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Biomedical subjects

J Winter

Publications and source records attributed to J Winter.

At least 127 records · Page 7Linked to original sources
PubMed1995

Nerve growth factor (NGF) differentially regulates the chemosensitivity of adult rat cultured sensory neurons.

We have studied the effects of NGF on the chemosensitivity of adult rat DRG neurons over a 1-2 week period in vitro, using voltage-clamp and radioactive ion flux methods. A sustained proton evoked current was reversibly lost in NGF-free medium after 1 week. Proton-evoked efflux of radioactive 86Rb+ ions was also depressed in NGF deprived cultures, although depolarization with 40 mM potassium still evoked a large 86Rb+ efflux. A similar reversible loss of capsaicin sensitivity was noted. The response to GABA and a second, transient proton evoked current were also regulated by NGF, but over a longer time course. In contrast, the sensitivity to ATP was not influenced by the presence or absence of NGF. These data show that NGF regulates some, but not all, chemosensitivities of DRG neurons and that loss of sensitivity occurs at different rates for different agonists. The precise co-regulation of the response to capsaicin and the sustained response to protons provides further evidence that protons activate capsaicin-operated ion channels.

Adenosine Triphosphate↗
PubMed1994

Neurite outgrowth and GAP-43 mRNA expression in cultured adult rat dorsal root ganglion neurons: effects of NGF or prior peripheral axotomy.

Adult dorsal root ganglion (DRG) cells are capable of neurite outgrowth in vivo and in vitro after axotomy. We have investigated, in cultured adult rat DRG cells, the relative influence of nerve growth factor (NGF) or a prior peripheral nerve lesion on the capacity of these neurons to produce neurites. Since there is evidence suggesting that the growth-associated protein GAP-43 may play a crucial role in axon elongation during development and regeneration, we have also compared the effect of these treatments on GAP-43 mRNA expression. NGF increased the early neurite outgrowth in a subpopulation of DRG cells. This effect was substantially less, however, than that resulting from preaxotomy, which initiated an early and profuse neurite outgrowth in almost all cells. No difference in the expression of GAP-43 mRNA was found between neurons grown in the presence or absence of NGF over 1 week of culture, in spite of the increased growth produced by NGF. In contrast, cultures of neurons that had been preaxotomized showed substantial increases in GAP-43 mRNA and NGF had, as expected, a significant effect on substance P mRNA levels. Two forms of growth may be present in adult DRG neurons: an NGF-independent, peripheral nerve injury-provoked growth associated with substantial GAP-43 upregulation, and an NGF-dependent growth that may underlie branching or sprouting of NGF-sensitive neurons, but which is not associated with increased levels of GAP-43 mRNA.

Animals↗
PubMed1994

The discovery of capsazepine, the first competitive antagonist of the sensory neuron excitants capsaicin and resiniferatoxin.

Capsaicin and resiniferatoxin are natural products which act specifically on a subset of primary afferent sensory neurons to open a novel cation-selective ion channel in the plasma membrane. These sensory neurons are involved in nociception, and so, these agents are targets for the design of a novel class of analgesics. Although synthetic agonists at the capsaicin receptor have been described previously, competitive antagonists at this receptor would be interesting and novel pharmacological agents. Structure-activity relationships for capsaicin agonists have previously been rationalized, by ourselves and others, by dividing the capsaicin molecule into three regions--the A (aromatic ring)-, B (amide bond)-, and C (hydrophobic side chain)-regions. In this study, the effects on biological activity of conformational constraint of the A-region with respect to the B-region are discussed. Conformational constraint was achieved by the introduction of saturated ring systems of different sizes. The resulting compounds provided agonists of comparable potency to unconstrained analogues as well as a moderately potent antagonist, capsazepine. This compound is the first competitive antagonist of capsaicin and resiniferatoxin to be described and is active in various systems, in vitro and in vivo. It has recently attracted considerable interest as a tool for dissecting the mechanisms by which capsaicin analogues evoke their effects. NMR spectroscopy and X-ray crystallography experiments, as well as molecular modeling techniques, were used to study the conformational behavior of a representative constrained agonist and antagonist. The conformation of the saturated ring contraint in the two cases was found to differ markedly, dramatically affecting the relative disposition of the A-ring and B-region pharmacophores. In agonist structures, the A- and B-regions were virtually coplanar in contrast to those in the antagonist, in which they were approximately orthogonal. A rationale for agonist and antagonist activity at the capsaicin receptor is proposed, based on the consideration of these conformational differences.

