Social determinants of antidepressant continuation during pregnancy in the USA: findings from the ABCD cohort study.

PURPOSE: Patients and healthcare professionals overestimate the risks of using antidepressants during pregnancy. According to current literature, approximately half of people stop taking an anti-depressant medication when they become pregnant. Discontinuing antidepressants during pregnancy increases risks of postnatal relapses. Factors like socioeconomic status, education, and planned pregnancies play a role in the decision to continue antidepressant medication, which can worsen disparities in maternal and child health. Our aim was to identify the sociodemographic factors associated with antidepressant continuation after awareness of pregnancy. METHODS: We used representative data from the Adolescent Brain Cognitive Development (ABCD) study that captures maternal medication during pregnancy. We identified women who used antidepressants before awareness of their pregnancy. We calculated crude and adjusted associations between sociodemographic factors and continuation of antidepressant medication during pregnancy. Our model included age, education, ethnicity, first language, household income, living with a partner, having planned the pregnancy, pregnancy duration and smoking during pregnancy. RESULTS: In total, 199 women continued antidepressants and 100 discontinued. The logistic regressions resulted in only one significant factor: first language. Native English speakers were more likely to continue medication than other mothers (adjusted OR = 14.94, 95% CI = [2.40; 291.45], p = .015). CONCLUSIONS: Language differences were associated with continuation of antidepressants. Non-native English speakers were more likely to discontinue antidepressants, which may lead to health inequities. This finding should be taken into account to reinforce information about the limited risks of antidepressants among people with non-English speaking backgrounds in the USA.

Nurses and the doctorate: A mixed study in French health care organizations.

AIM: This research aims to understand the place and role of nurses holding a PhD or PhD students (nurse doctor [ND]/nurse doctoral students [NDS]) in health care organizations in France. CONTEXT: Worldwide, many nurses are undertaking doctoral studies. France is no exception. However, in France, there is no doctorate dedicated to nursing. The question of ND/NDS integration into health organizations is thus raised in a specific manner. METHODS: We used a two-stage mixed methodology. The first stage used data from questionnaires that were sent to 165 ND/NDS in France. To contextualize issues raised by these data, we used qualitative methods which comprised 45 semi-structured interviews with nurses, 10 interviews with health managers and chief nurses and 27 h of in situ observations with research coordinators. RESULTS: Seventy-nine participants (47.9% response rate) completed questionnaires. The data showed that work organization in some departments-intensive care units (ICUs), oncology and psychiatry-favoured the development of scientific expertise among nurses. Favourable elements promoting the professional and academic development of ND/NDS included the potential for medical teaching in healthcare services, participation in research projects and, most importantly, medical proximity. Conversely, our data also identified poor visibility and recognition of nursing doctoral courses in French health organizations: A lack of task missions, a lack of suitable posts and poor integration into the nursing profession. Currently, French nurses define their profession as providing direct care to patients and their families-yet this definition fails to consider other important professional elements, such as research. CONCLUSIONS: Our study identified how proper ND/NDS integration is important to health care organizations. We identified key organization factors facilitating the integration of ND/NDS, such as participating in research teams and providing research support management. IMPLICATIONS FOR NURSING MANAGEMENT: In recent years, the nursing profession has significantly evolved. We are interested in the impact of these changes in work organizations following the development of new scientific skills. Our study investigates all aspects of the nursing profession (teaching, practice, research and organizations). Our study advocates managerial roles, among others, to improve ND and NDS integration into work organizations. We directly observed work organizations that helped develop nursing research. Our study is also aimed at managers who have roles as decision-makers in promoting and facilitating research and nurse researchers.

Validity of the older people quality of life-7 domains (OQoL-7) scale.

