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Biomedical subjects

E Weber

Publications and source records attributed to E Weber.

At least 55 records · Page 3Linked to original sources
PubMed2000

Influence of age and duration of symptoms on fibre type distribution and size of the back muscles in chronic low back pain patients.

Many studies have documented an association between chronic low back pain (LBP) and deficits in back muscle strength and endurance. The sub-optimal performance is believed to be the result of alterations in the size and structure of the muscle, although the long-standing issue of whether the observed changes precede or are a consequence of the pain remains unresolved. If consequent to the problem, and predominantly related to disuse of the muscles, then it may be expected that a relationship between muscle structure and symptom duration would exist. Lumbar paraspinal muscle samples were obtained from 59 chronic LBP patients using the percutaneous biopsy technique. The samples were subject to routine histochemical analysis for the examination of muscle fibre type characteristics and cytochemical architectural changes. In 55 of the patients, the gross cross-sectional areas of magnetic resonance images of the trunk muscles were also measured. Multivariate analysis showed that symptom duration was the strongest predictor of the individual proportions of the fast-fatigable type IIX fibres; with age and gender included in the model, nearly 30% of the variance in fibre type distribution could be accounted for. Duration of pain had no influence on fibre size. Gross muscle cross-sectional area correlated directly with lean body mass and inversely with age, but showed no relationship with symptom duration. Pathological changes in the internal fibre structure were more frequently encountered in older patients, and were independent of symptom duration. The results suggest that, over the long term, fibre type transformations rather than alterations in fibre size are the predominant changes to be found in the muscles of chronic LBP patients. The direction of change supports the results of many previous studies that have demonstrated corresponding differences in the fatigability of the muscles. There is a strong case for the early implementation of active measures to attempt to offset the development of these changes in back pain patients.

Adult↗
PubMed2000

Identification, cloning, and characterization of a major cat flea salivary allergen (Cte f 1).

An 18 kDa protein isolated from saliva of the cat flea, Ctenocephalides felis, elicits a positive intradermal skin test (IDST) in 100 and 80% of experimental and clinical flea allergic dogs, respectively. Using solid-phase enzyme-linked immuno assay (ELISA), this protein detected IgE in 100 and 80% of experimental and clinical flea allergic dogs, respectively. A cDNA (pFSI) encoding a full-length Cte f 1 protein was isolated from a C. felis salivary gland cDNA library, using a combination of PCR and hybridization screening. This cDNA is 658 bp in length, and contains an open reading frame of 528 bp. The open reading frame encodes a protein of 176 amino acids, consisting of an 18 amino acid signal sequence and a 158 amino acid mature protein. The calculated molecular weight and pI of the mature protein are 18106 Da and 9.3, respectively. The protein, named Cte f 1, is the first novel major allergen described for canine flea allergy. Recombinant Cte f 1 (rCte f 1) was expressed in Escherichia coli, Pichia pastoris and baculovirus infected Trichoplusia ni cells. Approximately, 90% of the rCte f 1 expressed in E. coli accumulated in insoluble inclusion bodies, which could be refolded to a soluble mixture of disulfide isomers with partial IgE binding activity. Small quantities of an apparently correctly refolded form of rCte f 1, which had IgE binding activity equal to the native antigen, was isolated from the soluble fraction of E. coli cells. However, P. pastoris and baculovirus infected insect cells expressed and secreted a fully processed, correctly refolded and fully active form of rCte f 1. Mass spectrometry analysis of the active forms of rCte f 1confirmed that eight intact disulfide bonds were present, matching the number observed in the native allergen. The relative ability of rCte f 1 to bind IgE in the serum of flea allergic animals, produced in these three expression systems, matched that of the native allergen. Competition ELISA demonstrated that approximately 90% of the specific IgE binding to native Cte f 1 could be blocked by the different forms of rCte f 1.

Alkylation↗
PubMed2000

The expression of surface markers on dendritic cells as indicators for the sensitizing potential of chemicals.

