The Rieske/cytochrome b complex of Heliobacteria.

Heliobacteria have a Rieske/cytochrome b complex composed of a Rieske protein, a cytochrome b(6,) a subunit IV and a di-heme cytochrome c. The overall structure of the complex seems close to the b(6)f complex from cyanobacteria and chloroplasts to the exception of the di-heme cytochrome. We show here by biochemical and biophysical studies that a heme c(i) is covalently attached to the Rieske/cytochrome b complex from Heliobacteria. We studied the EPR signature of this heme in two different species, Heliobacterium modesticaldum and Heliobacillus mobilis. In contrast to the case of b(6)f complex, a strong axial ligand to the heme is present, most probably a protonatable amino acid residue.

Relationship between tumour growth rate and carbogen-based functional MRI for a chemically induced HCC in mice.

We previously performed MRI studies of HCC (hepatocellular carcinomas) in mice showing the feasibility of measuring a carbogen effect. In the present study carbogen response of the whole tumour was compared with growth characteristics during longitudinal follow-up. HCC were chemically induced. The imaging protocol at 4.7 T comprised a fast spin-echo sequence for high-resolution screening and measurement of growth curves, and a fast gradient echo sequence allowing an entire T2*w image acquisition per respiratory cycle to perform fMRI under carbogen breathing. A new parameter, T+, the fraction of tumour voxels with increased intensity under carbogen was measured on manually defined ROIs. Twenty-two HCC were followed for 3-10 weeks. Tumours were divided into two groups, "regularly" and "irregularly" growing tumours. A linear correlation between T+ and tumour growth rate was observed only for "regularly" growing HCC. These results suggest a link between tumour growth rates and tumour fractions exhibiting signal increase upon carbogen breathing. They are compatible with observations by others that rapidly growing tumours are more hypoxic than slowly growing ones. Combined measurement of T+ and tumour growth may become a useful noninvasive follow-up approach for assessment and/or management of therapies involving vasculature-targeting and anti-proliferative drugs.

[Hypersensitivity pneumonitis in a patient taking pravastatin]. / Une pneumopathie iatrogènique rapportée à la prise de pravastatine.

A 41-year-old man who had been taking pravastatin for two years developed hypersensitivity pneumonitis. The initial examination found intestinal pneumonitis and hypereosinophilia. The patient's syndromes gradually resolved with withdrawal of pravastatin. As HMG coenzyme A reductase inhibitors are commonly prescribed, any respiratory symptoms in this setting should be considered with special attention.

[Asbestosis and sarcoid-like thoracic lesions: a case report]. / Asbestose et lésions thoraciques sarcoid like

Mediastinal nodes evidenced in a patient referred for an expert opinion concerning an occupational disease were found to have a sarcoid-like character. The patient was a former smoker who had been exposed to asbestos for 27 years. The patient also had an ENT neoplasia. The nodal enlargements evidenced at mediastinoscopy were the only manifestations compatible with sarcoidosis, a rare association recognized in asbestosis.

Methylenetetrahydrofolate reductase C677T genotype and venous thromboembolic disease.

BACKGROUND: Many studies have suggested an increased risk of venous thromboembolism (VTE) in patients with mild hyperhomocysteinemia. The C677T mutation in the MTHFR gene has recently been described as a cause of mild hyperhomocysteinemia. OBJECTIVES: To investigate the potential of the C677T mutation in the MTHFR gene in its homozygous state as a risk factor for VTE. METHODS: Case-control study design. The presence of the mutation was determined in all consecutive patients referred from July 1994 to September 1997 and in whom the diagnosis was duly confirmed. Analysis was carried out in a subgroup of VTE patients free from both acquired and genetic risk factors (factor-V mutation and/or prothrombin gene mutation). A control group consisted of 105 volunteer blood donors. RESULTS: In the 366 patients with a confirmed VTE, 253 presented acquired risk factors and 58 were carriers of the factor-V Leiden mutation and/or G20210A mutation of the prothrombin gene. In the remaining 55 patients, VTE was considered as 'unexplained', and the frequency of the C677T mutation MTHFR was 21.8% in its homozygous state and 34.5% in its heterozygous state. In the control group, 9.5% were found homozygous and 34.3% heterozygous. The odds ratio for having VTE in the presence of the mutation in its homozygous state was 2.9 (95% CI 1. 0-8.6). CONCLUSION: This study suggests that the homozygous C677T mutation in the MTHFR gene might be a risk factor of VTE in patients with spontaneous events and without other common genetic risk factors.

