CD137 (4-1BB) Engagement Fine-Tunes Synergistic IL-15- and IL-21-Driven NK Cell Proliferation.

To understand and dissect the mechanisms driving human NK cell proliferation, we exploited the methodology used in cell therapy to numerically expand NK cells in the presence of K562-derived artificial APC (aAPCs) and cytokines. For four consecutive weeks, high expression of CD137L by a K562-derived aAPC cell line could sustain NK cell expansion by 3 × 105-fold, whereas low expression of CD137L by the parental K562 cell line only supported the expansion by 2 × 103-fold. The level of expression of CD137L, however, did not modulate the sensitivity of K562 cells to the intrinsic cytotoxicity of NK cells. Similarly, the low NK cell proliferation in the presence of the parental K562 cell line and cytokines was increased by adding agonistic anti-CD137 Abs to levels similar to CD137L-expressing K562-derived aAPCs. Finally, synergy between IL-15 and IL-21 was observed only upon CD137 engagement and the presence of aAPCs. Therefore, we conclude that NK cell proliferation requires cell-to-cell contact, activation of the CD137 axis, and presence of IL-15 (or its membranous form) and IL-21. By analogy with the three-signal model required to activate T cells, we speculate that the cell-to-cell contact represents "signal 1," CD137 represents "signal 2," and cytokines represent "signal 3." The precise nature of signal 1 remains to be defined.

Les consommations de tabac, d'alcool et de pemba pendant la grossesse en Guyane française.

INTRODUCTION: The risks to the unborn child from maternal consumption of alcohol, tobacco and substances during pregnancy are well documented in the medical literature. Data on such consumption in Frensh Guyana are scattered and scarce, which prevents prevention policies from being adapted to the local context. METHOD: To compensate for the inadequacy of the data, a questionnaire survey was conducted in 2017-2018 in Guyana's three maternity units with 789 mothers. Among other things, this survey aimed at gathering data about consumption, about information received on substance consumption during pregnancy, and about the interest of professionals met by the women in these matters. RESULTS: Tobacco and alcohol consumption at the end of pregnancy were respectively 2% and 17%. Two profiles of alcohol consumers emerged: in Cayenne, French women with a high school level of education or more consuming on occasion wine and in Saint-Laurent-du-Maroni, regular beer consumers among women speaking a language of the river, born in Guyana. Finally, Pemba (clay) was used by 15% of the pregnant women. Although the percentage of smokers is much lower than that of metropolitan France, the percentage of alcohol consumers is significantly higher in Guyana. Women speaking in Creole and French or/and those with a high school level education and more would be less asked about their alcohol consumption. Finally, these women with a high school degree or more believe that they have had information about alcohol risk during school or through prevention campaigns, while those with a primary education level would have been better informed by health professionals. DISCUSSION: The low tobacco consumption of women in Guyana is in line with that of all the FODs. Alcohol consumption during pregnancy seems slightly higher than in metropolitan France. Alcohol users have specific profiles, linked to the isolation of the municipality of residence, a low level of education, traditional consumption of Pemba and previous experience of miscarriage. The prevalence of Pemba use is a source of concern for professionals, especially when associated with beer consumption. Mobilization of local teams on the issue of alcohol during pregnancy is strong. However, professionals tend to interview women in lower Professions and Socioprofessional Categories, or PCS, more often, as in metropolitan France, with a level of education below the high school degree or whose mother tongue differs from French or French Creole.

[Tabacco, alcohol and pemba consumption during pregnancy in French Guyana]. / Les consommations de tabac, d'alcool et de pemba pendant la grossesse en Guyane française.

INTRODUCTION: The risks to the unborn child from maternal consumption of alcohol, tobacco and substances during pregnancy are well documented in the medical literature. Data on such consumption in Frensh Guyana are scattered and scarce, which prevents prevention policies from being adapted to the local context. METHOD: To compensate for the inadequacy of the data, a questionnaire survey was conducted in 2017-2018 in Guyana's three maternity units with 789 mothers. Among other things, this survey aimed at gathering data about consumption, about information received on substance consumption during pregnancy, and about the interest of professionals met by the women in these matters. RESULTS: Tobacco and alcohol consumption at the end of pregnancy were respectively 2% and 17%. Two profiles of alcohol consumers emerged: in Cayenne, French women with a high school level of education or more consuming on occasion wine and in Saint-Laurent-du-Maroni, regular beer consumers among women speaking a language of the river, born in Guyana. Finally, Pemba (clay) was used by 15% of the pregnant women. Although the percentage of smokers is much lower than that of metropolitan France, the percentage of alcohol consumers is significantly higher in Guyana. Women speaking in Creole and French or/and those with a high school level education and more would be less asked about their alcohol consumption. Finally, these women with a high school degree or more believe that they have had information about alcohol risk during school or through prevention campaigns, while those with a primary education level would have been better informed by health professionals. DISCUSSION: The low tobacco consumption of women in Guyana is in line with that of all the FODs. Alcohol consumption during pregnancy seems slightly higher than in metropolitan France. Alcohol users have specific profiles, linked to the isolation of the municipality of residence, a low level of education, traditional consumption of Pemba and previous experience of miscarriage. The prevalence of Pemba use is a source of concern for professionals, especially when associated with beer consumption. Mobilization of local teams on the issue of alcohol during pregnancy is strong. However, professionals tend to interview women in lower Professions and Socioprofessional Categories, or PCS, more often, as in metropolitan France, with a level of education below the high school degree or whose mother tongue differs from French or French Creole.