Novel approaches to testing of skin sensitizing chemicals have made use of immature dendritic cells (DCs) cultured from different hematopoietic progenitors. These cells resemble Langerhans cells (LCs), which are the most potent antigen presenting cells in the skin. Former research has focused on the phenotypic and functional changes of LCs after application of skin sensitizers. But it has proven difficult to isolate sufficient numbers of LCs from skin. This disadvantage is overcome by cultures of immature DCs providing high numbers of reactive cells. The aim of the present investigation was to test the response of DC cultures established from different blood donors to known sensitizers, an irritant and a vehicle. The sensitizers NiSO(4), dinitrochlorobenzene (DNCB), 2,4,6 trinitrobenzene sulfonic acid (TNBS), alpha-hexylcinnamaldehyde (Cinn) and eugenol (Eu) induced the up-regulation of the co-stimulatory molecule CD86, of intercellular adhesion molecule CD54 and of the HLA-DR antigen. The irritant sodium dodecyl sulfate (SDS) and the vehicle dimethyl sulfoxide (DMSO) had no effect. A high rate of responders within blood donors was found for NiSO(4), TNBS, Cinn and Eu, while DNCB was less effective. The augmentation of surface marker expression in dendritic cells obtained from peripheral human blood seems to be a promising readout in prescreening for strong and moderate sensitizers. This test could thus help to reduce animal numbers for in vivo testing.

Acrolein↗
PubMed2000

A novel monoclonal antibody specific for lymphatic endothelium.

The difficulty of identifying and differentiating lymphatic and blood microvessels in tissue sections can be overcome by a monoclonal antibody specific for lymphatic endothelium. Unfortunately, the only known antibody also reacts with the endothelium of some blood vessels. The technique of double immunization (passive, with an antiserum to blood endothelium, and active, with a suspension of lymphatic endothelial cells) was, therefore, used to increase the chances of recognizing specific lymphatic antigens by the mouse immune system. The monoclonal antibody obtained, LyMAb, a G1 immunoglobulin, reacted strongly with the endothelium of bovine thoracic duct, mesenteric collecting vessels and lymphatic vessels of gallbladder and lymph nodes and moderately with those of the intestinal wall. Blood vessels (intercostal arteries, azygos vein and blood microvessels of all organs tested) were consistently negative. The antibody was species-specific and did not react with formalin-fixed, paraffin-embedded sections. Cross-reactivity was limited to some connective tissue fibres and scattered cells in the lymph node parenchyma, intestinal villi and hepatic lobules.

Animals↗
PubMed2000

[Review of infected total arthroplasties of the hip and knee--apropos of 28 cases].

This study is a long-term analysis of a group of patients with infected arthroplasties of the hip or the knee. We identified 28 patients with an infected arthroplasty (22 hips, 6 knees) documented by bacterial culture or on direct examination. At the time of diagnosis and on follow-up (a mean of 46 months after treatment) we evaluated the clinical picture, the radiological appearances of the articulation and the biological parameters. 19/28 patients showed a typical clinical picture, whereas in 9 others the picture was more doubtful. The treatments were 14 two-stage replacements of the arthroplasties, 7 simple resections, 5 conservative treatments and 2 one-stage replacements. On follow-up, 25 patients were considered as cured of their infection and 3 as failures. From a functional viewpoint, 9 patients showed no limitation, whereas 19 were limited in the daily activity. Half of the patients had no pain. Radiology showed that 20/26 evaluated patients had no signs of recurrence. Paraclinical examinations are important in the diagnosis of persistent low grade infections, particularly the demonstration of bacteria by pre-surgical sampling (fine needle aspiration, culture from draining sinuses). In spite of the cure of infection, the functional and painful sequellae are often considerable. As a result of our experience, we recommend a two-stage surgical procedure. Only when the general condition of the patient is poor, or when the infection is not under control, would we envisage an alternative procedure (arthrodesis, girdelstone, conservative).

Aged↗
PubMed2000

The incidence of transient neurological symptoms after spinal anaesthesia with lidocaine compared to prilocaine.

