glimepiride or acarbose in patients with Type 2 diabetes. METHODS: Two hundred and nineteen patients with Type 2 diabetes uncontrolled by diet alone were randomized to receive either glimepiride (1, 2, 3, 4 or 6 mg once daily, n = 111) or acarbose (50, 100, 150 or 200 mg 3 times daily, n = 108). Both drugs were titrated in a 6-week dose-finding phase to achieve a fasting blood glucose (FBG) concentration < or = 7.8 mmol/ (140 mg/dl). Patients achieving this target entered a 20-week treatment period. Efficacy was assessed by responder rate, number of patients achieving a FBG of < or = 7.8 mmol/l, HbA1c, blood glucose concentrations in response to a standard breakfast, body weight and compliance. RESULTS: Glimepiride was associated with a significantly greater responder rate than acarbose (61 vs 34%, p < 0.001), significantly greater decreases in HbA1c (2.5 +/- 2.2% vs 1.8 +/- 2.2%, p = 0.014) and FBG (2.6 +/- 2.6 mmol/l vs 1.4 +/- 2.8 mmo/l, p = 0.004), a decreased glucose response to breakfast compared with acarbose [area under curve (AUC) end: 8.9 +/- 2.7 mmol/l vs 11.3 +/- 3.9 mmol/l, p = 0.0001], and was accompanied by significantly greater compliance (91 < or = 12% vs 66 +/- 26%, p = 0.0001). Weight loss during the study was observed in both the acarbose group (1.9 +/- 3.9 kg, p = 0.001) and glimepiride group [0.4 +/- 5.2 kg, p = 0.8 (NS)]. CONCLUSIONS: Improved efficacy and greater compliance were observed in response to treatment with glimepiride compared with acarbose, in patients with Type 2 diabetes.

Acarbose↗
PubMed2002

[Localized invasive intracranial aspergillosis with multiple cranial nerve failure -- case report and review of the literature].

Contrary to the more frequent hematogenously spread cerebral aspergillosis, localized invasive intracranial aspergillosis is a fungal infection that can also occur in patients who are not severely immunosuppressed. This illness can be effectively treated in some of these patients by early and rigorous therapy. Localized invasion of the fungus, generally from one of the nasal sinuses, causes intracranial growth mainly along the base of the skull and larger vessels,where fibrous, granulomatous tissue develops. This generally leads to damage of the cranial nerves (primarily I-VI) as well as localized pain syndromes. We report on the clinical course documented by MRI of a patient with localized invasive intracranial aspergillosis who had multiple failure of cranial nerves following surgery for an aspergilloma of the maxillary sinus. Clinical course, imaging findings, and treatment of the illness are discussed with a review of the relevant literature.

Aged↗
PubMed2002

[The Würzburg questionnaire for assessing the quality of hearing in CI-children (WH-CIK)].

BACKGROUND: The goal of this study was to compare the auditory behaviour of bilaterally implanted children while using both CIs to their auditory behaviour during the time when they were using one CI. METHODS: For this purpose a questionnaire looking at different aspects of hearing such as hearing in background noise, in complex listening situations and directional hearing was developed. The questionnaire was completed by the parents of 28 bilaterally implanted children. They were instructed to state their judgement on the behaviour of their children. The parents scaled their judgements using a method of extended category scaling similar to that applied in the loudness scaling with the Würzburg hearing field (WHF). Each of the five verbal categories was subdivided into 10 numerical subdivisions, so that the parents were able to express judgements lying between the different categories. RESULTS: Eight out of eleven items showed that hearing with bilateral CIs was significantly better than with one CI (p < 0,003). The two items, which did not show a significant difference between the two conditions were those related to the interest in auditory rehabilitation and to aversion to noise. CONCLUSIONS: The questionnaire has proven to be a useful instrument to assess the quality of hearing in children. The possibility of bilateral implantation should be considered during the decision process prior to implantation.

Adolescent↗
PubMed2001

Differential expression of nitric oxide synthases in bacterial meningitis: role of the inducible isoform for blood-brain barrier breakdown.