Animals↗
PubMed1994

[Acute mitral insufficiency in osteogenesis imperfecta].

A 56-year-old woman with known osteogenesis imperfecta tarda but no obvious sign of cardiac disease developed increasing dyspnoea, eventually even at rest, with blood-streaked sputum over a period of 10 days. The chest radiograph demonstrated intraalveolar pulmonary oedema. Transthoracic echocardiography revealed as the likely cause of these signs chordal rupture of the anterior leaflet of the mitral valve with mitral regurgitation. After treatment of the cardiac failure with frusemide (up to 500 mg daily intravenously), nitrates and captopril (25 mg daily by mouth) the diagnosis was confirmed by transoesophageal echocardiography. Elective replacement of the mitral and aortic valves was performed 6 months later. Acid mucopolysaccharides were demonstrated histologically in the valvar stroma, a finding consistent with osteogenesis imperfecta. Echocardiography should be performed routinely in connective-tissue disease to reveal any possible cardiovascular involvement.

Aortic Valve↗
PubMed1994

Complications in endoscopy of the lower gastrointestinal tract. Therapy and prognosis.

This is a report on 126 prospectively registered and controlled complications in 29,695 consecutive endoscopic procedures of the lower gastrointestinal tract. The overall complication rate is 0.4%. All endoscopic procedures were performed in our institution; no referrals "from other hospitals" are included. The therapy and prognosis of occurring complications are described. Especially after therapeutic endoscopy--above all, after polypectomy--the complication rate of 0.83% is not negligible. A serious aspect is the average interval of 30 h from endoscopically caused complication to the onset of symptoms. Bleeding could be managed conservatively in 76% of cases. Nevertheless perforation and transmural burn injuries required surgical intervention in 78% of cases. The authors conclude that in the case of transmural burn an attempt at "active conservative treatment" is justified if the patient is under close surgical control, if the symptoms improve, and if there is a possibility of immediate surgery.

Adult↗
PubMed1994

Nerve growth factor induces expression of immediate-early genes NGFI-A (Egr-1) and NGFI-B (nur 77) in adult rat dorsal root ganglion neurons.

We have used primary cultures of adult rat dorsal root ganglia (DRG), enriched in sensory neurons, to investigate the induction of immediate-early genes by NGF and a variety of other growth factors. Using the polymerase chain reaction we have quantitatively amplified specific mRNA transcripts induced by NGF, in the presence and absence of the protein synthesis inhibitor cycloheximide. NGFIA (Egr-1) and NGFIB (nur 77) mRNAs were elevated in level within 60 min of NGF treatment and independently of de novo protein synthesis. This was consistent with the behaviour of immediate-early genes. These kinetics were seen at a range of NGF concentrations. NGFIA and NGFIB mRNAs were also found to be induced in DRG cultures by a variety of other growth factors. Different patterns of induction of NGFIA and NGFIB mRNA observed in DRG cultures suggested that transcript-specific pathways of signal transduction were operating within neurons, dependent upon the particular growth factor stimulus. Comparison of data reported from growth factor treatment of other cell types with data from DRG cultures also revealed patterns of NGFIA and NGFIB mRNA induction specific to DRG neurons.

Animals↗
PubMed1994

Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity.

