[Animal experiment studies on the effect of drugs on chrysene metabolism in vitro].
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Animals↗
Biomedical subjects
J Jacob
Publications and source records attributed to J Jacob.
Randomised trial of antivenom in snake envenomation with prolonged clotting time.
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Adult↗
Altered triple helical structure of type I procollagen in lethal perinatal osteogenesis imperfecta.
Cultured dermal fibroblasts from an infant with the lethal perinatal form of osteogenesis imperfecta (type II) synthesize normal and abnormal forms of type I procollagen. The abnormal type I procollagen molecules are excessively modified during their intracellular stay, have a lower than normal melting transition temperature, are secreted at a reduced rate, and form abnormally thin collagen fibrils in the extracellular matrix in vitro. Overmodification of the abnormal type I procollagen molecules was limited to the NH2-terminal three-fourths of the triple helical domain. Two-dimensional mapping of modified and unmodified alpha chains of type I collagen demonstrated neither charge alterations nor large insertions or deletions in the region of alpha 1(I) and alpha 2(I) in which overmodification begins. Both the structure and function of type I procollagen synthesized by cells from the parents of this infant were normal. The simplest interpretation of the results of this study is that the osteogenesis imperfecta phenotype arose from a new dominant mutation in one of the genes encoding the chains of type I procollagen. Given the requirement for glycine in every third position of the triple helical domain, the mutation may represent a single amino acid substitution for a glycine residue. These findings demonstrate further heterogeneity in the biochemical basis of osteogenesis imperfecta type II and suggest that the nature and location of mutations in type I procollagen may determine phenotypic variation.
Cyanogen Bromide↗
Human lymphoblastoid interferon treatment of Kaposi's sarcoma in the acquired immune deficiency syndrome. Clinical response and prognostic parameters.
Thirty consecutive patients with the acquired immune deficiency syndrome were treated with intramuscular human lymphoblastoid interferon for Kaposi's sarcoma. Patients were divided into three groups receiving 7.5 million units/m2 per day, 15 million units/m2 per day, or 25 million units/m2 per day for 28 days. Because of dose-limiting toxicity in the highest dose group, all patients received between 6 and 15 million units/m2 per day. There were three partial responses and four minor responses. The responses were not dependent on drug dose, but did correlate with higher total lymphocyte and OKT4-positive lymphocyte numbers and absence of prior opportunistic infection. Patients who had endogenous acid-labile alpha-interferon prior to therapy were more likely to have progressive disease during interferon administration.
Acquired Immunodeficiency Syndrome↗
Monooxygenase induction by various xenobiotics and its influence on the rat liver microsomal metabolite profile of benz[a]anthracene.
Several pesticides (lindane, carbaryl, pentachlorophenol, DDT), polycyclic aromatic hydrocarbons (PAH) and heterocyclic analogues (fluoranthene, dibenz[a,h]anthracene, dibenz[a,h]acridine, indeno[1,2,3-cd]pyrene, 10-azabenzo[a]pyrene) and pharmaceuticals (diphenylhydantoin, ethinylestradiol, levonorgestrel) were tested for their potencies to induce monooxygenase activities in the rat liver by means of recording the metabolite profile of benz[a]anthracene in rat liver microsomal incubations. Some of them were found to be weak or moderate inducers, but even less efficient ones altered the benz[a]anthracene metabolite profile significantly. Only indeno [1,2,3-cd]pyrene stimulated the bay-region oxidation of benz[a]anthracene. A sex-dependent metabolism was observed in both untreated and contraceptive-pretreated Wistar rats.
Animals↗
Viral infections and cell-mediated immunity in immunodeficient homosexual men with Kaposi's sarcoma treated with human lymphoblastoid interferon.
Herpesviral infections and cellular immunity were studied in 19 patients with acquired immunodeficiency syndrome who were treated with human lymphoblastoid interferon for Kaposi's sarcoma. Before treatment, cytomegalovirus (CMV) and Epstein-Barr virus were isolated from 18 of 19 patients and 13 of 14 patients, respectively. Serum levels of interferon were measurable in all cases. Concanavalin A induced lymphocyte proliferation normally in 16 of 18 patients, but CMV induced proliferation in only nine of 18 patients. Natural killer cell activity was normal in 12 of 19 patients and was augmented in vitro by interferon in six of 19 subjects. CMV-specific HLA-restricted cytotoxic T cell activity was found in only two of 15 cases. With therapy, serum levels of interferon increased in 15 of 18 patients. There were two partial tumor remissions but no improvements in viral infections. Natural killer cell activity was decreased in 11 of 14 cases, and in vitro augmentation by interferon was absent in all five previous responders. CMV-specific T cell activity did not improve, but HLA-unrestricted cytotoxicity was increased in four of eight cases.
