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Biomedical subjects

U Widmer

Publications and source records attributed to U Widmer.

At least 37 records · Page 2Linked to original sources
PubMed1999

[Adult progeria (Werner's syndrome)].

HISTORY: A 48-year-old man was referred with progressive claudication and nocturnal pain at rest in the right foot. During the last few years exercise-induced pain, ulcerations and necroses had developed in both legs without any evidence of relevant macroangiopathies. The patient showed marked morphological changes. He had bilateral cataracts since aged 35 years. At 40 years he had undergone a transurethral resection of a bladder carcinoma. One of his brothers showed similar morphological changes, but they were absent in his parents and three siblings. INVESTIGATIONS: Radiology of the right foot revealed extensive para-osseous soft-tissue calcifications. Direct right femoral angiography demonstrated distal occlusions of the anterior and posterior tibial arteries as well as subtotal occlusion of the fibular artery. Routine laboratory tests were normal, as were all measured antibody titres. TREATMENT AND COURSE: The peripheral vascular disease, stage IV, of the right leg were presumably caused by adult progeria (Werner's syndrome). Percutaneous transluminal angioplasty (PTAP) of the distal fibular and, later, of the posterior tibial artery was performed, and prostacyclins, antibiotics and platelet-aggregation inhibitors were administered. Although the PTAP was technically successful, the state of the right foot remained critical, due to the existing microangiopathy and the impaired proliferation and healing capacity of the tissues as part of the adult progeria. CONCLUSIONS: The diagnosis of adult progeria is usually made because of the patients' characteristic morphology and typical concomitant diseases. The average age of patients at diagnosis is 37 years. The syndrome is caused by a helicase defect. This enzyme group unwinds double-helix RNA and DNA. Because the syndrome is rare and gene analysis is complex, it is unlikely that a commercial screening test will become available.

Angiography↗
PubMed1999

Heterozygous defect in HIV-1 coreceptor CCR5 and chemokine production.

CC chemokine receptor 5 (CCR5) is a cell entry cofactor for macrophage-tropic isolates of human immunodeficiency virus 1 (HIV-1). An inactive CCR5 allele with a 32-nucleotide deletion (CCR5Delta32) has been described that confers resistance to HIV-1 infection in homozygotes and slows the rate of progression to AIDS in heterozygotes. We found the allele CCR5Delta32 to be not rare in 399 Swiss blood donors with a frequency of 0.080. To assess the influence of defective CCR5 on production of its ligands we determined the capacity to produce the chemokines macrophage inflammatory protein (MIP)-1alpha, MIP-1beta and RANTES in comparison with the production of the CXC chemokine IL-8 which does not bind to CCR5. Production of chemokines was determined during endotoxin stimulation of whole-blood samples ex vivo. Both, basal and LPS-induced chemokine production in 32 blood donors heterozygous for CCR5Delta32 were not significantly different when compared with 55 blood donors who were homozygous for the wild type CCR5 allele.

Alleles↗
PubMed1998

[Abdominal pain and flatulence. Intestinal and pulmonary tuberculosis. IgG kappa paraproteinemia].

A 21-year-old woman suffered from cramplike abdominal pain, flatulence and occasional diarrhoea for about one year. Over the past few weeks the abdominal symptoms exacerbated, besides productive cough and subfebrile temperatures developed. Coloscopy revealed two isolated, short ulcers in the proximal colon. The histological examination of the biopsies taken from these ulcers indicated granulomatous inflammation. Moreover small acinar infiltrates in both pulmonary apices were visualized. The findings in this patient originating from Turkey were suspicious for intestinal and pulmonary tuberculosis. Though sensitive methods were used (Ziehl-Neelson stam, amplified M. tuberculosis direct test, a polymerase chain reaction) direct tests allowed no detection of mycobacteria. Antituberculous therapy was initiated on a probatory basis to which the patient responded well and promptly. The diagnosis was confirmed by culture results: M. tuberculosis was grown from colonic biopsies, morning sputa and bronchioalveolar lavage.

Abdominal Pain↗
PubMed1998

[Ascites. Tuberculous peritonitis].

