Recurrence of hypertensive disorders of pregnancy: results from a nationwide prospective cohort study (CONCEPTION).

OBJECTIVE: To assess the risk of gestational hypertension (GH) and pre-eclampsia (PE) during a second pregnancy after occurrence during a first pregnancy. DESIGN: Prospective cohort study. SETTING: CONCEPTION is a French nationwide cohort study that used data from the National Health Data System (SNDS) database. METHODS: We included all women who gave birth for the first time in France in 2010-2018 and who subsequently gave birth. We identified GH and PE through hospital diagnoses and the dispensing of anti-hypertensive drugs. The incidence rate ratios (IRR) of all hypertensive disorder of pregnancy (HDP) during the second pregnancy were estimated using Poisson models adjusted for confounding. MAIN OUTCOME MEASURES: Incidence rate ratios of HDP during the second pregnancy. RESULTS: Of the 2 829 274 women included, 238 506 (8.4%) were diagnosed with HDP during their first pregnancy. In women with GH during their first pregnancy, 11.3% (IRR 4.5, 95% confidence interval [CI] 4.4-4.7) and 3.4% (IRR 5.0, 95% CI 4.8-5.3) developed GH and PE during their second pregnancy, respectively. In women with PE during their first pregnancy, 7.4% (IRR 2.6, 95% CI 2.5-2.7) and 14.7% (IRR 14.3, 95% CI 13.6-15.0) developed GH and PE during their second pregnancy, respectively. The more severe and earlier the PE during the first pregnancy, the stronger the likelihood of having PE during the second pregnancy. Maternal age, social deprivation, obesity, diabetes and chronic hypertension were all associated with PE recurrence. CONCLUSION: These results can guide policymaking that focuses on improving counselling for women who wish to become pregnant more than once, by identifying those who would benefit more from tailored management of modifiable risk factors, and heightened surveillance during post-first pregnancies.

Arterial and venous complications after fertility treatment: A French nationwide cohort study.

OBJECTIVES: To determine whether the risk of thromboembolic complications is higher in women following unsuccessful fertility treatment (FT) and in pregnant women following successful FT, and whether the risk differs according to FT type. STUDY DESIGN: This is an observational prospective cohort study. All French women aged 18-45 years who received FT between 2013 and 2015 were selected from the French health insurance claim database which registers healthcare consumption for the entire French population. All FT reimbursed over a 28-day period from the date of the first FT were considered to constitute one FT cycle. Each FT cycle was classified according to type: either simple ovulation induction (OI) or ovulation stimulation (OS). All hospitalisations with a diagnosis of venous thromboembolism (VTE), arterial thrombosis (AT) or ovarian hyperstimulation syndrome (OHSS) were identified for the selected women in the French hospital discharge database. Poisson regressions were used to estimate incidence rate ratios (IRR) by comparing i) the incidence of thromboembolic complications (i.e., VTE and AT) and OHSS following unsuccessful FT cycles with the incidence of these two diseases in all non-pregnant women of the same age range (i.e. non-pregnant control group), and ii) incidence of thromboembolic complications and OHSS in women who became pregnant following successful FT with the incidence in women of the same age range with spontaneous (i.e., no FT) pregnancies (i.e., pregnant control group (spontaneous pregnancy)). RESULTS: During the study period, 277,913 women underwent FT, for a total of 788,007 FT cycles, with 82,821 FT-related pregnancies. Among unsuccessful FT cycles, 75 VTE and 43 AT were observed. OS treatment cycles but not OI were associated with a higher risk of VTE than in reference group (age-adjusted IRR 1.74, 95%CI [1.30-2.34]). Among FT-related pregnancies, 207 VTE and 35 AT were reported. VTE and AT incidence rates during the first trimester were higher after OS treatment cycles than in the pregnant control group (spontaneous pregnancy) after adjusting for age and twin/multiple pregnancies (IRRVTE = 3.29, 95%CI [2.24-4.81]; IRRAT = 2.63, 95%CI [1.06-6.51]). CONCLUSION: Monitoring women undergoing FT, especially OS, irrespective of pregnancy status is crucial. The risk of thromboembolic complications in the first trimester for FT-related pregnancies seems to be higher than that for spontaneous pregnancies.