BACKGROUND: The Older people Quality of Life-7 domains (OQoL-7) is a 28-item multidimensional questionnaire developed to measure community-dwelling older people's QoL. The OQoL-7 assesses both importance of and satisfaction in seven QoL domains (Material resources; Close entourage; Social and cultural life; Esteem and recognition; Health and mobility; Feeling of safety; and Autonomy). This study aimed to investigate concurrent and construct validity of the OQoL-7. A secondary aim was to compare different methods of weighting participants' ratings of satisfaction according to their individual ratings of importance, as compared to the OQoL-7 total score (unweighted). METHODS: Data came from the first and second samples of the Lausanne cohort 65+ study, assessed at the same age of 72-77 years in 2011 (N = 1117) and 2016 (N = 1091), respectively. To assess concurrent validity, the OQoL-7 was compared to other measures of the same concept (single QoL item) or related concepts (self-rated health, SF-12). Construct validity was tested by comparing subscores in the seven QoL domains in the presence and absence of two stressful events during the preceding year (financial difficulties and relationship difficulties). The effect of importance weighting was assessed using moderated regression analysis. RESULTS: The OQoL-7 total score was significantly associated with the single QoL item (Spearman's rho 0.46), self-rated health (Spearman's rho 0.34), SF-12 physical (Spearman's rho 0.22) and mental (Spearman's rho 0.28) component scores. Large differences (Cohen's d > 0.8) were observed in the presence or absence of stressful events in the expected QoL domains: "Material resources" in the presence or absence of "Financial difficulties" (Cohen's d 1.34), and "Close entourage" in the presence or absence of "Relationship difficulties" (Cohen's d 0.84). Importance weighting resulted in a very small improvement in the prediction of the single QoL item (ΔR2 0.018). All results were highly consistent across 2011 and 2016 samples. CONCLUSIONS: The OQoL-7 showed adequate concurrent and construct validity in two samples of older people. In future studies, the decision to use weighted or unweighted scores will depend on the priority given to either optimizing the prediction of QoL or limiting the burden on respondents and the amount of missing data.

Detecting computer-generated random responding in questionnaire-based data: A comparison of seven indices.

With the development of online data collection and instruments such as Amazon's Mechanical Turk (MTurk), the appearance of malicious software that generates responses to surveys in order to earn money represents a major issue, for both economic and scientific reasons. Indeed, even if paying one respondent to complete one questionnaire represents a very small cost, the multiplication of botnets providing invalid response sets may ultimately reduce study validity while increasing research costs. Several techniques have been proposed thus far to detect problematic human response sets, but little research has been undertaken to test the extent to which they actually detect nonhuman response sets. Thus, we proposed to conduct an empirical comparison of these indices. Assuming that most botnet programs are based on random uniform distributions of responses, we present and compare seven indices in this study to detect nonhuman response sets. A sample of 1,967 human respondents was mixed with different percentages (i.e., from 5% to 50%) of simulated random response sets. Three of the seven indices (i.e., response coherence, Mahalanobis distance, and person-total correlation) appear to be the best estimators for detecting nonhuman response sets. Given that two of those indices-Mahalanobis distance and person-total correlation-are calculated easily, every researcher working with online questionnaires could use them to screen for the presence of such invalid data.

Substance Use in Young Swiss Men: The Interplay of Perceived Social Support and Dispositional Characteristics.

BACKGROUND: Social environment plays a central role in substance use behaviors. However, it is not clear whether its role varies as a function of individual dispositional characteristics. OBJECTIVES: To investigate the interaction between dispositional characteristics (i.e. sensation seeking, anxiety/neuroticism) and social environment (i.e. perceived social support [PSS]) in association with substance use. METHODS: A representative sample of 5,377 young Swiss males completed a questionnaire assessing substance use, sensation seeking, anxiety/neuroticism, and PSS from friends and from a significant other. RESULTS: Sensation seeking and anxiety/neuroticism were positively related to most substance use outcomes. PSS from friends was significantly and positively related to most alcohol and cannabis use outcomes, and significantly and negatively associated with the use of hard drugs. PSS from a significant other was significantly and negatively associated with most alcohol and cannabis use outcomes. The associations of sensation seeking with drinking volume, alcohol use disorder and the use of illicit drugs other than cannabis were stronger in individuals reporting high levels of PSS from friends than those with low levels. The associations of sensation seeking with risky single-occasion drinking and the use of hard drugs were weaker in participants reporting high levels of PSS from a significant other than in those with low levels. CONCLUSIONS: Sensation seeking and anxiety/neuroticism may constitute risk factors for substance use and misuse. PSS from friends may amplify the risk for alcohol and illicit drug use (other than cannabis) associated with high sensation seeking, whereas the PSS from a significant other may reduce it.