Because of deteriorating general health, weight loss of 5 kg and leftsided epigastric pain a 44 year old innkeeper was evaluated unsuccessfully for 1 month. Thereafter a protein- and lymphocyte-rich ascites developed. CT-scans revealed a thickened visceral peritoneum and multiple, marginally increased retroperitoneal lymph nodes. The history of the patient originating from former Jugoslavia was suspicious for inadequately treated tuberculous pericarditis. Hence this diagnosis tuberculous peritonitis became probable but for practical reasons could not be proven neither by biopsy nor by culture. Under probatory antituberculous treatment the patient's general condition improved rapidly, the ascites disappeared and initially elevated parameters for infection normalized.

Adult↗
PubMed1998

Fatal air embolism in an airplane passenger with a giant intrapulmonary bronchogenic cyst.

Considering the large number of airplane passengers with a variety of medical conditions, the incidence of in-flight emergencies on commercial airline flights is low. Only few cases of pulmonary barotrauma in airplane passengers with prior lung pathologies have been reported. We present the unusual case of a female airplane passenger with a previously diagnosed asymptomatic giant intrapulmonary bronchogenic cyst who experienced fatal air embolism on a commercial airline flight. We believe that preventive surgical resection is mandatory in asymptomatic patients with large intrapulmonary cysts prior to exposure to even small alterations in ambient pressure as, for instance, prior to airplane flight or use of mountain cable cars. However, screening for pre-existent lung pathologies in the growing mass of commercial airline travelers is not justified.

Adult↗
PubMed1997

Novel agonists of 5HT2C receptors. Synthesis and biological evaluation of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2-b]pyrrol-1-yl)-1-methylethylamines. Improved therapeutics for obsessive compulsive disorder.

The syntheses of a series of substituted 2-(indol-1-yl)-1-methylethylamines and 2-(indeno[1,2- b]pyrrol-1-yl)-1-methylethylamines are reported. The binding affinities of the compounds at 5HT2C and 5HT2A receptors (79% homology in the transmembrane domain) were determined. The ligands displayed selectivity for 5HT2C receptors relative to 5HT2A receptors. Compounds were functionally characterized both in vitro and in vivo as 5HT2C receptor agonists. 5f, 5l, 5n, 5o, 5q, 14c, 14f, 14k, and 14m exhibited anticompulsive activity in an animal model of obsessive compulsive disorder.

3T3 Cells↗
PubMed1997

C-X-C and C-C chemokines are expressed in the cerebrospinal fluid in bacterial meningitis and mediate chemotactic activity on peripheral blood-derived polymorphonuclear and mononuclear cells in vitro.

The appearance of polymorphonuclear and mononuclear leukocytes in the cerebrospinal fluid (csf) is an important hallmark of bacterial meningitis. Chemokines are candidate mediators of cell migration from blood into the subarachnoid space. Therefore, concentrations of C-X-C and C-C chemokines in the csf of patients with pyogenic meningitis were measured by ELISA. Highly significant elevations of chemokine levels in comparison with noninflammatory csf controls were found for IL-8 (median, 21.6 ng/ml; range, < 0.1 to 191.3), growth-related gene product alpha (median, 5.6 ng/ml; range, < 0.1 to 48.2), monocyte chemotactic protein-1 (median, 26.4 ng/ml; range, < 0.2 to 193.8), macrophage inflammatory protein-1 alpha (MIP-1 alpha; median, 1.8 ng/ml; range, < 0.5 to 18.0), MIP-1 beta (median, 10.6 ng/ml; range, < 0.3 to 84.4), but not for RANTES (regulated upon activation, normal T cell expressed and secreted). The csf of bacterial meningitis were chemotactic for neutrophils and mononuclear leukocytes. Correlation analysis demonstrated a strong association between individual chemokine levels and chemotactic activity mediated by csf. A significant reduction of neutrophil chemotaxis was obtained by anti-IL-8 and anti-growth-related gene product alpha Abs, and a reduction of mononuclear cell migration was achieved by a combination of anti-monocyte chemotactic protein-1, anti-MIP-1 alpha, and anti-MIP-1 beta Abs. Since no significant correlation was found between csf leukocyte counts and chemokine concentrations or chemotactic activity mediated by csf, additional factors influence the extent of pleocytosis in vivo.