Acquired Immunodeficiency Syndrome↗
Interferon-induced 2'-5' oligoadenylate synthetase during interferon-alpha therapy in homosexual men with Kaposi's sarcoma: marked deficiency in biochemical response to interferon in patients with acquired immunodeficiency syndrome.
Titers of circulating interferon (IFN) and the activity of 2'-5' oligoadenylate (2-5A) synthetase, an enzyme specifically induced by IFN, were measured in 28 homosexual men with acquired immunodeficiency syndrome (AIDS) who received one- to six-month courses of antineoplastic therapy with IFN-alpha and in homosexual and heterosexual controls. Fifteen of the patients and two of seven healthy homosexual men had high endogenous levels of 2-5A synthetase. IFN therapy induced further increases in this enzyme in only 10 of the 28 patients with AIDS. Furthermore, peripheral blood cells from all but one of the patients with AIDS and homosexual controls tested were markedly deficient in their ability to respond to IFN in vitro, as measured by increased levels of 2-5A synthetase. We did not find a statistical correlation between cytomegalovirus viremia and pretherapy endogenous circulating IFN, nor any apparent correlation between disseminated infection with cytomegalovirus and either basal levels of 2-5A synthetase or changes in enzyme level during therapy. Pretherapy circulating IFN was significantly correlated with progressive Kaposi's sarcoma during therapy, but rises in levels of 2-5A synthetase were not sufficient to predict a good clinical response.
2',5'-Oligoadenylate Synthetase↗
Activation of monocyte-mediated tumoricidal activity in patients with acquired immunodeficiency syndrome.
The purpose of these studies was to determine whether peripheral blood monocytes from acquired immunodeficiency syndrome (AIDS) patients with Kaposi's sarcoma could be activated to lyse human tumor target cells in vitro. Monocytes were isolated and incubated for 24 hours in vitro with either medium (control), a crude mitogen-induced lymphokine preparation (MAF), or endotoxin before the addition of [125I]IUdR-labeled A375 melanoma target cells. Cytolysis was determined 72 hours later. Twelve (100%) of 12 patients tested had monocyte-mediated cytotoxicity values that were comparable to those of normal individuals. Recombinant human gamma interferon (IFN gamma) activated both normal and AIDS monocyte-mediated tumoricidal function only when combined with lypopolysaccharide (LPS). In addition, mononuclear cells from ten AIDS patients were also tested for their ability to secrete MAF and IFN gamma in response to a mitogenic stimulus. Lymphokines generated from all ten patients contained substantial amounts of IFN gamma (100 to 2,500 U/mL); however, three of these ten lymphokine preparations failed to activate normal monocytes to lyse tumor cells. These results suggest that monocyte-mediated tumoricidal function of AIDS patients is intact and thus suggest new approaches for the therapy of AIDS.
Acquired Immunodeficiency Syndrome↗
Determination of mutagenic activities in different fractions of automobile exhaust condensate by the Salmonella/oxygenase mutagenicity test system.
Automobile exhaust condensate of a passenger car (gasoline engine) was separated into fractions of 2-3 rings containing -, 4-7 rings containing polycyclic aromatic hydrocarbons (PAHs) and PAH-free fractions. All fractions were tested for mutagenicity by the Ames system. The highest dose-dependent increase in revertant colonies was found for the 4-7 ring PAH-fraction when tested with Salmonella typhimurium TA 98 and TA 100. These results are compatible with data obtained in in-vivo tests by previous investigations. The mutagenicity of these fractions in the absence of the oxygenase was negligible.
Animals↗
Regulation of body temperature and nociception induced by non-noxious stress in rat.