Experimental inflammation produced by an intraplantar injection of complete Freund's adjuvant results in local sensory hypersensitivity and up-regulates the neuropeptides substance P and calcitonin gene related peptide in the primary sensory neurons innervating the inflamed tissue. The inflammation also elevates nerve growth factor levels in the skin. Systemic administration of anti-NGF neutralizing antibodies prevent the behavioral sensitivity, the up-regulation of neuropeptides and the inflammation-induced expression of the immediate early gene c-fos in dorsal horn neurons, without modifying swelling and erythema. Elevation of the neurotrophin NGF in the periphery is a major contributor, therefore, of inflammatory pain.

Animals↗
PubMed1994

The effect of the orally active platelet-activating factor antagonist WEB 2086 in the treatment of asthma.

Platelet-activating factor (PAF) may be a major mediator of asthma and bronchial hyperreactivity through its many proinflammatory actions. Specific antagonism of PAF might offer an alternative anti-inflammatory treatment to inhaled corticosteroids. To test this, we have studied the effect of an orally active PAF antagonist, WEB 2086, on the inhaled steroid requirements of symptomatic atopic asthmatics in a double-blind randomized placebo-controlled parallel group study. The inhaled corticosteroid dose required for symptomatic control of asthma was established and further steroid reduction was attempted after treatment with WEB 2086 40 mg three times daily for 12 wk. Of 106 patients recruited, 68 entered the treatment phase and 65 completed 6 wk of treatment. The mean daily corticosteroid dose (SE) at study entry was 1,257 (75) micrograms which was reduced by 323 (66) micrograms during the run-in period without loss of symptomatic control. A further 416 (57) micrograms reduction in inhaled corticosteroid dosage was possible during the treatment phase but this was almost identical in the WEB 2086 and placebo-treated groups, amounting to 353 (92) and 481 (65) micrograms/day respectively (not significant [NS]). Rate of relapse following corticosteroid reduction was a continuous variable and relapse occurred at different times depending on the variable used to define it. Time to relapse measured by an increase in symptoms correlated with disease duration (r = 0.41, p < 0.01) and with the dose of inhaled corticosteroid at study entry (r = 0.36, p < 0.01) but no other measured variable predicted the time to relapse.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1994

The influence of iodine on the intensity of the intrathyroidal autoimmune process in Graves' disease.

Several lines of evidence support an etiological role of iodine for the initiation and perpetuation of autoimmune thyroid disease. However, varying relapse rates after increased iodine supplementation have been reported for Graves' disease. Furthermore the effects of iodine on the intensity of human autoimmune thyroiditis have previously only been investigated by indirect parameters and actions of iodine on thyroid function and a possible enhancement of the intrathyroidal autoimmune process in Graves' disease are difficult to separate in previous studies. Moreover lymphocytic thyroiditis in animal models has always been induced by considerably higher iodine doses as those used in in vivo studies. Therefore we investigated the effect of low and high iodine concentrations on the intensity of the intrathyroidal autoimmune process in Graves' disease. The intensity of intrathyroidal infiltration by lymphocytes, memory T cells, plasma cells and antigen presenting cells was determined by quantitative immunohistologic methods in 38 Graves' disease patients. 12 patients received additional preoperative iodine (group II) and 26 were treated with thiourelene antithyroid drugs only (group I). Urinary and intrathyroidal iodine concentrations were determined by a modified cer arsenite method in both groups. Application of high iodine doses in group II induced a significant increase of kappa and lambda positive plasma cells and interdigitating reticulum cells. This was not observed for activated T cells. There was no correlation between the extent of intrathyroidal infiltration by activated T cells, plasma cells and antigen presenting cells, and intrathyroidal or urinary iodine or intrathyroidal iodine concentrations in group I.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Phase I trial of high-dose melphalan, high-dose etoposide and autologous bone marrow re-infusion in solid tumors: an Eastern Cooperative Oncology Group (ECOG) study.