The purpose of this double-blind study was to investigate the incidence of transient neurological symptoms after the use of isobaric lidocaine and isobaric prilocaine for spinal anaesthesia. Seventy patients (ASA 1-2, age between 18 and 70 years) were randomly assigned to two groups of 35 patients each, to receive either isobaric 2% lidocaine 4 ml or isobaric 2% prilocaine 4 ml intrathecally, at the L3-4 interspace. One patient in the prilocaine group could not be included because data were incomplete. On the first postoperative day, patients were evaluated for transient neurological symptoms. Pain was scored on a 10-point scale. Seven patients (20%) in the lidocaine group had transient neurological symptoms with a mean pain score of 5.3, whereas no patient in the prilocaine group had these complaints (p = 0.006). Symptoms disappeared within 4 days. Prilocaine results in a lower incidence of transient neurological symptoms than lidocaine intrathecally and therefore it is more suitable for short surgical procedures.

Adolescent↗
PubMed2000

An evolutionarily conserved tripartite tryptophan motif stabilizes the prodomains of cathepsin L-like cysteine proteases.

Cathepsin L-like cysteine proteinases contain an evolutionarily highly conserved alpha-helical motif in the proregion. This is called the ER(F/W)N(I/V)N motif according to the conserved amino acids along one side of the helix. We studied the function of this motif using site-directed mutagenesis experiments of human procathepsin S. We replaced each of these amino acids with alanine and constructed deletion mutants lacking parts of the helix. All mutants were expressed in HEK 293 cells, but only one, W52A, was not processed to mature cathepsin S, nor was it phosphorylated or secreted into the culture medium. W52 is part of the hydrophobic core in the propeptide region of cathepsin S comprising two additional tryptophan residues, W28 and W31, also conserved among cathepsin L-like cysteine peptidases. Replacement of the latter with alanine led to consequences similar to those with the W52A mutation. Recombinant propeptides containing mutations of one of the three tryptophan residues were three orders of magnitude less effective as inhibitors of mature cathepsin S than the wild-type propeptide. The results point to a dominant role of the respective hydrophobic stack in the proper folding, transport and maturation of procathepsin S and related cathepsin L-like cysteine proteinases.

Amino Acid Sequence↗
PubMed2000

Highly potent inhibitors of human cathepsin L identified by screening combinatorial pentapeptide amide collections.

By screening a combinatorial pentapeptide amide collection in an inhibition assay, we systematically evaluated the potential of 19 proteinogenic amino acids and seven nonproteinogenic amino acids to serve as building blocks for inhibitors of human cathepsin L. Particularly efficient were aromatic, bulky, hydrophobic amino-acid residues, especially leucine, and positively charged residues, especially arginine. Building blocks for potential inhibitory peptides were combined by random selection from their activity pattern. This random approach for the design of inhibitors was introduced to compensate for the inaccuracy induced by shifted docking of combinatorial compound collections at the active center of cathepsin L. Thereby, we obtained structurally defined pentapeptide amides which inhibited human cathepsin L at nanomolar concentrations. Among the most potent novel inhibitors, one peptide, RKLLW-NH2, shares the amphiphilic character of the nonamer fragment VMNGLQNRK of the autoinhibitory, substrate-like, but reverse-binding prosegment of human cathepsin L which blocks the active center of the enzyme. Obviously, RKLLW-NH2 carries the functions that are important for enzyme-peptide interaction in a condensed form. This hypothesis was confirmed by structure-activity studies using truncated and modified pentapeptides.

Amides↗
PubMed2000

Occupational exposure to static, ELF, VF and VLF magnetic fields and immune parameters.