Adult↗
PubMed1996

A non peptidic corticotropin releasing factor receptor antagonist attenuates fever and exhibits anxiolytic-like activity.

The multiple actions of corticotropin-releasing factor (CRF) on neuroendocrine and behavioural functions can now be examined using new, high affinity, non peptidic antagonists which exhibit central activity upon systemic application. We have shown that compound CP 154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo [2,3-d]pyrimidin-4-yl]amine) displaces [125I][Tyr0]CRF from rat hippocampal CRF receptors (IC50 = 0.5 nM) and from pituitary CRF receptors (IC50 = 0.04 nM). The same compound inhibits in a concentration-dependent manner the ovine CRF (0.1 microM)-stimulated adenylate cyclase activity in membranes of a mouse pituitary adenoma cell line, AtT20, with an IC50 value of 50 nM. Systemic application of the CRF receptor antagonist (0.16 mg/kg i.p.) blocked recombinant human interleukin-1 beta 5 micrograms/kg i.p.) induced fever in rats. The CRF receptor antagonist CP 154,526 (1 mg/kg i.p.) also exhibited signs of anxiolytic-like activity in the elevated plus-maze test in rats.

Analgesics, Non-Narcotic↗
PubMed1995

Experimental Listeria meningoencephalitis. Macrophage inflammatory protein-1 alpha and -2 are produced intrathecally and mediate chemotactic activity in cerebrospinal fluid of infected mice.

In bacterial meningitis, the recruitment of leukocytes across the blood-brain barrier into the central nervous system may be crucial for both elimination of pathogens and tissue injury. In addition to bacterial cell wall products, host factors including chemokines may lead to accumulation of phagocytes within the central nervous system. As shown by Northern analysis, brains of mice infected intracerebrally with Listeria monocytogenes (LM) express mRNA for three chemokines, the macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and MIP-2. The cellular sources of these chemokines comprise both the blood-derived polymorphonuclear leukocytes (PMNs) and monocytes infiltrating the meninges, the ventricular system and the periventricular area. In the course of meningitis a time-dependent increase of MIP-1 alpha and MIP-2 was found in the cerebrospinal fluid (CSF) by ELISA. CSF taken 24 h after infection (CSF-LM24) induced migration of human leukocytes when treated in chemotactic chambers in vitro. Neutralizing Abs to chemokines identified MIP-1 alpha and MIP-2 to be responsible for CSF-LM24 mediated chemotaxis of monocytes and PMNs, respectively. CSF obtained from mock-infected animals contained no MIP-1 alpha or MIP-2 and did not lead to migration of leukocytes. When testing CSF-LM24 on mouse spleen cells, the chemotactic activity detected for mononuclear cells was only partly inhibited by Abs to MIP-1 alpha and -1 beta. Thus, in addition to MIP-1 and -2 other not yet defined chemotactic factors are of importance for recruitment of leukocytes in bacterial meningitis.

Animals↗
PubMed1994

[Diagnosis and course assessment of collagenoses and vasculitides].

The different forms of vasculitis and connective tissue disorders are multisystem diseases which must be distinguished from a variety of infectious illnesses, neoplastic and degenerative diseases. The diagnosis, established by clinical, radiographic, laboratory and histologic investigation, influences treatment and thereby the outcome of the disease. A diagnostic approach to the patient with possible vasculitis and/or connective tissue disease is described.

Clinical Laboratory Techniques↗
PubMed1993

Genomic cloning and promoter analysis of macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta, members of the chemokine superfamily of proinflammatory cytokines.