The aim of the study was to determine the differential expression of nitric oxide (NO) synthase (NOS) isoforms and the pathophysiologic relevance of inducible NOS (iNOS) in experimental pneumococcal meningitis. By use of reverse transcription-polymerase chain reaction analysis, immunohistochemistry, and Western blotting, increased brain mRNA and increased protein levels of endothelial NOS (eNOS) and iNOS were detected 24 h after intracisternal pneumococcal inoculation. In iNOS-deficient mice, disruption of the blood-brain barrier (BBB) was significantly reduced, compared with that in wild-type mice. This beneficial effect of iNOS deficiency was associated with a lack of nitrotyrosine immunoreactivity. Furthermore, brain protein levels of interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha and brain mRNA levels of macrophage inflammatory protein (MIP)-1alpha and MIP-2 were significantly reduced in infected animals lacking iNOS. These findings suggest that (1) not only iNOS but also eNOS is up-regulated in the acute phase of experimental bacterial meningitis, and (2) iNOS-derived NO contributes to peroxynitrite formation and BBB breaching in this disease.

Animals↗
PubMed2001

Acute severe spinal cord dysfunction in bacterial meningitis in adults: MRI findings suggest extensive myelitis.

BACKGROUND: Bacterial meningitis is rarely complicated by acute spinal cord involvement (eg, myelitis, ischemic infarction, spinal abscess, or epidural hemorrhage). In spinal cord dysfunction, magnetic resonance imaging (MRI) is the imaging modality of choice. Still, MRI findings of myelitis due to bacterial meningitis in adults have not been reported. METHODS: Spinal MRIs were obtained during the acute stage of meningitis and on follow-up in 3 adults with bacterial meningitis that was complicated by paraparesis or tetraparesis and bowel and bladder incontinence. The causative pathogens were Streptococcus pneumoniae and Neisseria meningitidis; in 1 patient, the pathogen was not identified. RESULTS: In all cases, spinal MRI ruled out a compression of the cord by an extramedullary mass but demonstrated hyperintensities on T2-weighted images that predominantly involved the gray matter and extended from the cervical to the lumbar cord. Leptomeningeal and discrete nodular intramedullary enhancement on T1-weighted images was detected only in 1 patient. Follow-up examinations revealed that hyperintensities resolved completely in 1 patient, while a central cavitation developed in the cervical spinal cord of another, and the MRI findings were progressive during the first 4 weeks in the third patient. In all cases, severe paresis and bowel and bladder incontinence persisted. CONCLUSION: We demonstrate for the first time the MRI findings of adults with acute spinal cord involvement during bacterial meningitis. Magnetic resonance imaging showed central intramedullary hyperintensities on T2-weighted images that extended from the cervical to the lumbar cord, indicating myelitis. Clinical follow-up examinations suggest that myelitis during bacterial meningitis has an unfavorable prognosis.

Adolescent↗
PubMed2001

Superantigen overcomes resistance of IL-6-deficient mice towards MOG-induced EAE by a TNFR1 controlled pathway.

Experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide 35-55 (MOG) leads to a chronic form of disease characterized by demyelination, inflammation and gliosis in the central nervous system (CNS). Recently IL-6 and LT alpha were found to be required for induction of the disease. The main features associated with EAE resistance of IL-6(-/-) and LT alpha(-/-) mice were reduced T cell proliferation and endothelial activation. As shown here treatment of MOG-immunized IL-6(-/-) mice with staphylococcal enterotoxin B (SEB)reversed their resistance to MOG-induced EAE. SEB failed to restore susceptibility to EAE in LT alpha(-/-) mice. The effect of SEB to induce EAE in IL-6(-/-) mice depends on TNF receptor type 1 (TNFR1) signaling because IL-6/TNF/LT alpha(-/-) and IL-6/TNFR1(-/-) are refractory to SEB. TNFR1 is involved in SEB induced trafficking of T cells into the CNS as evidenced by the failure to up-regulate VCAM-1 on CNS endothelium and lack of accumulation of V beta 8(+) T cells in the CNS of IL-6/TNFR1(-/-) mice upon immunization with MOG and treatment with SEB. The course of SEB triggered EAE in MOG immunized IL-6(-/-) mice was characterized by reduced severity and duration of clinical manifestations, which were associated with a significant drop of CNS infiltrating neutrophils and MIP-2 expression after peak disease. Taken collectively the effect of SEB to overcome EAE resistance points to a transient IL-6 independent but TNFR1 dependent proinflamatory pathway in EAE pathogenesis and suggests a crucial function for IL-6 in disease perpetuation.

Animals↗
PubMed2001

Lack of endothelial nitric oxide synthase aggravates murine pneumococcal meningitis.