The purpose of this work was to determine the maximum tolerated (phase II) dose of melphalan and etoposide that can be given in conjunction with autologous BM re-infusion in patients who have refractory or relapsed solid tumors. Twenty-six patients with refractory or relapsed breast cancer (n = 15), small cell lung cancer (n = 1), ovarian cancer (n = 3), colorectal cancer (n = 3) or malignant melanoma (n = 4) were enrolled and treated in this phase I study. Patients ranged in age from 31 to 60 years (median 44.5 years). Melphalan 180 mg/m2 (60 mg/m2/day for 3 consecutive days i.v. over 30 min) and etoposide 1200-3600 mg/m2 (400-1200 mg/m2/day for 3 consecutive days i.v. over 4 h) were given followed by autologous BM infusion 60-72 h after completion of chemotherapy. Ten patients received GM-CSF or G-CSF therapy after marrow re-infusion. Regimen-related toxicities included fever, pancytopenia, mucositis, nausea, vomiting, diarrhea, esophagitis, hepatic dysfunction and infection. Neutrophils recovered to > 500 x 10(6)/l and platelets recovered to > 20 x 10(9)/l (without transfusions) a median of 17 days and 20.5 days after marrow infusion, respectively. Dose-limiting toxicity occurred at an etoposide dose of 3600 mg/m2, since 4 of 6 patients treated at this dose level experienced grade 4 NCI Common Toxicity Criteria (mucositis (n = 3) and infection (n = 1)). Complete responses were noted in 7 patients (breast cancer (n = 5), colorectal cancer (n = 1) and melanoma (n = 1)); partial responses were observed in 5 patients. Melphalan 180 mg/m2 and etoposide 3000 mg/m2 is a potent high-dose chemotherapy regimen with significant antineoplastic activity, particularly for breast cancer, and has acceptable toxicity when administered in conjunction with autologous BM re-infusion.

Adult↗
PubMed1994

[DNA cytophotometry of oxyphilic thyroid tumors].

Paraffin-embedded surgical specimen from 47 Hürthle cell tumours of the thyroid gland were examined for DNA content by image cytometry to assess the diagnostic and prognostic utility of ploidy determination in oxyphilic tumors. Both adenomas (31 cases) and carcinomas (16 cases) were studied. As a control for the algorithm of DNA-interpretation, 10 randomly selected normal thyroid tissues were analysed. All control cases showed normal diploid DNA content. Among the Hürthle cell tumours, aneuploid peaks were present in 15 adenomas (48%) and in 13 carcinomas (81%). These findings demonstrate a limited value of aneuploidy as diagnostic feature for malignancy in Hürthle cell tumours of the thyroid. In view of prognosis, there is no unfavourable predictive prognostic value for abnormal DNA content in histologically benign Hürthle cell tumours. No metastases or recurrences occurred in this group during a mean follow up period of 4.4 years. Three patients with aneuploid carcinomas and local recurrences or metastases had higher levels of basic DNA indices. This suggests that aneuploidy has a prognostic value for histologically defined carcinomas.

Adenoma↗
PubMed1993

Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 1. The aromatic "A-region".

A series of analogues of capsaicin, the pungent principle of chilli peppers, was synthesized and tested in assays for capsaicin-like agonism in vitro. The results of these assays were compared with activities in an acute nociceptive model and a correlation was observed which established that the results of these in vitro assays were predictive of analgesia. Using a modular approach the structure-activity profile of specific regions of capsaicin congeners was established using an in vitro assay measuring 45Ca2+ uptake into neonatal rat dorsal root ganglia neurones. Substituted benzylnonanamides 2a-z and N-octyl-substituted phenylacetamides 4a-v were made to test the requirements for activity in the aromatic "A-region" of the molecule. Compounds with the natural substitution pattern (2b and 4c) and the corresponding catechols (2i and 4g) were the most potent, although the catechols were less potent in vivo. Other substitution patterns have reduced activity. These results have established stringent structural requirements for capsaicin-like activity in this part of the molecule.

Analgesics↗
PubMed1993

Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 2. The amide bond "B-region".