Macrophage inflammatory protein (MIP)-2, MIP-1 alpha, and MIP-1 beta all belong to the newly recognized "chemokine" superfamily of structurally related, activation-inducible cytokines with inflammatory and growth regulatory activities. We report the isolation and sequencing of genomic clones for murine MIP-2 and murine MIP-1 beta, and analyze their regulatory sequences in comparison with each other and with several other members of the chemokine family. The murine (mu)MIP-2 genomic clone displays the canonical four exon/three intron structure typical of other genes in the chemokine alpha subfamily (e.g., IL-8). Potential cis regulatory elements in the proximal promoter region were highly conserved between muMIP-2 and its three most closely related human homologs: human (hu)GRO-alpha, huGRO-beta, and huGRO-gamma. A mouse macrophage cell line, RAW 264.7, was transfected with a growth hormone reporter construct driven by a proximal fragment of the muMIP-2 5' promoter, and nested deletion mutant analysis localized the LPS responsive element to a region that contains a conserved NF kappa B consensus motif and lies 51 to 70 bp 5' from the transcription start site. In contrast to that of MIP-2, the muMIP-1 beta genomic clone exhibited the three exon/two intron structure characteristic of the chemokine beta family members (e.g., MCP-1). A comparison of the promoters for muMIP-1 beta and muMIP-1 alpha reveals a conserved CK-1 element, but transient expression studies in RAW 264.7 macrophages with proximal fragments of either the muMIP-1 beta or the muMIP-1 alpha 5' promoter fused to a human growth hormone reporter gene link LPS-inducibility in both to promoter segments near to, but not identical with, the consensus CK-1 sequence. Proximal 5' promoter fragments cloned from both the MIP-1 alpha and MIP-1 beta genes unexpectedly conferred constitutive expression on the fused reporter gene sequences in macrophage-like cells, but initial 5' deletion analysis did not link this responsiveness to known sequence motifs. The muMIP-1 beta promoter, but not the muMIP-1 alpha promoter, was constitutively active in B16 mouse melanoma cells, and both promoters were active in the myelomonocytic cell line WEHI 3B(A)d-, the muMIP-1 alpha promoter being three times stronger.

Amino Acid Sequence↗
PubMed1992

Behavioral profile of the 5HT1A receptor antagonist (S)-UH-301 in rodents and monkeys.

The effects of the new 5HT1A receptor antagonist (S)-UH-301 were investigated in several neurological and behavioral tests in rodents and monkeys. By itself, (S)-UH-301 was found to decrease palatable food consumption in rats, to exhibit anticonvulsant activity in mice, and anxiolytic-like properties in two rodent models of anxiety (light-dark test and elevated plus-maze test). (S)-UH-301 antagonized various symptoms and behaviors induced by the selective 5HT1A receptor agonist 8-OH-DPAT, such as lower lip retraction and flat body posture in rats, hyperphagia for palatable food in rats, and displacement activities (considered as indices of anxiety) in squirrel monkeys. These results further characterize (S)-UH-301 as an in vivo active 5HT1A receptor antagonist and suggest that this antagonistic activity might confer the compound with anxiolytic-like properties.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Genomic structure of murine macrophage inflammatory protein-1 alpha and conservation of potential regulatory sequences with a human homolog, LD78.

The gene for a murine macrophage inflammatory cytokine, MIP-1 alpha, belongs to a newly recognized superfamily encoding small, inducible peptides shown to be up-regulated in association with cellular activation or transformation (tentatively designated the scy, or small cytokine, gene family). Secreted scy family peptides as a group, and MIP-1 alpha in particular, have inflammatory and mitogenic activities, and the family has been divided into CXC and CC subfamilies according to the spacing of conserved cysteine residues in the primary amino acid sequences. We have isolated and characterized a genomic clone encoding the CC subfamily member MIP-1 alpha. The organization of the murine MIP-1 alpha gene into three exons interrupted by two introns is identical to that found for other members of the CC subfamily (e.g., huLD78, muJE, huJE/MCP-1, muTCA3, and hul-309), which has been taken as evidence of evolution from a common ancestral gene. With the exception of the ratPF4 gene, which shares the two-intron/three-exon pattern typical of the CC subfamily, sequenced genes encoding CXC subfamily peptides (e.g., hulL-8 and hulP-10) include an additional intervening sequence that creates a fourth exon. Genomic nucleotide sequences 5' of the MIP-1 alpha cap site are highly homologous to corresponding regions of the human gene encoding a CC peptide variously designated as LD78/GOS19/pAT464, including consensus regulatory motifs in common, reinforcing the contention that MIP-1 alpha and LD78 may be interspecies homologs.

Amino Acid Sequence↗