Nitric oxide (NO) plays a central role in the pathogenesis of bacterial meningitis. However, the role of NO produced by endothelial NO synthase (eNOS) in meningitis is still unclear. We investigated the influence of eNOS depletion on the inflammatory host response, intracranial complications, and outcome in experimental pneumococcal meningitis. Leukocyte accumulation in the cerebrospinal fluid was more pronounced in infected eNOS-deficient mice than in infected wild type mice. This effect could be attributed to an increased expression of P-selectin, macrophage inflammatory protein-2, keratinocyte-derived cytokine, and interleukin (IL)-1beta in the brain of infected eNOS-deficient mice. However, no differences in the cerebral expression of intercellular adhesion molecule-1, tumor necrosis factor-alpha, and IL-6 as well as of neuronal NOS and inducible NOS could be detected between infected wild type and mutant mice. In addition to enhanced leukocyte infiltration into the CSF, meningitis-associated intracranial complications including blood-brain barrier disruption and the rise in intracranial pressure were significantly augmented in infected eNOS-deficient mice. The aggravation of intracranial complications was paralleled by a worsening of the disease, as evidenced by a more pronounced hypothermia, an enhanced weight reduction, and an increased death rate. The current data indicate that eNOS deficiency is detrimental in bacterial meningitis. This effect seems to be related to an increased expression of (certain) cytokines/chemokines and adhesion molecules; thus leading to increased meningeal inflammation and, subsequently, to aggravated intracranial complications.

Animals↗
PubMed1999

Reciprocal changes in endothelial and inducible nitric oxide synthase expression following carotid angioplasty in the pig.

OBJECTIVE: Nitric oxide produced by nitric oxide synthase appears to have an important role in the regulation of arterial tone, platelet adhesion and smooth muscle cell proliferation. Our aim was to investigate the effects of balloon angioplasty on expression of endothelial NO synthase (cNOS) and inducible NO/synthase (iNOS) in the pig carotid artery and to relate any changes in expression to the processes of reendothelialisation and vascular repair. METHODS: Pigs were sacrificed at various time points to follow NOS expression in the neointima, media and regenerated endothelium. Immunocytochemical staining was used to localize cNOS and iNOS expression in the vessel wall. Relative amounts of cNOS were measured using quantitative in vitro alitoradiography. cNOS mRNA and iNOS mRNA was quantified by competitive PCR based on the sequenced cDNA of porcine cNOS and iNOS. RESULTS: Uninjured carotid arteries exhibited dense uniform luminal endothelial staining for cNOS. Balloon angioplasty caused denudation of cNOS immunoreactive cells and a marked reduction of cNOS gene expression but a complete recovery was noted by day 35. In normal uninjured carotid arteries no evidence of iNOS immunoreactivity was demonstrable but 24 h after injury, marked homogeneous iNOS immunoreactivity was detected in medial vascular smooth muscle cells. By 5 days, staining was evident in cells within the forming neointimal layer with no evidence of iNOS immunoreactivity in the media. iNOS immunoreactivity persisted in cells at the luminal surface at 7 days and iNOS gene expression appeared to be sustained in some animals with ruptured internal elastic lamina at 21 days. CONCLUSION: Balloon injury is associated with de-endothelialisation and a marked reduction in cNOS gene expression and activity. iNOS is induced throughout the arterial media within VSMC soon after balloon injury and persists for up to 21 days. These observations imply an important regulatory role for locally generated NO in the pathophysiological response to balloon injury.

Amino Acid Sequence↗
PubMed1999

Renin inhibition by substituted piperidines: a novel paradigm for the inhibition of monomeric aspartic proteinases?

BACKGROUND: The aspartic proteinase renin catalyses the first and rate-limiting step in the conversion of angiotensinogen to the hormone angiotensin II, and therefore plays an important physiological role in the regulation of blood pressure. Numerous potent peptidomimetic inhibitors of this important drug target have been developed, but none of these compounds have progressed past clinical phase II trials. Limited oral bioavailability or excessive production costs have prevented these inhibitors from becoming new antihypertensive drugs. We were interested in developing new nonpeptidomimetic renin inhibitors. RESULTS: High-throughput screening of the Roche compound library identified a simple 3, 4-disubstituted piperidine lead compound. We determined the crystal structures of recombinant human renin complexed with two representatives of this new class. Binding of these substituted piperidine derivatives is accompanied by major induced-fit adaptations around the enzyme's active site. CONCLUSIONS: The efficient optimisation of the piperidine inhibitors was facilitated by structural analysis of the renin active site in two renin-inhibitor complexes (some of the piperidine derivatives have picomolar affinities for renin). These structural changes provide the basis for a novel paradigm for inhibition of monomeric aspartic proteinases.