Regional disparities in acute and post-acute care of stroke patients in France, 2015.

OBJECTIVE: The aim of this study was to assess regional variations of the hospital management of stroke patients during acute and post-acute phases in France in 2015. MATERIAL AND METHODS: Hospitalized patients coded with stroke as their main diagnosis or, if hospitalized in several different wards, any main ward diagnosis were identified in the 2015 French national hospital discharge database for acute care. Rates of hospitalization in stroke units (SUs) were assessed at a national level and in all metropolitan and overseas regions. All stroke survivors discharged at the end of the acute phase were subsequently identified in the national database for post-acute rehabilitation hospitalization (PARH) within 3 months. RESULTS: In the acute phase, half the stroke patients hospitalized for intracerebral hemorrhage, cerebral infarction or unspecified stroke were admitted to SUs. However, there were variations across metropolitan regions (from 30% to 69%) and in overseas regions (from 1% to 59%); these rates correlated with regional ratios of SU beds/100,000 inhabitants. There were also regional differences in PARH rates-in hemiplegic stroke patients, 62% were admitted for PARH (range: 58% to 67%) in metropolitan regions and, overseas, from 8% to 67%-as well as geographical discrepancies in PARH rates to specialized rehabilitation units. Hospitalization rates of hemiplegic stroke patients in neurological rehabilitation centers were 30% for the whole country, but ranged from 23% to 36% in metropolitan regions and from 2% to 45% in overseas regions. CONCLUSION: This study focused on hospital-based management of stroke patients. In spite of the creation of new SUs over the past decade in France, there are persistent regional differences in the number of SU beds/100,000 inhabitants and, consequently, in the rate of stroke patients managed in SUs. However, rates continue to improve with the creation of new SUs and the expansion of existing ones. Regional variations were also noted for post-acute hospitalization rates and PARH beds/places.

Time trends in hospital admissions and mortality due to abdominal aortic aneurysms in France, 2002-2013.

BACKGROUND: Abdominal aortic aneurysms (AAA) are serious disease with a high fatality rate but recent epidemiologic data showed a decrease of AAA mortality. Our objective was to estimate, in France, the hospitalization, inhospital mortality and mortality rates due to AAA and to analyze their trends over time. METHODS: Hospitalization data were extracted from the hospital discharge summaries in the national database between 2002 and 2013. The analysis covered all patients hospitalized for AAA as a principal diagnosis. During the same period, all death certificates mentioning AAA as an initial cause of death were included in the study. Crude and standardized rates were calculated according to age and sex. Poisson regression was used to analyze the average annual percent change. RESULTS: In 2013, there were 8853 patients hospitalized for AAA in France (7986 unruptured and 867 ruptured). Between 2002 and 2013, the rate of patients hospitalized for unruptured AAA decreased slightly in men (-5.0%) but increased in women (+5.2%). By contrast, the rate of patients hospitalized for ruptured AAA has decreased by >20% in men and women. The proportion of endovascular treatment of unruptured AAA rose from <10% in 2005 to 35% in women and 40% in men in 2013. In 2013, 939 deaths from AAA were recorded. Mortality for this disease declined significantly from 2002 to 2013 in men and women. CONCLUSION: The unfavorable epidemiological trends in women and important evolution of the management of AAA call for an epidemiological surveillance of this disease.

Differential trends in myocardial infarction mortality over 1975-2010 in France according to gender: An age-period-cohort analysis.

BACKGROUND: A dramatic reduction in mortality from myocardial infarction (MI) has been observed in France as in other western countries. The dynamics of this decline are likely to have differed according to age and sex. Our study sought to clarify the contributions of age, period and birth-cohort effects on post-MI mortality in France between 1975 and 2010 and to identify gender-specific trends. METHODS: Trends were analysed using an age-period-cohort (APC) model. MI mortality data were selected using the International Classification of Diseases (ICD) (8, 9 and 10th revision) codes from the French national mortality databases. RESULTS: Age-standardised MI mortality rates decreased by 70% from 1975 to 2010 in both sexes. Linear trend (drift) accounted for the majority of this decline and appeared very similar between genders. However, we found that increased MI mortality with advancing age was more pronounced in women than men beyond the age of 50. We also observed a slowdown in the decline among cohorts born after 1945, particularly in women. CONCLUSIONS: MI mortality showed a dramatic downward trend for the last 35years in France. The linear decline was modulated by cohort effects, whereas no major period effect was identified. This study also showed noticeable differential age and cohorts' effects between genders, especially the no longer decline in MI mortality for women born after World War II. This highlights the need for specific preventive measures to target this population in the future.