A series of compounds incorporating replacements for the amide bond "B-region" moiety of capsaicin have been synthesized, including vanillylamides and esters, homovanillic acid amides and esters, ureas, and thioureas. These have been tested in an in vitro assay for agonism (45Ca2+ influx into dorsal root ganglia neurones), which is predictive of analgesic activity, to investigate the requirements in this region of capsaicin for activity. N-(4-Hydroxy-3-methoxybenzyl)-N'-octylthiourea (14a) emerged as the most potent analogue (EC50 = 0.06 microM). An operational model based on multiple hydrogen-bonding interactions is proposed to explain the structure-activity profile observed. In combination with studies on the other regions of the capsaicin molecule these results describe a picture of the molecular interactions of capsaicin with its putative receptor.

Analgesics↗
PubMed1993

Analogues of capsaicin with agonist activity as novel analgesic agents; structure-activity studies. 3. The hydrophobic side-chain "C-region".

Structural variants of the hydrophobic side chain ("C region") of the capsaicin molecule have been incorporated into a series of vanillylamides and vanillylthioureas. These compounds have been tested in an in vitro assay for agonism (45Ca2+ influx into dorsal root ganglia neurones), previously shown to be predictive of analgesic activity. The results of this study have established the requirement for a hydrophobic substituent of limited size (molar refractivity, MR, < 55) in order to obtain high potency. Combination of the information gained here about the "C-region" of the capsaicin molecule with the studies described in the preceding two papers provides a rational basis for the design of compounds of increased potency.

Analgesics↗
PubMed1993

Antibody as a surrogate receptor in the screening of a phage display library.

Polyclonal antibody (Ab) against biotin (anti-biotin Ab) was evaluated as a source of shape mimics for the biotin-binding pocket of streptavidin (Sv). A 6-mer phage display library was panned with anti-biotin and the selected peptide sequences compared to those obtained by panning directly with Sv. The consensus XXYYLH was identified with the anti-biotin Ab probe, while GDWVFI and PWPWLG were the major motifs identified by Sv panning. Although some similarities were observed between sequences of the products from both pannings, only phage displaying the GDWVFI and PWPWLG peptides demonstrated biotin-sensitive Sv binding in ELISA and micropanning assays. Phage displaying GDWVFI could be eluted from Sv with either acid or biotin, but not phosphate-buffered saline (PBS), whereas phage displaying PWPWLG eluted with acid, biotin and PBS.

Amino Acid Sequence↗
PubMed1993

Fluctuations in infant mortality rates in Berlin during and after the First World War.

"This paper will examine infant mortality in Berlin during and after [World War I].... We argue that the social crisis of war, defeat and postwar instability is reflected in the history of infant mortality in Berlin.... We conclude...that the history of infant mortality in Berlin between 1914 and 1923 is one in which members of marginalized groups, specifically the children of unmarried women, paid an exceptionally high price for the war." (SUMMARY IN FRE)

Demography↗
PubMed1993

Characterization of resiniferatoxin binding sites on sensory neurons: co-regulation of resiniferatoxin binding and capsaicin sensitivity in adult rat dorsal root ganglia.

Binding of [3H]resiniferatoxin was seen by autoradiography in sections of rat dorsal root ganglia and the superficial dorsal horn of the spinal cord. Membranes from rat dorsal root ganglia and spinal cord, but not other tissues, had saturable high-affinity binding sites for [3H]resiniferatoxin. A series of capsaicin analogues competed for these sites. The sites probably correspond to capsaicin receptors. Systemic pretreatment of rats with capsaicin caused loss of capsaicin sensitivity in sensory neurons and a reduction in binding of resiniferatoxin to rat dorsal root ganglia, measured by binding assays and autoradiography. Adult rat dorsal root ganglion neurons cultured without nerve growth factor also lost their capsaicin-sensitivity and showed reduced resiniferatoxin binding. Therefore, capsaicin responses in sensory neurons may be regulated by nerve growth factor through control of the number of capsaicin receptors.

Animals↗