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Biomedical subjects

A Hirsch

Publications and source records attributed to A Hirsch.

At least 91 records · Page 5Linked to original sources

Furosemide inhibits bradykinin-induced contraction of human bronchi: role of thromboxane A2 receptor antagonism.

Bradykinin contracts human isolated small bronchi through prostanoid release and subsequent TP receptor stimulation. Furosemide 10(-4) to 10(-3) M concentration dependently inhibited bradykinin- and the stable TP receptor agonist U-46619-induced contraction of human isolated small airways. The inhibitory effect of furosemide on U-46619-induced contraction involves competitive antagonism at TP receptors. Such an inhibition of TP receptors could a least partly explain the inhibitory effect of furosemide on bradykinin-induced contraction, and could be one of the mechanisms of the protective effect of furosemide in asthma.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

Role of thromboxane A2 in bradykinin-induced human isolated small bronchi contraction.

We previously demonstrated that the bradykinin-induced contraction of human isolated small bronchi is inhibited by indomethacin, capsaicin (N-methyl-N-6-nonenamide) and ruthenium red but not by tachykinin receptor antagonists. The thromboxane A2 receptor (TP receptor) antagonist GR32191 ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-(+)-7-(5-(((1,1'-biphenyl)-4-yl)- methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, hydrochloride) (10(-10) to 10(-8) M) dose dependently inhibited the effect of bradykinin, suggesting the mediation of the TP receptor in the action of bradykinin. With higher concentrations of GR32191 (10(-7) and 10(-6) M) bradykinin induced a relaxation which was inhibited by indomethacin and by the bradykinin B2 receptor antagonist Hoe 140 (D-Arg0[Hyp3,Thi-5,D-Tic7,Oic8]bradykinin). The thromboxane A2 synthase inhibitor dazoxiben (4-(-2-(1H-imidazol-1-yl)ethoxy) benzoic acid hydrochloride) 10(-6) M inhibited the bradykinin-induced contraction, suggesting that thromboxane A2 was involved in TP receptor stimulation. The thromboxane A2 mimetic U-46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F2 alpha)-induced contraction of human distal bronchi was not inhibited by capsaicin and ruthenium red. Our data suggest that bradykinin contracts human isolated small bronchi through thromboxane A2 release. The inhibitory effect of ruthenium red and capsaicin on the bradykinin response may be due to inhibition of thromboxane A2 release or arachidonic mobilisation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

Purification, characterization, crystallization, and preliminary X-ray results from Paracoccus denitrificans porin.

The porin from Paracoccus denitrificans ATCC 13543 was purified and crystallized. Two crystal forms were obtained from porin solutions with beta-d-octylglucopyranoside as detergent. Crystals of form I belong to the monoclinic spacegroup C2 with unit cell dimensions a = 112.2 A, b = 193.8 A, c = 100.5 A and beta = 129.2 degrees. There is 1 trimer per asymmetric unit. Crystals of form II are triclinic with a = 89.7 A, b = 98.8 A, c = 112.5 A, alpha = 112.5 degrees, beta = 101.8 degrees, gamma = 106.7 degrees (2 trimers per asymmetric unit). Both crystal forms diffract to 3 A.

Crystallization↗

European School of Oncology Advisory report to the European Commission for the "Europe Against Cancer Programme" European Code Against Cancer.

A European School of Oncology Advisory Group has reviewed the European Code Against Cancer after its initial use over a 6-year period. With minor modifications, the original ten recommendations were found to be adequate, although it was agreed that an Annex was necessary to explain the scientific evidence supporting each point, and is presented herewith. Tobacco smoking clearly remains the most important cause of cancer, and now it can be quantified better than ever before. It is also clear that it is never too late to stop smoking: stopping even in middle age, prior to the onset of serious illness has a beneficial effect on life expectancy. Alcohol drinking is an important cause of cancer, and yet modest consumption levels protect against cardiovascular disease mortality. The optimal strategy seems to be a consumption not exceeding 2-3 drinks per day, although this limit may be lower for women. Increased consumption of fruits and vegetables, reduction in consumption of fatty foods, reduction of obesity and increased physical activity can all be recommended to reduce cancer risk. Exposure to excessive sunlight remains a problem which should be limited. Control of occupational cancer is a three-way partnership: legislation identifies and limits exposure to known carcinogens, employers enact the legislation and workers should respect the measures introduced. There are a number of signs and symptoms which may lead to cancer being diagnosed earlier, and patients with these should be referred to a doctor. For women, participation in organised programmes of cervical cancer and breast cancer (after 50 years of age) should lead to a reduction in mortality from these forms of cancer. The key element is organised programmes, where quality control and quality assurance are in force. These revised recommendations are the result of an agreement following advice, review and dialogue with cancer experts throughout Europe. They were approved by the European Community Cancer Experts at their meeting in Bonn on 28-29 November 1994. Their implementation by the European population should greatly reduce cancer incidence and mortality.