Despite the important role of the immune system in defending the body against infections and cancer, very few investigations have been undertaken to study possible effects of electromagnetic fields on human immunity. The aim of the present study was to examine the effect of occupational exposure on hospital personnel operating magnetic resonance tomographs and on industrial workers at induction heaters. In both categories of workplaces, magnetic flux densities exceeding Austrian exposure standards have been registered. Because of the complexity and high redundancy of the immune system, an extensive range of assay systems was applied: relative and absolute numbers of lymphocytic subsets were counted, the proliferative activity of T and B cells determined, the production of interleukin 2, interferon gamma and tumour necrosis factor alpha analysed, serum immunoglobulins evaluated, as well as non-specific immunity of monocytes and granulocytes measured by their oxidative burst. The number of natural killer cells and oxidative burst in monocytes showed statistically significant differences in workers at induction heaters and controls. The observed effect on oxidative burst was counteracted by a higher number of active cells in the exposed group, indicating normal non-specific immunity. The high number of natural killer cells, observed in some of the study subjects working at induction heaters, was reconfirmed in another investigation and deserves a further follow-up.

Adult↗
PubMed2000

Weight change in older depressed patients during acute pharmacotherapy with paroxetine and nortriptyline: a double-blind randomized trial.

The authors examined weight change in 32 elderly patients treated for 12 weeks with either nortriptyline or paroxetine during acute-phase pharmacotherapy. Random assignment to treatment and double-blind assessment of weight change were performed, including ascertainment of premorbid (i.e., pre-depression) weight. Pretreatment severity of depression was correlated with weight loss during the depressive episode and depression-related weight loss, in turn, correlated with weight regained during antidepressant treatment. There was no differential weight change associated with nortriptyline vs. paroxetine. Rather, subjects in both groups approximated their premorbid weights by 12 weeks of acute-phase pharmacotherapy with either agent. However, additional investigation of weight change during continuation and maintenance pharmacotherapy is necessary and would be clinically useful for the long-term management of elderly patients with depression.

Aged↗
PubMed2000

[Severe cardiac insufficiency and type Ib pseudohypoparathyroidism].

The authors report the case of a 28 year old woman with acute left ventricular failure associated with severe hypocalcaemia (1.7 mmol/l) without chronic renal failure or hypoproteinaemia. The echocardiographic appearances were those of dilated and globally hypokinetic cardiomyopathy with a severely depressed left ventricular ejection fraction (23%). Haemodynamic improvement was only obtained by the association of calcium supplements and Vitamin D derivatives (Un-Alfa) to conventional treatment. A low serum calcium associated with hyperphosphotaemia, hypocalciuria, hypophosphaturia and, above all, a high parathormone concentration, provided the diagnosis of a sporadic form of type Ib pseudohypoparathyroidism. Secondary cardiac failure to the hypocalcaemia is mainly observed in children and young adults in the context of chronic renal failure or true hypoparathyroidism. Pseudohypoparathyroidism is a very rare condition and systolic LV dysfunction for which hypocalcaemia is responsible, would seem to be totally reversible after calcium supplementation.

Adult↗
PubMed2000

Specific adhesion molecules bind anchoring filaments and endothelial cells in human skin initial lymphatics.

Anchoring filaments are a characteristic feature of initial lymphatic vessels. They connect the abluminal membrane of endothelial cells to the surrounding elastic fibers. The main molecular component of anchoring filaments is fibrillin. Initial lymphatic vessels of human skin were stained with monoclonal antibodies to fibrillin, integrins alpha 2 beta 1, alpha 3 beta 1 and alpha v beta 3, vinculin, talin, beta-actin and focal adhesion kinase (FAK). A double-labeling immunofluorescence method was used to simultaneously stain fibrillin and alpha 3 beta 1 integrin or FAK. Close contiguities between integrins and anchoring filaments were observed. These results suggest that the anchoring filaments connect the extracellular matrix and the endothelial cell cytoskeleton through the transmembrane integrin and FAK molecule. The results also demonstrate the presence of focal adhesions in the wall of initial lymphatic vessels. These connections possibly enable transmission of chemical and/or mechanical stimuli from the extracellular matrix to the endothelial cells. Here, they are transformed in cytoskeleton rearrangements and intracellular signaling events, some of which may contribute to the initial formation of lymph.