Caspase-activated ROCK-1 allows erythroblast terminal maturation independently of cytokine-induced Rho signaling.

Stem cell factor (SCF) and erythropoietin are strictly required for preventing apoptosis and stimulating proliferation, allowing the differentiation of erythroid precursors from colony-forming unit-E to the polychromatophilic stage. In contrast, terminal maturation to generate reticulocytes occurs independently of cytokine signaling by a mechanism not fully understood. Terminal differentiation is characterized by a sequence of morphological changes including a progressive decrease in cell size, chromatin condensation in the nucleus and disappearance of organelles, which requires transient caspase activation. These events are followed by nucleus extrusion as a consequence of plasma membrane and cytoskeleton reorganization. Here, we show that in early step, SCF stimulates the Rho/ROCK pathway until the basophilic stage. Thereafter, ROCK-1 is activated independently of Rho signaling by caspase-3-mediated cleavage, allowing terminal maturation at least in part through phosphorylation of the light chain of myosin II. Therefore, in this differentiation system, final maturation occurs independently of SCF signaling through caspase-induced ROCK-1 kinase activation.

[Telomeres and telomerase: relevance and future prospects in systemic lupus erythematosus]. / Télomères et télomérase : intérêts et perspectives dans le lupus érythémateux systémique.

Telomeres are specialized structures that cap and protect the end of chromosomes. Telomeres progressively shorten after each cellular division unless an enzyme, the telomerase, counteracts. Telomeres are implicated in cellular senescence, acting like a biological clock. Telomere length and telomerase activity are important in the physiopathology of cancer. In the past years, research has focused on them in order to find new therapeutic targets. Yet, oxidative stress, inflammation and increased leucocytes renewal are major environmental factors associated with telomeres shortening acceleration and thus in concordance with biological age. Thus, telomeric erosion induces cell apoptosis; indeed, apoptotic cell clearance is impaired in systemic lupus. Considering these elements and data resulting from oncology, telomere/telomerase couple was studied during the last decade in systemic lupus erythematosus. The objective was to know if this couple could have an implication in the physiopathology of this disease. A systematic review of literature is proposed about telomere and/or telomerase in systemic lupus erythematosus in order to discuss their physiopathological implication. Among 273 tested patients, telomere seems to be eroded and telomerase activity insufficiently increased but correlated to the activity of the disease. The analysis of telomere length and telomerase activity could be useful as prognosis factor or disease activity index. Telomere erosion could reflect an accelerated replicative senescence of the immune system. The role of the regulator T lymphocytes has not yet been precised. Standardized studies on larger population could be realized in systemic lupus and open new avenues of research and/or therapy based upon the telomere/telomerase biology.

Molecular and cellular aspects of HTLV-1 associated leukemogenesis in vivo.

Most cancers and leukemias are preceded by a prolonged period of clinical latency during which cellular, chromosomal and molecular aberrations help move normal cell towards the malignant phenotype. The problem is that premalignant cells are usually indistinguishable from their normal counterparts, thereby ruling out the possibility to investigate the events that govern early leukemogenesis in vivo. Adult T cell leukemia/lymphoma (ATLL) is a T cell malignancy that occurs after a 40-60-year period of clinical latency in about 3-5% of HTLV-1-infected individuals. ATLL cells are monoclonally expanded and harbor an integrated provirus. A persistent oligo/polyclonal expansion of HTLV-1-bearing cells has been shown to precede ATLL, supporting the fact that in ATLL tumor cells arise from a clonally expanding non-malignant cell. It is possible to isolate infected, ie preleukemic, cells during the premalignant asymptomatic phase of the infection, thus providing an exceptional system to study the mechanisms underlying human cancers. Here we review some of the consequences of HTLV-1 on its host cell in vivo, at different stages of infection.