Subthreshold problem drinkers in DSM-5 alcohol use disorder classification.

BACKGROUND AND OBJECTIVES: The DSM-5 defined alcohol use disorder (AUD) to better cover undiagnosed subthreshold alcohol users, but few studies have investigated this topic. This study aimed to test whether subthreshold problem drinkers were a distinct subgroup of undiagnosed drinkers according to the DSM-5 AUD classification by investigating drinking patterns and longitudinal trajectories. METHODS: Data were collected in the Cohort Study on Substance Use Risk Factors from young Swiss men in their early twenties (n = 4,630) at two time points. Participants responded to the 11 criteria of the DSM-5 AUD and to variables related to drinking patterns. RESULTS: Among drinkers, 23.2% and 23.5% of the participants were subthreshold problem drinkers at baseline and follow-up, respectively. The trends showed that 29.4% of them remained subthreshold problem drinkers over time. Those who remained subthreshold problem drinkers or progressed to AUD status were likely to meet the same criterion/add a new one. Subthreshold problem drinkers showed concurrent and later drinking patterns that were in between those of symptom-free drinkers and AUD drinkers. DISCUSSION AND CONCLUSION: Subthreshold problem drinkers were an important subgroup of drinkers with risky drinking patterns, but they did not necessarily progress to later AUD status and did not appear to be a consistent subgroup over time. SCIENTIFIC SIGNIFICANCE: Subthreshold problem drinkers did not seem to be a subgroup of undiagnosed problem drinkers in the current DSM-5 classification. The results showed that AUD appeared to be a dimensional construct, in which one additional criterion was associated with worse alcohol-related outcomes. (Am J Addict 2016;25:408-415).

Is the relationship between major depressive disorder and self-reported alcohol use disorder an artificial one?

AIMS: Many studies have suggested a close relationship between alcohol use disorder (AUD) and major depressive disorder (MDD). This study aimed to test whether the relationship between self-reported AUD and MDD was artificially strengthened by the diagnosis of MDD. This association was tested comparing relationships between alcohol use and AUD for depressive people and non-depressive people. METHODS: As part of the Cohort Study on Substance Use Risk Factors, 4352 male Swiss alcohol users in their early twenties answered questions concerning their alcohol use, AUD and MDD at two time points. Generalized linear models for cross-sectional and longitudinal associations were calculated. RESULTS: For cross-sectional associations, depressive participants reported a higher number of AUD symptoms (ß = 0.743, P < 0.001) than non-depressive participants. Moreover, there was an interaction (ß = -0.204, P = 0.001): the relationship between alcohol use and AUD was weaker for depressive participants rather than non-depressive participants. For longitudinal associations, there were almost no significant relationships between MDD at baseline and AUD at follow-up, but the interaction was still significant (ß = -0.249, P < 0.001). CONCLUSION: MDD thus appeared to be a confounding variable in the relationship between alcohol use and AUD, and self-reported measures of AUD seemed to be overestimated by depressive people. This result brings into question the accuracy of self-reported measures of substance use disorders. Furthermore, it adds to the emerging debate about the usefulness of substance use disorder as a concept, when heavy substance use itself appears to be a sensitive and reliable indicator.

Associations of physical activity and sport and exercise with at-risk substance use in young men: a longitudinal study.