Alcohol Drinking↗

Clinico-pathological features and survival of lung cancer patients in Paris, France.

We studied the clinico-pathological features of 750 lung cancers identified in Paris, France, during 1988. An internal comparison was performed between adenocarcinomas and other subtypes. Survival of 502 patients was studied. 85% of patients were males; 93% were smokers or ex-smokers. Squamous cell carcinomas, adenocarcinomas, small cell carcinomas and large cell cancers accounted for 51, 22, 15 and 12% of all cases, respectively. Differences were found for the distribution of histological subtyping according to sex (P = 0.001) and smoking status (P = 0.0001) with a greater proportion of adenocarcinomas for women and non-smokers. Median overall survival was less than one year. In multiple regression analysis, small cell lung cancer patients appeared to have a worse prognosis than other histological subtypes. This study describes patients who were treated in community practice and might be more representative of the real clinico-pathological profile of this disease in France.

Adult↗

Serum p53 antibodies as early markers of lung cancer.

The p53 alteration is the most common alteration found in human cancer. It usually involves missense mutations that stabilize the p53 protein, which in turn accumulates, reaching levels detectable by immunohistochemistry. We and others have demonstrated that this overexpression of mutant p53 protein can induce a specific humoral response in cancer patients. This result was assessed by the presence of p53 antibodies in sera of patients with various types of cancers, whereas normal populations do not exhibit such antibodies. In lung cancer, the prevalence of p53 antibodies is high (30%) and is correlated with a very high rate of p53 mutations in this cancer (60-70%). We show that these antibodies are always present at the time of diagnosis, but never appear during tumour development, an observation strengthened by the fact that these antibodies are mostly IgG, corresponding to a secondary immune response. These results suggest that the humoral response is an early event and that p53 antibodies can be used as a precocious marker of p53 alteration before clinical manifestation of the disease.

Adult↗

Influence of the lipid matrix on incorporation and function of LPS-free porin from Paracoccus denitrificans.

We have studied the role of lipopolysaccharide (LPS) for the insertion of LPS-free porin from Paracoccus denitrificans into planar lipid bilayers and its function therein. For this, we reconstituted the porin into different asymmetric planar lipid bilayers with or without LPS and into symmetric phospholipid bilayers. LPS-free porin added to the various bilayer systems was found to induce a step-wise increase in membrane conductance with different incorporation rates, depending on the presence of LPS in the bilayer leaflet opposite to porin addition. The incorporation rate into asymmetric LPS/phospholipid membranes from the phospholipid side was more than 10-fold higher than that observed for pure phospholipid membranes. The porin formed general diffusion pores without any salt specificity. The mean single-channel conductance did not depend on the presence of LPS and was about 4.2 nS for a subphase containing 1 M KCl in all systems tested. At certain applied transmembrane voltages, which depended on membrane composition and were approximately greater than 100 mV for the LPS/phospholipid system, single-channel closing in three steps was observed. Differences in the voltage dependence of porin-channel closing could be correlated with the surface charge of the bilayer. From the voltage-dependent gating behaviour proof for an oriented incorporation of the porin molecules, depending on the side of porin addition, and evidence for their orientation could be derived. Measurements at temperatures above and below the beta<==>alpha phase transition temperature of LPS gave evidence for the influence of membrane rigidity on the gating behaviour.

Carbohydrate Sequence↗

Smoking cessation methods: recommendations for health professionals. Advisory Group of the European School of Oncology.

Smoking is the leading preventable cause of death. Approximately 40% of Europeans now smoke. Many smokers want to stop but do not make the attempt, and of those who try, most are unsuccessful. Primary care health providers can help their patients to stop by using brief behavioural and pharmacological interventions. Specialised smoking cessation clinics can support selected patients referred by primary care providers. This report reviews intervention techniques for health care providers, which, in combination with effective legislative and educational interventions, can significantly reduce the prevalence of smoking.

Adolescent↗

Analyses of p53 antibodies in sera of patients with lung carcinoma define immunodominant regions in the p53 protein.