Somatic mutation in human T-cell leukemia virus type 1 provirus and flanking cellular sequences during clonal expansion in vivo.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1), the causative agent of adult T-cell leukemia/lymphoma, shows intrapatient genetic variability. Although HTLV-1 can replicate via the reverse transcription of virion RNA to a double-stranded DNA provirus (the conventional manner for retroviruses), its predominant mode of replication is via the clonal expansion (mitosis) of the infected cell. This expansion is achieved by the viral oncoprotein Tax, which keeps the infected CD4 T lymphocyte cycling. Because Tax also interferes with cellular DNA repair pathways, we investigated whether somatic mutations of the provirus that occur during the division of infected cells could account for HTLV-1 genetic variability. METHODS: An inverse polymerase chain reaction strategy was designed to distinguish somatic mutations from reverse transcription-associated substitutions. This strategy allows the proviral sequences to be isolated together with flanking cellular sequences. Using this method, we sequenced 208 HTLV-1 provirus 3' segments, together with their integration sites, belonging to 29 distinct circulating cellular clones from infected individuals. RESULTS: For 60% of the clones, 8%-80% of infected cells harbored a mutated HTLV-1 provirus, without evidence of reverse transcription-associated mutations. Mutations within flanking cellular sequences were also identified at a frequency of 2.8 x 10(-4) substitution per base pair. Some of these clones carried multiple discrete substitutions or deletions, indicating progressive accumulation of mutations during clonal expansion. The overall frequency of somatic mutations increased with the degree of proliferation of infected T cells. CONCLUSIONS: These data indicate that, in vivo, HTLV-1 variation results mainly from postintegration events that consist of somatic mutations of the proviral sequence occurring during clonal expansion. The finding of substitutions in flanking sequences suggests that somatic mutations occurring after integration, presumably coupled with selection, help move the cellular clones toward a transformed phenotype, of which adult T-cell leukemia/lymphoma is the end point.

Two-step nature of human T-cell leukemia virus type 1 replication in experimentally infected squirrel monkeys (Saimiri sciureus).

After experimental infection of squirrel monkeys (Saimiri sciureus) with human T-cell leukemia virus type 1 (HTLV-1)-infected cells, the virus is transcribed only transiently in circulating blood, spleen, and lymph nodes. Stable disappearance of viral expression occurs at 2 to 3 weeks after inoculation. This coincides with the development of the anti-HTLV-1 immune response and persistent detection of the provirus in peripheral blood mononuclear cells (PBMCs). In this study, the HTLV-1 replication pattern was analyzed over time in PBMCs and various organs from two HTLV-1-infected squirrel monkeys. Real-time quantitative PCR confirmed that PBMCs and lymphoid organs constitute the major reservoirs for HTLV-1. The PCR amplification of HTLV-1 flanking sequences from PBMCs evidenced a pattern of clonal expansion of infected cells identical to that observed in humans. Dissemination of the virus in body compartments appeared to result from cellular transport of the integrated provirus. The circulating proviral burden increased as a function of time in one animal studied over a period of 4 years. The high proviral loads observed in the last samples resulted from the accumulation of infected cells via the extensive proliferation of a restricted number of persistent clones on a background of polyclonally expanded HTLV-1-positive cells. Therefore, HTLV-1 primary infection in squirrel monkeys is a two-step process involving a transient phase of reverse transcription followed by persistent multiplication of infected cells. This suggests that the choice of the target for blocking HTLV-1 replication might depend on the stage of infection.

Basis of HTLV type 1 target site selection.

