[Sleep apnea syndrome and abdominal aortic aneurysm: Study of the prevalence of sleep apnea syndrome in patients with aneurysm and research of association. Clinical study on 52 patients]. / Syndrome d'apnée du sommeil et anévrisme de l'aorte abdominale : étude de la prévalence du syndrome d'apnée du sommeil chez les patients présentant un anévrisme et recherche d'une association. Étude clinique sur 52 patients.

OBJECTIVES: Prevalence of abdominal aortic aneurysms (AAA) in Europe is between 4.1 % and 8.9 %. The risk of rupture of AAA is related to the evolution of its diameter. The role of sleep apnea (SA) remains still discussed. The objective of this study was to study the prevalence of SA in patients presenting with AAA in comparison with the general population as well as the relation between the AAA diameter and the severity of SA. MATERIALS AND METHODS: Between June 2012 and December 2014, we included all patients referred for surgical treatment of an AAA. All the patients had a preoperative polysomnography and angio-scanner. An apnea/hypopnea index (AHI)>10/h was chosen for the diagnosis of SA. SA prevalence was compared with the prevalence in general population. The patients were also divided into two groups according to the severity of SA: group 1 (no SA and light SAS); group 2 (moderate and severe SA). RESULTS: Fifty-two patients were included. Fifty-six percent of the patients presented SA - prevalence was significantly higher than in the general population (56 vs. 8 %, P<0.001). The distribution of the two groups was: group 1, n=27 patients, group 2, n=25 patients. AAA diameter and BMI were higher in group 2 than in group 1, respectively 61mm vs. 55mm, P=0.03 and 28 vs. 23, P=0.02. CONCLUSION: Prevalence of SA in patients with an AAA seems to be significantly higher than in general population. The growth of the aneurysm seems to be linked to the severity of SA.

[Lung cancer and HIV infection]. / Cancer du poumon et infection par le Virus de l'Immunodéficience Humaine.

AIDS was the cause of the majority of deaths from HIV infection before 1996 but since the introduction of antiretroviral therapies the causes of mortality have changed considerably. In 2010, 75 % of deaths were due to diseases other than AIDS, the majority being cancers. Lung cancer is the most common in terms of both incidence and mortality. It shows specific features when compared to the general population: there is an excess risk due to heavy smoking but also probably due to immunosuppression. The age of onset is younger and the prognosis worse than in the general population. Management is difficult, partly due to the aggressive nature of the tumor and partly to co-morbidities and potential interactions between anticancer and antiretroviral therapies. A phase II therapeutic trial (IFCT-CHIVA 1001) is under way nationally.

Clinical and molecular features in patients with advanced non-small-cell lung carcinoma refractory to first-line platinum-based chemotherapy.

Most of the cases of non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage and are treated with platinum-doublet chemotherapy. However, some patients are refractory to this treatment. The aim of this study was to identify the clinical and molecular characteristics of patients with refractory disease. All consecutive patients between 2003 and 2006, who received a platinum-doublet chemotherapy as first-line treatment for stage IIIb-IV NSCLC, were included. Refractory patients were defined as early progressive disease (PD) at the first evaluation of chemotherapy according to WHO criteria. The clinical, histo-pathological, and molecular characteristics (EGFR: exon 19, 20, 21 and KRAS: exon 2 by PCR sequencing; ALK by immunohistochemistry) and survival of refractory patients with initial PD (r-patients) and controlled disease (c-patients) were compared by univariate analyses. Factors that differed between the two groups (p-value <0.25 in univariate analyses) were entered into multivariate analysis. In this study, 178 patients were included. The first tumor assessment was carried out after a median of three cycles (range 1-4). Forty-six (25.8%) patients were refractory. Clinical presentation was similar between r- and c-patients. The sarcomatoid histological subtype was more common in r-patients than c-patients (10.9% vs. 1.5%, respectively; p=0.057). The proportion of EGFR (5.2% vs. 9.6%, p=0.224) and KRAS mutations (11.1% vs. 5.7%, p=0.357), and the expression of ALK (6.3% vs. 2.5%, p=0.327) did not differ significantly between the two groups. In multivariate analysis, sarcomatoid histological subtype was the only factor associated with early PD (OR=7.50; 95%CI: 1.02-55.45; p=0.048). r-Patients had significantly shorter survival than c-patients (median 5 months (IQR 3.2-9.9) vs. 15.4 months (IQR 9.9-22.5), respectively; p<0.0001). In conclusion, patients with early PD under platinum-doublet chemotherapy had shorter survival than c-patients. Sarcomatoid histological subtype was the only independent factor associated with early PD.