Antibodies specific for human p53 were analysed in sera of lung cancer patients. We detected p53 antibodies in the sera of 24% (10/42) of patients with lung carcinoma. The distribution was as follows: 4/9 small-cell lung carcinomas (SCLCs), 2/18 squamous cell lung carcinomas (SCCs), 2/10 adenocarcinomas (ADCs) and 2/5 large-cell lung carcinomas (LCCs). p53 antibodies were always present at the time of diagnosis and did not appear during progression of the disease. Using an original peptide-mapping procedure, we precisely localised the p53 epitopes recognised by p53 antibodies. Immunodominant epitopes reacting with antibodies were localised in the amino and carboxy termini of the protein, similar to those found in breast carcinoma patients or in animals immunised with p53. In light of these data, we suggest that p53 antibodies occur via a self-immunisation process that is the consequence of p53 accumulation in tumour cells. p53 antibodies were also detected in two patients without detected malignant disease. One of these patients died 6 months later of lung carcinoma, suggesting that p53 antibodies may be a precocious marker of p53 alteration.

Adenocarcinoma↗

Exposure to passive smoking during pregnancy and childhood, and cancer risk: the epidemiological evidence.

There are relatively few studies on the association between environmental tobacco smoke (ETS) during pregnancy and childhood, and cancer in childhood, adolescence or adulthood. The associations between maternal smoking during pregnancy and childhood cancer have been studied intensively, but there is no clear association overall, or for specific sites. The association between childhood cancer and smoking by the father in the preconceptional period, and by either parent during the child's lifetime, has been little studied. Again, no clear associations have been identified. However, evidence from studies of exposure to known carcinogens from ETS, and of genotoxic effects indicates that any effect, if present, is expected to be weak, and therefore could not have been detected by most of the studies which have been performed, due to the small number of cases included. There is some consistency of association between ETS exposure in childhood and the risk of lung cancers in adulthood. There is therefore a need for further epidemiological studies on ETS exposure during pregnancy and childhood and the occurrence of cancers.

Adolescent↗

Contractile effects of bradykinin on the isolated human small bronchus.

Bradykinin (Bk) induced a contraction in all small bronchi samples (diameter, 0.5 to 1 mm) from 20 patients. pD2 was 7.7 +/- 0.1 (pD2 = -log EC50) and maximal effect (Emax) was 36.2 +/- 4.7% of the maximal response to acetylcholine. The B2 agonist [Hyp3TyrMe8]Bk contracted airway smooth muscle with a pD2 of 7.8 +/- 0.2 and an Emax of 39 +/- 9%. The B1 agonist [Sar1dPhe8desArg9]Bk induced only a weak contraction at 10(-6) M. The effect of Bk was abolished by the B2 (Hoe 140) but not by the B1 [Leu8desArg9]Bk receptor antagonist. Indomethacin 10(-6) M abolished Bk-induced contraction, suggesting that cyclooxygenase products are involved in Bk action. Capsaicin 10(-5) M, which selectively depletes C fibers from airway mediators through the ruthenium red pathway, and ruthenium red 10(-5) M significantly inhibited the concentration-response curves to Bk. However, tetrodotoxin (+/-)-CP-96,345, SR 48968, and atropine did not significantly affect Bk concentration-response curves, suggesting that nerve conduction, substance P (SP), neurokinin A (NKA), and acetylcholine release are not involved in Bk action. Our data indicate that Bk contracts human distal airway smooth muscle through the Bk B2 receptor and a cyclooxygenase pathway. This effect appears to involve capsaicin and ruthenium red pathways but neither acetylcholine nor NKA and SP release.

Acetylcholine↗

Exposure to environmental tobacco smoke and adult non-neoplastic respiratory diseases.

Exposure to environmental tobacco smoke (ETS) is widespread in European countries, the most serious exposures occurring at home and in the workplace. Epidemiological studies have, essentially, addressed the association between ETS exposure and respiratory health in children, and increased risk of lung cancer among adult nonsmokers. Relatively few studies have been reported on ETS and adult non-neoplastic respiratory diseases. On the basis of the available data, no definite conclusion (excluding the acute irritating effect of ETS on respiratory mucous membranes) can be drawn. Although biologically plausible, it remains controversial whether ETS exposure is associated with chronic respiratory symptoms and occurrence of chronic obstructive pulmonary disease, including asthma. Most of the studies that have used the most sensitive indicators of pulmonary function have suggested a negative impact of ETS exposure. However, if really present, the physiological significance of such small changes is unclear, and the relationship to long-term changes in lung function is not established. Moreover, the possibility of bias and confounding factors must be taken into account. Thus, there is a need for further epidemiological studies on ETS exposure and adult non-neoplastic respiratory disorders.

Environmental Exposure↗

Endobronchial presentation of Hodgkin's disease: a report of nine cases and review of the literature.