Warning about drinking during pregnancy: lessons from the French experience.

BACKGROUND: In France, since 2007, there is a compulsory warning recommending abstinence during pregnancy on every container of alcohol. Awareness of this warning, which consists of a small pictogram, is unknown. The aim of this study was to assess awareness of the warning and risk perceptions about prenatal drinking in pregnant and postpartum women. METHODS: A cross-sectional survey was carried out by telephone five years after the introduction of the warning label. A total of 3603 pregnant or postpartum French women participated. A quota sampling method was used to ensure the sample reflected the population. Multivariate analyses examined the characteristics associated with knowledge of risks and with awareness of the warning label. RESULTS: The warning label had been noticed by 66.1% of women and 77.3% of drinkers. Of those who had noticed the warning, 98.6% thought that it suggested abstinence. Overall, 40.8% of the women thought that spirits were more harmful than wine or beer, and 8.9% thought that drinking beer was recommended for lactation. CONCLUSION: Awareness of the warning is high but knowledge about the risks associated with wine and beer is poor. PRACTICE IMPLICATIONS: Future information campaigns should educate women about standard drinks and their pure alcohol equivalent. They should emphasize the risks associated with drinking during breastfeeding.

Basic Beliefs About Behavioural Addictions Among Finnish and French Treatment Professionals.

The ways in which addictive behaviours are perceived may decisively influence the ways they are handled. This study explores how treatment professionals' cultural and other background variables influence their beliefs about gambling and Internet addictions. Mailed surveys were conducted with addiction treatment professionals in Finland (n = 520) in 2007-2008 and France (n = 472) in 2010-2011. The data were analysed by descriptive statistical methods and logistic regression analysis. Cultural differences were the most consistent predictors of the responses concerning gambling and Internet addictions. The French professionals assessed the dependence risk in these behaviours as higher (P < 0.001) and they believed less than the Finns in the power of treatment (P < 0.001). The latter attributed more responsibility to the individual for solving these non-substance addictions (P < 0.001). The general views of gambling and Internet addictions mostly resembled each other but they varied with culture. The Finnish professionals' lower concern for the risk of dependence and the French professionals' distrust in treatment together with both groups' tendency to blame the individual for becoming addicted may all reduce professionals' willingness to help people who require treatment for their behavioural addictions.

[Neonaticides in France: analysis of 357 cases identified in the press (1993-2012)]. / Les néonaticides en France : analyse de 357 cas identifiés dans la presse (1993-2012).

Background and objectives: Despite easy access to contraception and child abandonment in France, neonaticides continue to occur and, although rare, are widely publicized. The objective of this study was to characterize neonaticides and their perpetrators over a twenty-year period in France based on cases reported in the press. Methods: 2,319 press articles describing the discovery of a newborn corpse in the regional and national press were extracted from electronic databases or other digital supports. A total of 357 neonaticides were described, corresponding to a mean annual rate of 2.34 per 100,000 births. Results: The mother was identified in 74% of cases. The corpse was usually discovered in the house or garden (35%, mostly in the rubbish bin and 6% in the freezer), but also in the wilds (31%). In almost one-quarter of cases, the mother had suffered a haemorrhage. Most neonates were killed by asphyxiation (35%), direct blows or being thrown out of a window (11%), or drowning (11%). Only 22% of neonates died without the mother's intervention, due to lack of care or neglect. Marked regional disparities were observed, even after calculation of regional rates. The mothers responsible (230 women due to 19 multiple neonaticides) had a mean age of 27.8 years and half of them had at least one other living child. Conclusions: Media coverage of neonaticides and access to electronic databases provide an opportunity to describe a rare phenomenon, for which it is difficult to collect sufficient sample sizes to allow analysis of the perpetrators and court rulings.

A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy.