[A simple view on lung cancer biology: the MET pathway]. / Un regard simple sur la biologie du cancer bronchique : MET.

MET is a cell membrane tyrosine kinase receptor for its ligand the hepatocyte growth factor (HGF), also called scatter factor (SF). MET conveys mitogenic, motogenic and proangiogenic signals, important during embryonic development and during the development of cancer. Activation of the HGF-MET pathway seems to be associated with a poor prognosis in lung cancer. Activation in lung cancer may be related to several molecular anomalies: ligand overexpression, receptor overexpression, genomic amplification or MET mutation. In MET amplified or mutated lung cancer, MET may be an important oncogene, as the tumor appears "MET addicted". In other lung cancers, MET may be implicated in tumour progression by tissue invasion and formation of metastases. MET amplification is also a mechanism known to be implicated in 20% of secondary resistance to EGFR inhibitors in patients presenting EGFR mutated lung cancer. Different strategies of MET inhibition in lung cancer are being studied, particularly in EGFR mutated lung cancer. In this review we discuss the structure of the MET receptor, the activated pathways, the main genomic anomalies in lung cancer and the development of MET inhibitors.

[Update on diagnosis and treatment of high-risk pulmonary embolism]. / Prise en charge diagnostique et thérapeutique de l'embolie pulmonaire grave.

INTRODUCTION: High-risk pulmonary embolism (PE) is associated with a significant early mortality, approaching 25%, and is defined by the presence of cardiogenic shock. STATE OF THE ART: The high early mortality rate for patients with shock requires a rapid diagnostic approach with bedside tests. Right ventricular dilatation assessed by echocardiography in patients with a high clinical probability for PE confirms the diagnosis without the need for additional testing. Spiral CT pulmonary angiography remains the first line investigation for patients without shock. Anticoagulant treatment should be started as soon as pulmonary embolism is suspected. Fibrinolytic therapy is recommended for patients with high-risk pulmonary embolism. The prognostic value of cardiac biomarkers, such as B natriuretic peptide, troponins and right ventricular dilatation for early mortality has been demonstrated. These markers permit the identification of an intermediate risk group of patients with normotensive pulmonary embolism and prognostic scores have been developed. PERSPECTIVES: It remains to be established whether fibrinolysis can have a clinical benefit or reduce mortality in patients with intermediate risk pulmonary embolism. A large randomised placebo-controlled study is currently under way to answer this question. Further studies will more clearly define the role of various predictive rules to identify patients requiring hospital care or those who should be considered for outpatient management.

[Cancer and venous thromboembolism]. / Maladie veineuse thromboembolique et cancer.

INTRODUCTION: Cancer and venous thromboembolism are frequently associated. STATE OF THE ART: Venous thromboembolism is associated with a worse prognosis in patients with cancer. Thrombosis in cancer patients is related to the expression of tissue factor and other procoagulants by tumour cells. Surgery, chemotherapy and antiangiogenic agents are also associated with an increased risk of thrombosis. Venous thromboembolism may be the first manifestation of cancer, the risk being especially increased during the first six months following an unexplained episode of idiopathic thrombosis. Current evidence does not suggest that a systematic screening for cancer after an unexplained thrombosis is associated with a clinical benefit. Risk factors for thrombosis specific to the cancer population have been identified. A recent controlled trial suggests that low-molecular weight heparin may reduce the incidence of venous thromboembolism in patients with cancer. These results need to be confirmed. Treatment of venous thromboembolism in cancer patients is primarily based on low-molecular weight heparin administered for three or six months. PERSPECTIVES: Low-molecular weight heparin may increase the survival of patients with cancer through a direct effect on tumour biology. Several clinical trials are underway to confirm this hypothesis. CONCLUSION: Thrombosis in cancer patients is a frequent and difficult to treat condition. The role of long-term prophylaxis remains to be defined. The treatment of venous thromboembolism in cancer patients is primarily based on low-molecular weight heparin. Large clinical trials are currently assessing the effect of low-molecular weight heparin on the long-term survival of patients with cancer.

In vivo importance of actin nucleotide exchange catalyzed by profilin.