The effects of 3 different non-noxious stressors on body temperature (Tb) were investigated in the rat: (1) loose restraint in cylinders, (2) removal of the rats from cylinders, exposure to a novel environment and replacement in cylinders, a stressor called here 'novelty', and (3) gentle holding of the rats by the nape of the neck. Loose restraint and 'novelty' produced hyperthermia. On the contrary, holding induced hypothermia. Hypophysectomy (HX) reduced basal Tb, abolished restraint hyperthermia and reduced both 'novelty' hyperthermia and holding hypothermia. Dexamethasone ( DEXA ) had no effect upon either restraint or novelty hyperthermia but reduced the hypothermia. Naloxone (Nx) produced a slight fall in basal Tb accounting for its reduction of restraint and 'novelty' hyperthermias ; it did not affect holding hypothermia. The inhibitory effects of HX suggest a participation of the pituitary in the hyperthermias ; the neurointermediate lobe would be involved as the hyperthermias were not affected by DEXA , which is known to block the stress-induced release of pituitary secretions from the anterior lobe but not from the neurointermediate lobe. In contrast, substances from the anterior lobe might participate in hypothermia due to holding since it is reduced by HX and DEXA . As to the effects of Nx, endogenous opioids would not be significantly involved in the thermic effects of the stressors used in this study; they might play, if any, only a minor role in the regulation of basal Tb. These results are compared with those previously obtained on nociception using the same non-noxious stressors. It emerges that, depending on the stressor, different types of association between thermoregulation and nociception may occur, i.e. hyperthermia with analgesia, hyperthermia with hyperalgesia and hypothermia with hyperalgesia.
Animals↗
The influence of 18 environmentally relevant polycyclic aromatic hydrocarbons and Clophen A50, as liver monooxygenase inducers, on the mutagenic activity of benz[a]anthracene in the Ames test.
In the presence of various liver S9 preparations induced by different polycyclic aromatic hydrocarbons, the weak carcinogen, benz[a]anthracene, exhibited mutagenic activities comparable to those of benzo[a]pyrene in the Ames test. A series of positive correlations were found between mutagenic activity and the hydroxylation products of benz[a]anthracene at the 3,4-, 5,6- and 8,9-positions, of which 5,6-position was the most pronounced one (p less than 0.01). Our results suggest that the observed mutagenic activity is due mainly to the generation of K-region epoxides.
Animals↗
Malignancies in the AIDS patient: natural history, treatment strategies, and preliminary results.
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Acquired Immunodeficiency Syndrome↗
High-dose cisplatin in hypertonic saline.
To overcome the dose limiting toxicity of cisplatin we have administered high-dose cisplatin (200 mg/m2 body surface area in five divided daily doses with each dose administered in 250 mL of 3% saline) together with extensive hydration (250 mL/h normal saline with 20 meq KCI/L). In 17 previously untreated patients with poor prognosis nonseminomatous testicular cancer, 8 with tumor-associated obstructive uropathy, there was no statistically significant decrease in creatinine clearance or elevation of serum creatinine after three to four cycles of a high-dose cisplatin in combination chemotherapy regimen. High-dose cisplatin in combination with vinblastine, bleomycin, and VP-16 produced an 88% complete response rate in these high-risk patients who are characterized primarily by the presence of advanced bulky lung and abdominal disease. Six patients with ovarian cancer who had a relapse after treatment with standard dose cisplatin regimens were treated with high-dose cisplatin and three partial responses were seen. Four patients had no adverse effects on renal function whereas 2 patients had transient elevations in serum creatinine (4 to 5 mg/dL). Hypertonic saline did not provide protection against the nonrenal toxicities of cisplatin.
Adolescent↗
Hepatitis B vaccine safety monitoring in the chimpanzee: interpretation of results.
In September, 1983, a group of French and American experts met at the French National Health Laboratory to discuss their experience in monitoring for the safety of a hepatitis B vaccine in 42 chimpanzees. The observations made, conclusions reached, and recommendations for future studies are presented.
Alanine Transaminase↗
Hyper- and hypothermia induced by non-noxious stress: effects of naloxone, diazepam and gamma-acetylenic GABA.
Rats subjected to non-noxious, anxiogenic stressors were found to exhibit either hyperthermia or hypothermia depending on the nature of the stressor. The present work examines the effects of naloxone (Nx), diazepam (DZP) and gamma-acetylenic GABA (AcG), an inhibitor of GABA catabolism, on these phenomena. Nx reduced stress hyperthermia and basal temperature by similar amounts; it did not affect stress hypothermia. DZP also reduced basal Tb but was able to completely inhibit and even reverse stress hyperthermia and to reduce stress hypothermia. The effects of AcG were similar to those of DZP. In conclusion, it appears that endogenous opioids are not involved in the thermic responses to our emotional stressors whereas GABA would be an important modulator. It is suggested that DZP, through a GABAergic link might inhibit the release of hyperthermic pituitary factors from the neurointermediate lobe and of hypothermic substances from the anterior lobe.