Aspartic Acid Endopeptidases↗
PubMed1999

[Morphogenesis of the submucosal gland of cattle (Bos primigenius f. taurus)].

In the 10th week of gestation the development of duodenal glands in the bovine intestinum starts by circumscript epithelial proliferation. Their secretory channels are in contact with the crypts. Already in the early fetal stage ultrastructurally there are an inconspicuous equipment with organelles in the apical cytoplasm and single globular granules, which demonstrate the differentiation of epithelial cells into duodenal glandular cells. Until the mid-point of the pregnancy the granular endoplasmic reticulum strongly develops as a condition for the impressive increase in the formation of the prosecretory granules. Finally, in the second half of the pregnancy, granules varying in structure and electronic density, but mostly showing an intensively osmiophilic and fine granular material, are the predominant cytoplasmic structures. Like in goblet cells capsulated vacuoles seem to play a role in the formation of the secretory granules. Recent, extensive studies concerning our results have been discussed.

Animals↗
PubMed1999

[Further contribution on the fine structure of fetal goblet cells. Investigations on the small intestine of cattle].

Early in the fetal development, i.e. at the time both of the growth of intestinal villi and crypts and the epithelial cell differentiation the goblet cells also appear. The maturation of goblet cells progresses during their migration from the base of the villi respectively of the crypts to the villous top. As in the bovine large intestine there are vesicles and capsulated vacuoles, which contain vesicles, as single elements or as conglomerates in the immature goblet cells of the small intestine. These images deliver a scenario of the mechanism of secretory granule production and probably play a role in the formation of mucus.

Animals↗
PubMed1999

[Further contribution on glycogen in fetal intestinal epithelium].

In the first half of pregnancy the well-known occurrence of glycogen incorporation in the supra- and infranuclear cytoplasm of the villous enterocytes was verified. This enormous glycan store is evidently of very little functional importance. It seems to be an expression of a disordered glycogenolysis. These masses of glycogen are incorporated into impressive glycogenosomes, which are the predominante cytoplasmic inclusions for a short period of time. According to the present results it is not certain whether lysosomal glycogenolysis happens. There is no morphological or functional evidence for a utilization og glycogen.

Animals↗
PubMed1998

Structure-based design of beta-lactamase inhibitors. 1. Synthesis and evaluation of bridged monobactams.

Bridged monobactams are novel, potent, mechanism-based inhibitors of class C beta-lactamases, designed using X-ray crystal structures of the enzymes. They stabilize the acyl-enzyme intermediate by blocking access of water to the enzyme-inhibitor ester bond. Bridged monobactams are selective class C beta-lactamase inhibitors, with half-inhibition constants as low as 10 nM, and are less effective against class A and class B enzymes (half-inhibition constants > 100 microM) because of the different hydrolysis mechanisms in these classes of beta-lactamases. The stability of the acyl-enzyme complexes formed with class C beta-lactamases (half-lives up to 2 days were observed) enabled determination of their crystal structures. The conformation of the inhibitor moiety was close to that predicted by molecular modeling, confirming a simple reaction mechanism, unlike those of known beta-lactamase inhibitors such as clavulanic acid and penam sulfones, which involve secondary rearrangements. Synergy between the bridged monobactams and beta-lactamase-labile antibiotics could be observed when such combinations were tested against strains of Enterobacteriaceae that produce large amounts of class C beta-lactamases. The minimal inhibitory concentration of the antibiotic of more than 64 mg/L could be decreased to 0.25 mg/L in a 1:4 combination with the inhibitor.

Acylation↗
PubMed1998

Comparative investigations of algorithms for the detection of breaths in newborns with disturbed respiratory signals.

The correct detection of the beginning of inspiration and expiration in the respiratory signals is an essential prerequisite for accurate lung function testing in newborns. Five algorithms for breath detection using pneumotachographically measured flow and volume signals were investigated with regard to the error rate. To compare and to evaluate the reliability of these algorithms 12 minimally and 12 severely disturbed flow and volume signals from spontaneously breathing newborns were used. With the exception of an algorithm based on Walsh-transformed signals, all algorithms work reliably (error rate <1.1%) if disturbances are minimal. In severely disturbed signals there is a great difference between the algorithms. The most robust algorithm tested (trigger of the flow signal with an additional plausibility check of the recognized breath) resulted in an error rate of <3.4%. Not all algorithms tested are suitable for real-time applications because they differ considerably in delay time for breath detection.

Algorithms↗