The actin monomer-binding protein, profilin, influences the dynamics of actin filaments in vitro by suppressing nucleation, enhancing nucleotide exchange on actin, and promoting barbed-end assembly. Profilin may also link signaling pathways to actin cytoskeleton organization by binding to the phosphoinositide PIP(2) and to polyproline stretches on several proteins. Although activities of profilin have been studied extensively in vitro, the significance of each of these activities in vivo needs to be tested. To study profilin function, we extensively mutagenized the Saccharomyces cerevisiae profilin gene (PFY1) and examined the consequences of specific point mutations on growth and actin organization. The actin-binding region of profilin was shown to be critical in vivo. act1-157, an actin mutant with an increased intrinsic rate of nucleotide exchange, suppressed defects in actin organization, cell growth, and fluid-phase endocytosis of pfy1-4, a profilin mutant defective in actin binding. In reactions containing actin, profilin, and cofilin, profilin was required for fast rates of actin filament turnover. However, Act1-157p circumvented the requirement for profilin. Based on the results of these studies, we conclude that in living cells profilin promotes rapid actin dynamics by regenerating ATP actin from ADP actin-cofilin generated during filament disassembly.

New actin mutants allow further characterization of the nucleotide binding cleft and drug binding sites.

We have generated 9 site-specific mutations in Saccharomyces cerevisiae actin. These mutants display a variety of phenotypes when expressed in vivo, including slow actin filament turnover, slow fluid-phase endocytosis, and defects in actin organization. Actin mutation D157E confers resistance to the actin-sequestering drug, latrunculin A. Latrunculin A inhibits nucleotide exchange on wild-type yeast actin but not on D157E actin, suggesting that this residue is part of the latrunculin A binding site. We have refined our earlier map of the phalloidin binding site on actin, demonstrating a requirement for residue G158 in addition to D179 and R177. The nine new actin mutants as well as a large collection of existing actin mutants were also used to identify the putative binding site of another actin binding drug, tolytoxin, on actin. The actin alleles that result in decreased sensitivity to this drug cluster at a site near the nucleotide-binding pocket. Actin purified from one of these mutants has a reduced affinity for tolytoxin. In addition, tolytoxin causes a 2.4-fold increase in the t1/2 of ATP exchange, further suggesting that this drug binds near the nucleotide-binding pocket of actin. We note that the binding sites for latrunculin A, phalloidin, and tolytoxin all map close to the actin nucleotide binding pocket.

A change in actin conformation associated with filament instability after Pi release.

The ability of actin to both polymerize into filaments and to depolymerize permits the rapid rearrangements of actin structures that are essential for actin's function in most cellular processes. Filament polarity and dynamic properties are conferred by the hydrolysis of ATP on actin filaments. Release of inorganic phosphate (Pi) from filaments after ATP hydrolysis promotes depolymerization. We identify a yeast actin mutation, Val-159 to Asn, which uncouples Pi release from the conformational change that results in filament destabilization. Three-dimensional reconstructions of electron micrographs reveal a conformational difference between ADP-Pi filaments and ADP filaments and show that ADP V159N filaments resemble ADP-Pi wild-type filaments. Crystal structures of mammalian beta-actin in which the nucleotide binding cleft is in the "open" and "closed" states can be used to model actin filaments in the ADP and ADP-Pi conformations, respectively. We propose that these two conformations of G-actin may be related to two functional states of F-actin.

The yeast V159N actin mutant reveals roles for actin dynamics in vivo.

Actin with a Val 159 to Asn mutation (V159N) forms actin filaments that depolymerize slowly because of a failure to undergo a conformational change after inorganic phosphate release. Here we demonstrate that expression of this actin results in reduced actin dynamics in vivo, and we make use of this property to study the roles of rapid actin filament turnover. Yeast strains expressing the V159N mutant (act1-159) as their only source of actin have larger cortical actin patches and more actin cables than wild-type yeast. Rapid actin dynamics are not essential for cortical actin patch motility or establishment of cell polarity. However, fluid phase endocytosis is defective in act1-159 strains. act1-159 is synthetically lethal with cofilin and profilin mutants, supporting the conclusion that mutations in all of these genes impair the polymerization/ depolymerization cycle. In contrast, act1-159 partially suppresses the temperature sensitivity of a tropomyosin mutant, and the loss of cytoplasmic cables seen in fimbrin, Mdm20p, and tropomyosin null mutants, suggesting filament stabilizing functions for these actin-binding proteins. Analysis of the cables in these double-mutant cells supports a role for fimbrin in organizing cytoplasmic cables and for Mdm20p and tropomyosin in excluding cofilin from the cables.

Identification of a protein that interacts with tubulin dimers and increases the catastrophe rate of microtubules.

Using a polymerization inhibition assay, we have purified a small, heat stable protein that physically interacts with tubulin dimers and increases the catastrophe rate of microtubules. Sequence analysis identified this protein as oncoprotein 18 (Op18)/stathmin, a conserved phosphoprotein that is highly expressed in leukemia cells. Immunodepletion experiments in Xenopus egg extracts showed that Op18/stathmin is involved in physiological regulation of mitotic microtubule dynamics. Op18/stathmin is a microtubule regulator that preferentially interacts with unpolymerized subunits. It is a candidate for increasing the microtubule catastrophe rate in mitosis and might also regulate microtubule dynamics in response to external signals.