Direct in vivo observation of 5-fluorouracil release from a prodrug in human tumors heterotransplanted in nude mice: a magnetic resonance study.

A glucuro-conjugated carbamate derivative of 5-fluorouracil (5-FU), originally designed as a prodrug for antibody-directed enzyme prodrug therapy (ADEPT) application, has been used for direct in vivo observation of in situ 5-FU generation in two human colon tumors heterotransplanted in nude mice. Because of the very fast elimination of glucuro-conjugated drugs, this observation required intratumoral injection. These tumors, when becoming necrotic, are rich enough in beta-glucuronidase to allow (19)F magnetic resonance spectroscopy monitoring, at the tumor level, of both prodrug elimination and 5-FU liberation without preliminary treatment by a specifically targeted enzyme conjugate. Convenient tumors have been selected by magnetic resonance imaging (MRI) on the basis of a correlative study between MRI and conventional histology. This contribution is the first report evidencing such a direct intra-tumoral conversion of a glucuro-conjugated prodrug into the expected active drug. This method, which should allow overall estimation of the beta-glucuronidase content of tumors, might also be helpful for selecting tumors as specific targets for non-toxic glucuro-conjugated prodrugs without prior treatment with a fusion protein.

[Current trends in asthma management]. / Actualités de la prise en charge de la maladie asthmatique.

INHALED CORTICOSTEROIDS: There has been substantial improvement in asthma management over the last few years. Inhaled glucocorticoids (ICS) are the most effective therapy in the treatment of asthma. COMPLEMENTARY TREATMENTS: Additional treatments such as theophyllines, long-acting beta 2 agonists or more recently leukotriene antagonists allow in most cases the maintenance of ICS at safe dosages without substantial adverse effects. COMPLIANCE: Compliance is a major issue that can only be improved using global management strategies in which asthma education plays a prominent role.

[What investigations should be done following the first episode of pulmonary embolism?]. / Quel bilan réaliser au décours d'un premier épisode d'embolie pulmonaire?

Thromboembolic venous disease is both common and potentially serious, thus the first episode of pulmonary embolus calls for careful assessment. This involves two stages: a search for a venous localization of the pulmonary embolus and a search for risk factors contributing to thromboembolic venous disease. The emergence of non-invasive echographic-Doppler techniques and echocardiography make possible the localization of any residual venous thrombus. The risk of post thrombotic disease is raised in symptomatic thrombotic venous disease which requires wearing elastic stockings for a least two years. On the other hand this risk has not been assessed in asymptomatic cases of venous thrombosis. A search for risk factors requires a detailed history, a rigorous clinical examination and a routine list of laboratory investigations. Some complex investigations for detecting the early stages of a neoplasm would not appear justified unless there is objective evidence to support his. At the same time thrombophilia studies are not currently performed routinely for a first episode but may be suggested in the following cases: family history of thromboembolic venous disease, age less than 45, including those in whom the episode occurs at the same time as pregnancy, or whilst taking hormone therapy, idiopathic thromboembolism, the association of arterial and venous thrombi and finally venous thromboses occurring in an unusual anatomical site. Prospective studies have shown the value of long term anticoagulation in patients suffering from constitutional hemostatic anomalies. Finally, if there is an after thought of occult cancer or constitutional thrombocytopenia a careful follow up should be performed particularly during the first year.

Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients.

BACKGROUND: The 20210 A allele variation in the 3' -untranslated region of the prothrombin gene was recently identified as a risk factor as regards deep venous thrombosis. AIM: To assess the frequency of the variation in unselected patients with a proven venous thromboembolism (VTE). METHODS: The presence of the prothrombin variation was determined in all consecutive patients referred from July 1994 to August 1997 for a clinical suspicion of VTE, and in whom the diagnosis was confirmed. A control group consisted of bone marrow volunteer donors. RESULTS: Of the 366 patients included, 17 (4.6%) were carriers of the 20210 A allele (95% CI, 2.4% to 6.7%). The mutation was present in 1.0% of the 400 controls. Odds ratio for having VTE in the presence of the 20210 A allele was 4.8 (95% CI, 1.5 to 19.8). Forty-six (12.5%) patients had the mutation of the factor V gene and five (1.4%) patients shared both mutations. After excluding the carriers of the factor V mutation, odds ratio for having VTE in the presence of the 20210 A allele was 3.7 (95% CI, 1.1 to 13.6). Mean age at admission as well as mean age of the first VTE episode were both significantly higher in patients free from the two mutations studied, as compared to carriers of the 20210 A allele (p = 0.04 and 0.01, respectively). CONCLUSION: Our findings in a large series of patients (1) confirm the 20210 A allele prothrombin gene as a risk factor for VTE. (2) suggest that its association with the factor V Leiden is not uncommon.