Although mediastinal involvement by Hodgkin's disease is frequent, the initial presentation of the lymphoma by an endobronchial lesion is rare. Therefore, the question of whether patients with Hodgkin's disease should undergo fibreoptic bronchoscopy as a staging procedure remains unresolved. In a series of 469 patients with newly diagnosed Hodgkin's disease during a 10 year period, we reviewed the clinical features of nine patients who presented with an endobronchial tumour. They were compared to 34 previously published cases. The major presenting symptoms were cough, wheezing and haemoptysis. Bulky mediastinum was seen in six cases. The three other patients presented respiratory symptoms evocative of endoluminal invasion. All but one of the patients received combined modality therapy, as currently accepted for patients with poor prognostic factors. The overall actuarial survival was 74% after 4 yrs of follow-up. A selective subgroup of patients with stage I-II supradiaphragmatic and endobronchial Hodgkin's disease may, thus, present without poor prognostic factors (but generally with respiratory symptoms), and might be undertreated if this localization is not recognized. We propose that these patients should undergo fibreoptic bronchoscopy.

Adult↗

Exposure to environmental tobacco smoke and risk of lung cancer: the epidemiological evidence.

Exposure of nonsmokers to environmental tobacco smoke (ETS) is widespread in European countries, the most serious exposures occurring at home and in the workplace. Epidemiological studies available up to 1986 have been reviewed by several international and national authorities, which agreed in concluding that ETS exposure is causally related to lung cancer. A number of epidemiological studies have been published since then, and have confirmed this association. The possibility of positive results due to bias has been envisaged; it seems, however, that such bias could not explain the whole excess of lung cancer. Few data are available on confounders, such as diet and previous history of lung disease, that might be responsible for the association; however, there is no evidence that they play an important role. Moreover, the biological plausibility of a causal association is supported by the similarity of the composition of ETS and active smoke. The causal association between ETS exposure and lung cancer now seems well-established; however, its public health impact is still debated. Estimates are available from the United States, Canada, Australia, New Zealand and England.

Humans↗

Prolonged survival after high-dose rate endobronchial radiation for malignant airway obstruction.

STUDY OBJECTIVE: To show that prolonged survival can be observed after high-dose rate (HDR) endobronchial brachytherapy as the sole treatment for some selected patients presenting with an endobronchial malignant obstruction. PATIENTS: Twenty-nine patients (group 1) who presented with an endoluminal localized tumor without metastatic extension were treated by HDR endobronchial brachytherapy and are compared with 22 subjects who presented with extraluminal dissemination and were palliatively treated (group 2). TREATMENT PROTOCOL: Treatment consisted of sessions of two exposures, delivering 7 Grays at a 10-mm radius from the center of the applicator each, and repeated every 15 days, to a maximum of six exposures. Endoscopic response and survival are the main criteria of assessment. RESULTS: Follow-up bronchoscopies, performed 2 months after the end of the procedure, showed tumor regressions: macroscopic complete responses (CR) were observed in 21 of 25 patients evaluable in group 1, and 6 of 22 in group 2, with histologic CR in 18 and 2 patients, respectively. Median overall survival was not reached in group 1 after 23 months of follow-up; it was 5 months for group 2. CONCLUSIONS: These results confirm that HDR brachytherapy can be used as a monotherapy for carefully selected patients who have small tumors to all appearances limited to the bronchial lumen and bronchial wall without adjacent parenchymal extension or metastatic disease.

Airway Obstruction↗

[The p53 gene and protein in bronchial carcinogenesis:from biological to clinical aspects].

The p53 gene codes for a nuclear phosphoprotein which is capable of modulating the expression of certain genes implicated in the regulation of cell division. The mutation of an allele on the p53 gene with loss of the healthy allele, in different tissues such as lung, larynx, bladder, liver, skin, colon and breast, which may or may not be exposed to chemical or physical carcinogens (tobacco, radon, ultraviolet, aflatoxin B1), is associated with the occurrence of cancer. Indeed, the mutated p53 protein loses its anti-proliferative properties favouring a de-regulation of cellular multiplication with the accumulation of genetic aberrations. The homozygous deletion of the p53 gene in germ cells in the members of certain family cancers (Li-Fraumeni syndrome) leads to an increased incidence of cancers in the child or young adult. The most frequent mutations of the p53 gene end in a stabilisation of the mutated protein with immuno-histochemical nuclear marking of the cells carrying such an alteration. In certain patients this stabilisation of the mutated protein ends in auto-immunisation with anti-p53 serum antibodies. Bronchial cancer is a cancer of which the mutations of p53 are the most frequent (45-65% of bronchial cancer) as result of the mutagenic effect of tobacco smoke. These mutations seem to be associated with a bad prognosis and indeed to chemo-and radiotherapeutic resistance. The early diagnosis of p53 alterations (in dysplastic lesions or tumours which are only slightly developed) would enable new therapeutic interventions in bronchial cancer such as gene therapy or radio-immunotherapy to either restore the p53 gene to normality or to eliminate the cells expressing the mutated p53 protein respectively.

Alleles↗