Adolescent↗
PubMed1999

Effects of ACEA-1328, a NMDA receptor/glycine site antagonist, on U50,488H-induced antinociception and tolerance.

Previously, we have shown that inhibition of the glycine site associated with the N-methyl-D-aspartate (NMDA) receptor is another viable approach to blocking morphine tolerance. In the present study, we sought to investigate the involvement of the NMDA receptor/glycine site in kappa-opioid receptor-mediated antinociception and tolerance in CD-1 mice. In antinociception studies, mice were injected with 5-nitro-6,7-dimethyl-1,4-dihydro-2, 3-quinoxalinedione (ACEA-1328), a systemically bioavailable NMDA receptor/glycine site antagonist, or the vehicle (Bis-Tris, 0.2 M) and then immediately with trans-(+/-)-3, 4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamid e methanesulfonate (U50,488H), a kappa-opioid receptor agonist. Thirty minutes later, mice were tested for changes in nociceptive responses in the tail flick assay. ACEA-1328, per se, prolonged tail flick latencies with an ED(50) of approximately 50 mg/kg. Concurrent administration of ACEA-1328, at doses that did not produce antinociception, with U50,488H increased the potency of U50,488H in a dose-dependent manner. In tolerance studies, mice were treated, either once a day for 9 days or twice daily for 4 days, with the vehicle or ACEA-1328. Immediately after the initial injection, mice then received an injection of saline or U50,488H. On the test day, mice were injected with U50,488H alone and tested for antinociception 30 min later. Chronic treatment with U50,488H by either method produced tolerance. Unlike the acute effect of the drug, chronic treatment with ACEA-1328 decreased the antinociceptive potency of U50,488H. Taken together, the data suggest that acute and chronic administration of ACEA-1328 differentially affected the antinociceptive effect of U50,488H. Furthermore, the decreased in the potency of U50,488H induced by chronic treatment with ACEA-1328 also confounded the interpretation of the tolerance data.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

The retinoblastoma tumor suppressor inhibits cellular proliferation through two distinct mechanisms: inhibition of cell cycle progression and induction of cell death.

Studies aimed at examining the precise function(s) of the retinoblastoma tumor suppressor protein, RB, have been hindered by the rapid phosphorylation and inactivation of ectopically expressed RB which occurs in the majority of cell types. Therefore, ectopically expressed RB is a poor inhibitor of cellular proliferation. We have designed constitutively active RB proteins, PSM-RB, that cannot be inactivated by phosphorylation. Using these proteins, we show that unlike wild-type RB, PSM-RB proteins inhibit cell cycle progression in a broad range of tumor cell types. Furthermore, unlike p16ink4a, PSM-RB is also a potent inhibitor of cell cycle progression in RB-deficient tumor cells. Surprisingly, we identified a tumor cell line that is resistant to the cell cycle inhibitory effects of PSM-RB. This finding challenges the hypothesis that RB must be inactivated in all cells for cell cycle progression to occur. Further characterization of this 'resistant' tumor line revealed that proliferation of these cells is still inhibited by PSM-RB. We show that this is due to PSM-RB-induced cell death. As such, these studies are the first to show that RB inhibits cellular proliferation through at least two distinct mechanisms - inhibition of cell cycle progression and induction of cell death.

Apoptosis↗
PubMed1999

Structure-activity relationship of N-(phenylalkyl)cinnamides as novel NR2B subtype-selective NMDA receptor antagonists.