4-Aminobutyrate Transaminase↗
Genetic differences in opioids binding sites and in antinociceptive activities of morphine and ethylketocyclazocine.
The pattern of [3H]Nx and [3H]EKC binding by brain homogenates was different for each of the three studied strains of mice. CXBH was rich in [3H]Nx and relatively poor in [3H]EKC sites; CXBK poor in the two sites; C3H rich in the two sites (especially [3H]EKC). Using two antinociceptive tests (hot plate: paw lick and D'Amour and Smith's; tail flick) the activities of morphine paralleled the number of [3H]Nx sites (CXBH greater than C3H much greater than CXBK) indicating that the number of mu sites is one of the genetic factors of the amplitude of the response to Mo. The same was true for the activities of EKC when the hot plate test was used (C3H much greater than CXBH congruent to CXBK) an observation which favours the view of an involvement of kappa sites in the regulation of the paw lick reaction. However, when the tail flick test was used, C3H still remained much more reactive to EKC than CXBK but CXBH were unexpectedly also very reactive; we tentatively suggest that EKC might then be acting through mu like sites. In this hypothesis mu and kappa sites would be involved in the regulation of paw lick but essentially a mu type site in that of tail flick. Further experimental evidence is needed.
Analgesia↗
Induction of specific monooxygenases by isosteric heterocyclic compounds of benz[a]anthracene, benzo[c]phenanthrene and chrysene.
Benzo[c]phenanthrene and a series of heterocyclic compounds (benzo[b]naphtho(1,2-d)thiophene; benzo[b]naphtho(2,1-d)thiophene; benz[a]acridine and benz[c]acridine) were tested to their capacity of inducing monooxygenase activity in rat liver by means of recording the metabolite profile of benz[a]anthracene formed in rat liver microsomal incubations. Although all compounds tested were found to be weak monooxygenase inducers the pretreatment of rats with them resulted in significant changes of the microsomal metabolite profile of benz[a]anthracene. The thiophenes equally gave rise to oxidation at the 5,6- and the 8,9-positions, whereas the benzacridines being isosteric to benz[a]anthracene favoured the K-region oxidation (5,6-oxidation). A structure-dependent effect of monooxygenase inducers on the metabolite profile of benz[a]anthracene is discussed.
Animals↗
Inventory and biological impact of polycyclic carcinogens in the environment.
The rapid development of the natural sciences and the technical progress during the last century have significantly changed our society and environment. During this period the average life expectancy for people in industrialized countries has doubled. A prolongation of life expectancy to this extent, due to for example, understanding of the relationship between various diseases and their corresponding causative agents, had never before occurred in mankind's history. It resulted in specific hygiene precautions. The recognition of such causal relationship was facilitated by the fact that infection diseases generally become apparent after a short incubation time, i.e. that an environmental situation causes health damage. At present, we are searching for origins of diseases of which the causal correlations with environmental influences are far more difficult to recognize than those of infection diseases, since long-term effects have to be observed. Do we have a situation similar to that which we had for infections at the end of the last century ? For diseases such as lung and larynx cancer, there are significant indications of carcinogenic compounds in the environment. Since both types of cancer are about 10 times more common among cigarette smokers who inhale than among non-smokers, a correlation to the risk factor "smoking" is beyond doubt. Living and working in larger cities or highly populated areas are additional factors which many enhance the lung cancer incidence ("urbanisation factor"). The air quality of these areas is supposed to be the reason for this effect. However, the present "bad air quality" at most doubles the disease incidence. A large number of epidemiological studies report on local differences of the incidence rates as well as significant increases or decreases of the mortality rates for some cancer diseases during comparatively short periods. A summary recently has been published by Misfeld (1). As an example, the mortality rate due to lung cancer for males in the F.R.G. has almost doubled during 1955-1975 from 36.5 per 100,000 to 65.9 per 100,000. This holds true for cancer of the rectum which increased from 8.8 per 100,000 to 18.9 per 100,000 during the same period. In contrast, mortality due to stomach cancer decreased from 59.3 to 36.6 per 100,000 and uterine cancer in females decreased from 16.6. to 8.5 per 100,000 (2). The pronounced changes in mortality rates cannot be explained by alterations of the genetic disposition during such a short period. Improved diagnostic and therapeutic techniques might explain decreases but not increases of mortality rates.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