Vps34 is a phosphoinositide 3-kinase (PI3K) class III isoform that has attracted major attention over the recent years because of its role in autophagy. Herein we describe the biological characterization of SAR405, which is a low-molecular-mass kinase inhibitor of Vps34 (KD 1.5 nM). This compound has an exquisite protein and lipid kinase selectivity profile that is explained by its unique binding mode and molecular interactions within the ATP binding cleft of human Vps34. To the best of our knowledge, this is the first potent and specific Vps34 inhibitor described so far. Our results demonstrate that inhibition of Vps34 kinase activity by SAR405 affects both late endosome-lysosome compartments and prevents autophagy. Moreover, we show that the concomitant inhibition of Vps34 and mTOR, with SAR405 and the US Food and Drug Administration-approved mTOR inhibitor everolimus, results in synergistic antiproliferative activity in renal tumor cell lines, indicating a potential clinical application in cancer.

Treatment Professionals' Basic Beliefs About Alcohol Use Disorders: The Impact of Different Cultural Contexts.

BACKGROUND: The treatment of alcohol abusers in different cultural contexts does not depend only on the methods used but also on the ways in which treatment providers perceive the problem and relate to their clients. OBJECTIVES: This study compares treatment professionals' basic beliefs about alcohol use disorders in two culturally different European countries to find out to what extent these ideas are shaped by the respondents' socio-cultural context, profession, and other background variables. METHODS: Similar postal surveys were conducted among professionals working in specialized addiction treatment units in Finland (n = 520) and France (n = 472). The data were analyzed by descriptive statistical methods and logistic regression analysis. RESULTS: Consistent cultural differences were found in almost all the questions asked and they remained significant even after controlling for the other background factors. The French professionals emphasized the addictiveness of alcohol more than their Finnish colleagues. They also believed less in the chances of recovery and attributed more responsibility for the problem to external factors, while the Finns emphasized individual responsibility. Profession, gender and some other background variables also modified beliefs about specific questions. CONCLUSIONS: Cultural factors shape the ways in which alcohol use disorders are perceived more pervasively than the other background variables. The French professionals' low trust in treatment and the Finnish professionals' lack of concern for the addiction potential of alcohol and stronger tendency to regard the person as responsible for the problem could be seen as potential impediments to effective ways of helping alcohol abusers in these countries.

[Tobacco, alcohol, marijuana and pregnancy: which women are at risk?]. / Tabac, alcool et cannabis pendant la grossesse?: qui sont les femmes à risque??

AIM: Substance use during pregnancy is an important health issue in view of the risks to the unborn child. Predictive factors related to risk behaviors need to be assessed in order to develop prevention strategies. This assessment can also elucidate the relationship between prenatal exposure to substances and the construction of social inequalities in health early in the life course. METHODS: This multicenter study was conducted in 14 maternity wards. Substance use was assessed by means of a self-administered questionnaire. Pregnancy outcomes were extracted from by birth registries. RESULTS: The study included 2,617 women and 2,342 newborns (88.2%). There was a marked contrast between drinkers, who were older, and with a higher socioeconomic status (SES), and smokers, who were younger, with a lower SES. Two patterns of alcohol use were observed. Binge drinking at the beginning of the pregnancy was more likely to be reported by primiparous women who had discovered they were pregnant later than average. This pattern differed from that of low regular alcohol use throughout pregnancy, which was more often reported by multiparous women. One case of FAS was observed. After adjusting for several confounders, a lower birth weight was observed only for children of smokers. The higher SES of drinkers raises the question of the importance of alcohol, compared to tobacco, in the construction of social inequalities in health. CONCLUSION: These results indicate the need for early and targeted interventions.

[Pregnancy and poly-drug use: changes in patient population and care, 1999-2008]. / Grossesse et polyconsommations de substances psychoactives : modifications de la clientèle et des prises en charge, 1999-2008.

Changes in drug use in the general French population over the last decade have also been observed among pregnant women. There have also been significant changes in the treatment of substance users. Data relating to maternal drug use and the treatment of drug-using mothers were collected based on a retrospective cohort of 170 newborns with mothers using at least two different substances. The decrease in the proportion of heroin-users, the rise of opiate maintenance treatments and cannabis, and the development of new forms of treatment are linked to shorter maternity stays for newborns and shorter treatments for neonatal abstinence syndrome. The percentage of preterm births and of children placed in foster care is also on the decrease. Changes in drug use among mothers and new forms of treatment given to mother-infant dyads may account for the decrease in treatment for NAS, the shorter length of hospital stays, and the decreasing number of children placed in foster care.

Pregnancy under subutex (buprenorphine): opinions expressed on French internet forums.