A novel series of N-(phenylalkyl)cinnamides related to N-(4-phenylbutyl)-3,4-dihydroxy-beta-cyanocinnamide (6, an EGFR-K inhibitor with high antiproliferative activity) was synthesized and tested for antagonism at N-methyl-D-aspartate (NMDA) receptor subtypes. Potency and subunit selectivity were assayed by electrical recordings in Xenopus oocytes expressing three binary combinations of cloned rat NMDA receptor subunits: NR1A expressed in combination with either NR2A, NR2B, or NR2C. The N-(phenylalkyl)cinnamides are selective antagonists of NR1A/2B receptors. Assayed under steady-state conditions, N-(4-phenylbutyl)-4-hydroxycinnamide (16) has an IC(50) value of 77 nM and >1000-fold selectivity with respect to NR1A/2A and NR1A/2C receptors. Potency at alpha(1) adrenergic receptors is low for the four cinnamides tested. Inhibition of NR1A/2B receptors does not correlate with EGFR and ErbB2/neu tyrosine kinase inhibitor activity. The N-(phenylalkyl)cinnamide series we describe provides a novel and structurally diverse framework for designing new NR2B-selective NMDA antagonists as potential CNS therapeutics.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1999

4-Hydroxy-1-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperidine: a novel, potent, and selective NR1/2B NMDA receptor antagonist.

A structure-based search and screen of our compound library identified N-(2-phenoxyethyl)-4-benzylpiperidine (8) as a novel N-methyl-D-aspartate (NMDA) receptor antagonist that has high selectivity for the NR1/2B subunit combination (IC(50) = 0.63 microM). We report on the optimization of this lead compound in terms of potency, side effect liability, and in vivo activity. Potency was assayed by electrical recordings in Xenopus oocytes expressing cloned rat NMDA receptors. Side effect liability was assessed by measuring affinity for alpha(1)-adrenergic receptors and inhibition of neuronal K(+) channels. Central bioavailability was gauged indirectly by determining anticonvulsant activity in a mouse maximal electroshock (MES) assay. Making progressive modifications to 8, a hydroxyl substituent on the phenyl ring para to the oxyethyl tether (10a) resulted in a approximately 25-fold increase in NR1A/2B potency (IC(50) = 0.025 microM). p-Methyl substitution on the benzyl ring (10b) produced a approximately 3-fold increase in MES activity (ED(50) = 0.7 mg/kg iv). Introduction of a second hydroxyl group into the C-4 position on the piperidine ring (10e) resulted in a substantial decrease in affinity for alpha(1) receptors and reduction in inhibition of K(+) channels with only a modest decrease in NR1A/2B and MES potencies. Among the compounds described, 10e (4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piperid ine, Co 101244/PD 174494) had the optimum pharmacological profile and was selected for further biological evaluation.

Animals↗
PubMed1999

Retinoic acid-mediated growth inhibition of small cell lung cancer cells is associated with reduced myc and increased p27Kip1 expression.

Human lung cancer cells, including small cell lung carcinoma (SCLC), frequently lose expression of retinoic acid receptor beta (RAR-beta) and are resistant to the growth inhibitory activity of all-trans retinoic acid (RA). To elucidate the role of RAR-beta in the growth regulation of SCLC by retinoids, we restored RAR-beta expression in RAR-beta-negative H209 SCLC cells by retroviral transduction (H209-RAR-beta). We found that H209-RAR-beta, but not parental H209 cells, underwent growth inhibition upon RA treatment. RA-treated H209-RAR-beta cells arrested in G1 and displayed reduced L-myc expression and cyclin-dependent kinase 2 (cdk2) activity compared with untreated cells. RA treatment of H209-RAR-beta cells was also accompanied by increased expression of the cdk inhibitor p27Kip1, whereas no differences in the expression of L-myc or p27Kip1 were detected upon RA treatment of parental H209 cells. The RA-induced growth arrest of H82 SCLC cells, which express endogenous RAR-beta, was also associated with reduced c-myc and increased p27Kip1 expression. We found that ectopic expression of p27Kip1 induced growth inhibition in both H209 and H82 cells, and that sustained myc expression in H209-RAR-beta cells promoted the induction of apoptosis upon RA addition. Our observations indicate that RAR-beta gene transfer can restore RA sensitivity in SCLC cells and suggest that myc and p27Kip1 may represent critical mediators of the RA-induced cell cycle arrest in SCLC cells expressing RAR-beta.

Antineoplastic Agents↗