Sequencing integration sites from >/=200 proviruses isolated from infected individuals revealed that HTLV-1 integration is not random at the level of the nucleotide sequence. The virus was found to integrate in A/T-rich regions with a weak consensus sequence at positions within and without the hexameric repeat generated during integration. These features were not associated with a preference for integration near active regions or repeat elements of the host chromosomes. However, about 6% of HTLV-1 proviruses were found to be integrated into transcription units, suggesting that in some cells, HTLV-1 integration may alter gene expression in vivo. Therefore, the target choice in vivo seems to be determined by local features rather than by the accessibility of specific regions. This led us subsequently to analyze the role of the DNA structure in HTLV-1 integration in vitro. Double-strand HTLV-1 or HIV-1 3' LTR extremities were used as substrates for in vitro strand transfer reactions using highly purified HTLV-1 and HIV-1 integrases (INs) expressed in Escherichia coli, and two synthetic naked 50-bp double-strand DNA molecules harboring different structures were used as targets. A fluorometric quantitative analysis of integration products was designed to assess the reaction efficiency for both target sequences. As suggested for HTLV-1 in vivo (present results), and, as previously described for other retroviruses in vitro, the structure of the target was found to greatly influence the site and the efficiency of integration. Both HIV-1 and HTLV-1 INs underwent the same target structural constraint, i.e., a strong preference for curved DNA. Altogether these results indicate that if most or all the regions of the genome appear to be accessible to HTLV-1 integration, local DNA curvature seems to confer a kinetic advantage for both in vitro and in vivo HTLV-1 integration.

High circulating proviral load with oligoclonal expansion of HTLV-1 bearing T cells in HTLV-1 carriers with strongyloidiasis.

Adult T cell leukemia (ATLL) develops in 3 - 5% of HTLV-1 carriers after a long period of latency during which a persistent polyclonal expansion of HTLV-1 infected lymphocytes is observed in all individuals. This incubation period is significantly shortened in HTLV-1 carrier with Strongyloides stercoralis (Ss) infection, suggesting that Ss could be a cofactor of ATLL. As an increased T cell proliferation at the asymptomatic stage of HTLV-1 infection could increase the risk of malignant transformation, the effect of Ss infection on infected T lymphocytes was assessed in vivo in HTLV-1 asymptomatic carriers. After real-time quantitative PCR, the mean circulating HTLV-1 proviral load was more than five times higher in HTLV-1 carriers with strongyloidiasis than in HTLV-1+ individuals without Ss infection (P<0.009). This increased proviral load was found to result from the extensive proliferation of a restricted number of infected clones, i.e. from oligoclonal expansion, as evidenced by the semiquantitative amplification of HTLV-1 flanking sequences. The positive effect of Ss on clonal expansion was reversible under effective treatment of strongyloidiasis in one patient with parasitological cure whereas no significant modification of the HTLV-1 replication pattern was observed in an additional case with strongyloidiasis treatment failure. Therefore, Ss stimulates the oligoclonal proliferation of HTLV-1 infected cells in HTLV-1 asymptomatic carriers in vivo. This is thought to account for the shortened period of latency observed in ATLL patients with strongyloidiasis. Oncogene (2000) 19, 4954 - 4960

Inositol polyphosphates regulate the membrane interactions of the endosomal p100, G-protein-related protein.

The protein, p100, was previously identified as a G-protein related protein that cycles on and off the cytoplasmic face of the endosome membrane (Traub et al., Biochem. J. 280 (1991) 171-178). Here we present evidence that the inositol polyphosphates, inositol 1,4, 5-trisphosphate (IP3) and inositol hexakisphosphate (IP6), release p100 from light-density microsomal membranes and inhibit rebinding of p100 through receptors, which are specific for IP3 or for IP6. These receptors can be co-extracted with p100 from the microsomes by 0.5 M Tris-HCl and, in the soluble state, they exhibit similar binding activity towards the inositol polyphosphates as do untreated microsomes. Soluble p100 self-aggregates and this aggregation is blocked by both IP3 and IP6. Stimulation of permeabilized rat basophilic leukemia (RBL-2H3) cells with carbachol, via transfected muscarinic m1 receptors, results in increased levels of inositol polyphosphates and the quantitative release of p100 into the cytosol. This effect is reversible and cytosolic p100 rebinds to the membrane as the levels of inositol polyphosphates decline. These findings suggest that p100 may belong to a family of IP-binding proteins whose intracellular localization is determined by extracellular signals.