[Characteristics of patients with domiciliary equipment for chronic respiratory diseases in Martinique]. / Particularités des patients appareillés au domicile pour pathologie respiratoire chronique en Martinique.

The incidence of chronic respiratory failure is underestimated in Martinique. The aim of our retrospective study was to determine local particularities. Between December 1991 and December 1995, 128 patients (55% men, mean age 60 years, range 18-89 years) were hospitalized in our pneumology unit to receive a respiratory device (oxygen concentrator, respirator, continuous positive pressure generator). The high percentage of continuous positive pressure generators contrasted with the low number of oxygen concentrators prescribed indicating that obstructive disease is relatively less common due to the absence of widespread smoking habits. Sleep apnea syndrome (SAS) was particularly frequent in women (44% of the SAS patients). 10% of the SAS patients had perturbed blood gases unexplained by an associated bronchopathy. SAS in obese, hypertensive, diabetic women in Martinique is a public health problem and should be assessed by a prospective study. We observed that home care was particularly difficult for the most severely diseased patients, especially those with a tracheotomy, due to the lack of a management structure.

[Chronic hyperventilation syndrome]. / Le syndrome d'hyperventilation chronique.

Hyperventilation syndrome is a frequent, but poorly understood clinical entity. The clinical expression is a rich combination of respiratory, cardiac and neurological signs which can simulate various organic diseases. Hypocapnia remains the primum movens for most authors although the relationship with psychiatric situations, in particular in anxious patients, is increasingly emphasized. The diagnosis is currently based on the elimination of diseases associated with hyperventilation, then on Nijmegen's questionnaire and is confirmed by the reproduction of the same clinical picture in a voluntary hyperventilation test. Respiratory function tests offer little information. Treatment is based on combining rehabilitation therapy focused on the diaphragm and on relaxation. Specialized care may be needed in psychiatric patients.

[Plastic bronchitis]. / La bronchite plastique.

We report a case of plastic bronchitis occurring in a 58 year-old man free from underlying pulmonary disease. Relief of symptoms was observed under steroid therapy (1 mg/kg), but relapse occurred as treatment being tapered. Such evolution is in accordance with recent published data.

In vivo eradication of Friend virus as an experimental HIV-model, by combination of zidovudine, acriflavine and an ellipticine analogue. Possible application to the treatment of human pre-AIDS?

Simultaneous administration of zidovudine, acriflavine and celliptium to Friend virus-injected mice eradicates the virus, as evidenced by the impossibility of the treated-mouse serum, when injected to virgin recipients, to induce spleen foci formation. An adapted preliminary protocol given to patients in whose p 24 antigen was present in the blood, lead to a considerable reduction of that marker. The cures lasted 3 weeks, and were repeated after 3-week intervals. Since p 24 antigen returns to pre-treatment levels at the end of the interval, research should concentrate on the maintenance of the effect during the interval.

The in vivo effect of ellipticine analogues on the blood concentration of Friend virus: a murine model for studying anti-HIV drugs.

The viremia of a mouse carrying a murine retrovirus, the Friend virus, was taken as a model for screening drugs which could be active on the human HIV retrovirus. Ellipticine and two of its analogues injected ip at appropriate doses drastically reduced the viremia of the Friend virus-injected mice, as measured by transfer of their serum on day 8 of the treatment to secondary recipients and numeration, in the spleens of the latter, of the foci the remaining virus had induced. Since phase I and II trials have already been published (for leukemia treatment), the efficacy of those drugs on HIV-1 positive AZT-resistant patients can be tested directly.

Virostatic in vivo effect of elliptinium on Friend's retrovirus (a model for HIV infection).