Internet forums record the opinions and advice exchanged about pregnancy under Subutex. Two hundred and fourteen messages under 92 nicknames from four forums, especially dedicated to this subject in France, from August 2005 to July 2008 were collected and analyzed with QSR NIVIVO8. Most of the Internet users were women, pregnant, or with children, using Subutex. Very few professionals took part in them. The analysis of the opinions and representations of this substance, of medical practices, of exchanged advice, particularly on posology, was realized by the construction of a thematic tree.

Alcohol Use During Pregnancy or Breastfeeding: A National Survey in France.

BACKGROUND: Adverse effects are associated with alcohol drinking during pregnancy and breastfeeding. Data are lacking on the size of the population at risk and on the characteristics of women engaging in risky behaviors such as daily consumption or repeated binge drinking. MATERIALS AND METHODS: A cross-sectional survey was carried out by telephone among a nationally representative sample of pregnant and postpartum women. Frequency of alcohol use and binge drinking was retrospectively measured according to distinct time periods. Multivariable regression models were used to identify the characteristics of women reporting risk-taking behaviors. RESULTS: A total of 3,603 women participated. Daily consumption was reported by 0.1% of pregnant women and by 0.4% of breastfeeding women. In early pregnancy, 8.0% of women reported binge drinking (≥1 episode) and 1.2% reported repeated binge drinking (≥3 episodes). Binge drinking was estimated at 1.1% in late pregnancy and at 6.8% during breastfeeding. Characteristics of drinkers varied across these different drinking patterns and subpopulations. Moderate drinking during pregnancy and breastfeeding was associated with higher educational level. Smoking increased with increased frequency of alcohol use. Repeated binge drinking in early pregnancy was associated with late recognition of the pregnancy, while binge drinking in late pregnancy was associated with smoking. CONCLUSIONS: Daily alcohol use during pregnancy or breastfeeding was limited, while binge drinking in early pregnancy was reported by a large proportion of women. Demographic and socioeconomic characteristics of drinkers varied across drinking patterns.

Prospective multicenter observational study of 260 infants born to 259 opiate-dependent mothers on methadone or high-dose buprenophine substitution.

Specialized prenatal care and substitution programs improve the perinatal prognoses of pregnant drug-abusers and their infants. Although methadone is well documented, little is known about high-dose buprenorphine (HDB). This prospective, multicenter (n = 35) observational study included 259 women on maintenance during pregnancy: 39% on methadone and 61% on HDB. Major findings were: 46% of them received good prenatal care; 62% had peridural analgesia; 12.3% delivered prematurely (<37 weeks); mean gestational age, 38.6 weeks; mean birth weight, 2822g. Three-quarters of the newborns developed neonatal abstinence syndrome (NAS) beginning at a mean age of 40h, with the mean maximum Lipsitz score of 9.1 at 72 h; half of them were treated, mainly with morphine hydrochloride. No baby died. Newborns were discharged with their mothers (96%) or placed in foster care (4%). Comparing methadone with HDB, respectively, mean age at the maximum Lipsitz score was 81 h versus 66 h (P = 0.066). The perinatal medical and social prognoses for these 259 drug addicts and their infants appeared to be improved by specialized prenatal care and was similar for methadone or BHD substitution during pregnancy.

Pregnancy under high-dose buprenorphine.

OBJECTIVE: This study was first conducted to compare the consequences of the use of methadone and high-dose buprenorphine in pregnancy in France and secondly to describe the heterogeneity of women under high-dose buprenorphine. This paper focuses on the second point only. STUDY DESIGN: From October 1998 to September 1999, data on pregnancy, delivery outcomes and neonatal parameters were collected for 251 addicted women on methadone or high-dose buprenorphine (HDB) substitution followed in 35 hospitals and clinics in continental France. Then the data of 159 women who had been taking HDB during pregnancy and had delivered 160 live infants were analyzed. RESULTS: Most of these women were treated as outpatients by general practitioners. 43% of them belong to what we considered a "hidden population" of drug users: most of them were native French citizens, who lived with the future fathers in their own homes, had at least some secondary education, and were usually not followed in specialized centers for drug addicts. Almost all the women smoked every day during their pregnancies; 20% used heroin during the last 4 weeks preceding delivery; 16% admitted having injected HDB at least once. Notably, neither the severity nor the duration of the neonatal abstinence syndrome (NAS) seemed to be related to the daily doses of the substitution agent. Half of the newborns were treated for NAS, mainly with morphine hydrochloride. CONCLUSION: Although two different populations of women were clearly identified, 64 with no social disadvantage and 95 socially disadvantaged, there was no difference between the groups as for the severity of NAS which was only related to the mothers' compliance with a programme of treatment against addiction.