Real-time visualization of cell cycle-dependent changes in microtubule dynamics in cytoplasmic extracts.

Using Xenopus egg extracts arrested in interphase or mitosis, we directly observed differences in microtubule dynamics at different stages of the cell cycle. Interphase extracts were prepared from eggs in the first interphase after meiosis. Mitotic extracts were prepared by addition of purified cyclin to interphase extracts. Microtubules were nucleated by the addition of centrosomes and visualized by fluorescence video-microscopy in extracts to which rhodamine-labeled tubulin had been added. We found a striking difference in microtubule dynamics in mitotic versus interphase extracts. Quantitative analysis revealed that the rates of polymerization and depolymerization are similar in interphase and mitosis and that within the spatial and temporal resolution of our experiments the difference in dynamics is due almost entirely to an increase in the frequency of transition from growing to shrinking (catastrophe frequency) in the mitotic extracts.

Genetic and molecular analysis of the SOE1 gene: a tRNA(3Glu) missense suppressor of yeast cdc8 mutations.

The CDC8 gene of Saccharomyces cerevisiae encodes deoxythymidylate (dTMP) kinase and is required for nuclear and mitochondrial DNA replication in both the mitotic and meiotic cell cycles. All cdc8 temperature-sensitive mutants are partially defective in meiotic and mitochondrial functions at the permissive temperature. In a study of revertants of temperature-sensitive cdc8 mutants, the SOE201 and SOE1 mutants were isolated. The SOE201 mutant is a disome of chromosome X to which the cdc8 gene maps. Using the chromosome X aneuploids to vary cdc8 gene dosage, we demonstrate that different levels of dTMP kinase activity are required for mitotic, meiotic or mitochondrial DNA replication. The SOE1 mutant contains a dominant suppressor that suppresses five different cdc8 alleles but does not suppress a complete cdc8 deletion. The SOE1 gene is located less than 1.5 cM from the CYH2 gene on chromosome VII and is adjacent to the TSM437-CYH2 region, with the gene order being SOE1-TSM437-CYH2. SOE1 is an inefficient suppressor that can neither suppress the cdc8 hypomorphic phenotype nor restore dTMP kinase activity in vitro. SOE1 is a single C to T mutation in the anticodon of a tRNA(3Glu) gene and thereby, produces a missense suppressor tRNA capable of recognizing AAA lysine codons. We propose that the resultant lysine to glutamate change stabilizes thermo-labile dTMP kinase molecules in the cell.

Mild mental retardation and severe mental retardation compared: experiences in eight less developed countries.

Frequencies of Severe Mental Retardation (SMR) and Mild Mental Retardation (MMR) were obtained from pilot surveys of severe childhood disability in 8 less developed countries. Approximately 1,000 children aged 3 to 9 years were surveyed in each location. The surveys used a Ten Question (TQ) door-to-door interview, usually of the mother, as a screening procedure and a systematic medical and psychological assessment for the diagnosis. Diagnostic categories of SMR (IQ less than or equal to 55) and MMR (IQ greater than 55, less than or equal to 70) were assigned by well trained local psychologists, using formal and informal techniques of assessment. Contrasting frequencies and distributions for MMR compared with SMR are shown for each location. No consistent pattern for MMR versus SMR emerged, neither regarding frequency, male/female ratio, average age nor socio-economic status of household. By contrast, MMR did differ from SMR consistently regarding consanguinity of parents, the presence of associated impairments and the positive report of symptoms at interview. Also, the families of all MR children were lower in SES than comparison families. An interpretation of these findings is offered: the more severely disabled children tend to be assessed as SMR, but so do other children who might, in better circumstances, be assessed as MMR. The relevance of this interpretation is discussed, in terms of assessment and of rehabilitation, and as a guide to further epidemiologic studies.

"Serious" mental retardation in developing countries: an epidemiologic approach.

In this paper we first present methods and preliminary results of pilot surveys of "serious" mental retardation (IQ less than or equal to 55); the surveys included screening and diagnostic components and were carried out in the less-developed world. Next we discuss two problems raised by these surveys: one is the diagnosis of a case and its clinical dimensions, and the other is the interpretation of prevalence. In the next section we illustrate epidemiological approaches to the analysis of such data, in particular their relevance to prevention. Lastly, we propose that the two-stage survey approach developed in the course of the pilot work can provide a valuable basis for planning and prevention, if certain key conditions can be met.