As we had discovered the virostatic effects of some analogues of acriflavine, a non-oncostatic intercalating agent, on HIV1 and on its best murine model, Friend's virus [7], we then studied other non- or poorly oncostatic intercalating agents, in particular ellipticins (whose negligible cytostatic effect with methoxy-9-ellipticin we first published. We report in this paper the in vivo virostatic effect of 2-methyl-9-hydroxy-ellipticinium (elliptinium) on Friend's virus.

Can virostatic chemotherapy and/or adoptive allogeneic immunotherapy eradicate in vivo Friend's virus infection?

While none of the three drugs which exert an in vitro anti-HIV effect, neither AZT nor the other two, acriflavine and elliptinium, which we have shown to be more efficient than AZT, is able to eradicate Friend's virus in vivo, the combination of the 3 drugs at much smaller doses than when given alone seems able to eradicate it in almost 30% of the infected animals. This possible eradicating effect of virostatics in combination is compared with the results we had previously obtained with lymphocytes of virus-immunized allogeneic donors.

Can neo-adjuvant chemotherapy prevent residual tumors?

MA 16/C is a spontaneous mouse mammary adenocarcinoma. It is hormone-dependent and was injected s.c. into C3H/He female mice on day 0. Tumors were excised on day 15. Neo-adjuvant treatments were applied from day 1 to day 21 for hormonotherapy and immunotherapy and on days 1, 5 and 9 for chemotherapy. Adjuvant treatments were applied from day 21 to day 42 for hormonotherapy and immunotherapy, and on days 21, 25 and 29 for chemotherapy. Mixed (neo-adjuvant and adjuvant) treatments combined the two patterns. Chemotherapy consisted of an oxalato-platinum complex of trans-l-dach (l-OHP) at a dose of 5 mg/kg i.p. Hormonotherapy consisted of the LH-RH agonist (D-Trp6) LH-RH, at a dose of 100 micrograms/kg i.p. Zinc gluconate (6mg/kg per os) and bestatin (6mg/kg per os) were administered as immunoregulators. Under present experimental conditions, surgery alone did not increase the life span. Both neo-adjuvant and adjuvant chemotherapy and neo-adjuvant hormonotherapy, however, when added to surgery, increased survival significantly (p less than 0.02-p less than 0.03).

Synthesis and evaluation of antileukemic activity of 5-thienyl- or 5-(2-furyl)-2,3-dihydro-6,7-bis(hydroxymethyl)-1H-pyrrolizine bis(alkylcarbamates) and derivatives.

Treatment of N-(2-furoyl)proline or N-thenoylprolines and N-(2-thenoyl)thiazolidine-4-carboxylic acid with acetic anhydride and dimethyl acetylenedicarboxylate gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate and derivatives of dimethyl 5-(2-thienyl)pyrrolo[1,2-c]thiazole. Reduction of 2 with lithium aluminum hydride gave the diols 3a, 3b, 3c and 3d. These diols yielded the corresponding diacetates 4 by treatment with acetic anhydride. The bis(methylcarbamates) 5a, 5b, 5c, and 5d and bis(isopropylcarbamates) 6b and 6c are obtained with the appropriate isocyanates. The 1-substituted pyrrolizines were synthesized, the 1-acetoxy compounds 7b and 7c further transformed into 1-hydroxy and 1-oxo analogues. The action of hydrochloric acid on 1-acetoxy derivatives gave 3H-pyrrolizines. Evaluation of antileukemic activity was investigated on the leukemia L1210 in vivo, on several bis(alkylcarbamates). The compounds 5c and 5d show good antileukemic activity comparable with the mitomycin.

Oxalato-platinum or 1-OHP, a third-generation platinum complex: an experimental and clinical appraisal and preliminary comparison with cis-platinum and carboplatinum.

A new platinum complex, oxalatoplatin or l-OHP, which, at the same metal dose in experimental tests is as efficient as cisplatin, and is more so at a lower metal dose than carboplatin; which is as efficient in human tumors of the testis and ovary as these other analogs, and more so in melanoma and breast cancer; which is not nephrotoxic, cardiotoxic or mutagenic, and hardly hematotoxic and neurotoxic, is described and compared with the above-mentioned platinum complexes. Combined with 5Fu, it induces a high number of remissions in colorectal cancer, and has brought about cures in inoperable gastric cancers. Combined with carboplatin, it has resulted in a high proportion of cures in L1210-carrying mice, which no other two-by-two combination of these complexes has achieved.