OBJECTIVE: This study aims to measure the associations of physical activity and one of its components, sport and exercise, with at-risk substance use in a population of young men. METHOD: Baseline (2010-2012) and follow-up (2012-2013) data of 4748 young Swiss men from the Cohort Study on Substance Use Risk Factors (C-SURF) were used. Cross-sectional and prospective associations between at-risk substance use and both sport and exercise and physical activities were measured using Chi-squared tests and logistic regression models adjusting for covariates. RESULTS: At baseline, logistic regression indicated that sport and exercise is negatively associated with at-risk use of cigarettes and cannabis. A positive association was obtained between physical activity and at-risk alcohol use. At baseline, sport and exercise was negatively associated with at-risk use of cigarettes and cannabis at follow-up. Adjusted for sport and exercise, physical activity was positively associated with at-risk use of cigarettes and cannabis. CONCLUSION: Sport and exercise is cross-sectionally and longitudinally associated with a low prevalence of at-risk use of cigarettes and cannabis. This protective effect was not observed for physical activity broadly defined. Taking a substance use prevention perspective, the promotion of sport and exercise among young adults should be encouraged.

Validation of the post-delivery perceived stress inventory.

This article presents the post-delivery perceived stress inventory (PDPSI) and its psychometric properties. This inventory is unique in that it links the measurement of perceived stress to events experienced during and after delivery. A total of 235 French-speaking, primiparous mothers completed the PDPSI two days after their delivery. To evaluate the predictive validity of the PDPSI on anxiety and depression, participants also completed the EPDS and the STAI two days and six weeks postpartum. The exploratory analysis revealed a 16-item structure divided into five factors: F1: relationship with the child; F2: delivery; F3: fatigue after delivery; F4: breastfeeding; and F5: relationship with the caregivers. The PDPSI demonstrated good internal consistency. Moreover, confirmatory factor analysis produced excellent indices, indicating that the complexity of the PDPSI was taken into account and its fit to the sample. The discriminant analysis showed that the PDPSI was not sensitive to specific changes in the sample making the inventory generalizable to other populations. Predictive validity showed that the scale significantly predicted depression and anxiety in the early postpartum period as well as anxiety six weeks postpartum. Overall, the PDPSI showed excellent psychometric qualities, making it a useful tool for future research-evaluating interventions related to perceived stress during the postpartum period.

Implementation and Evaluation of a Training Program for Traditional Healers to Improve Knowledge of Noma (Cancrum Oris) in Burkina Faso.

Noma (cancrum oris) is an orofacial gangrene affecting young children living in extreme poverty. The acute morbidity is high, and survivors suffer from physical and social sequelae. When diagnosed early, noma can be cured. Noma is especially prevalent in sub-Saharan Africa, where traditional medicine is the norm. The aim of this work was to provide 1-day training to traditional healers in Burkina Faso and to evaluate change in knowledge of noma across time. A sample of 78 healers who attended the training were asked to complete the same questionnaire before, immediately after, and 8 months after the training. A total of 66 healers completed the entire study. Before training, more than 40% of the participants did not know any of its key messages. Most of the key messages were acquired and still present after 8 months by a large proportion of the participants. Systematic intraoral examination was practiced by 7 (9.0%) of the traditional healers before training, and 43 (65.2%) reported doing so 8 months after training. The key messages aiming to improve early diagnosis as well as rapid and adequate treatment (the recognition of facilitating factors and the need to perform a systematic oral examination and to advise hospital transfer) have been well integrated. The study suggests that organizing a self-managed training program is feasible when done within an association, as was the case here, and owing to the willingness to collaborate shown by the traditional healers who participated in our study.

Swiss cohort on Traumatic Childbirth and Health (SwiTCH): protocol for a prospective, population-based cohort study on parents' mental health from pregnancy to one year postpartum.

INTRODUCTION: Approximately 4%-5% of mothers develop childbirth-related post-traumatic stress disorder (CB-PTSD) and approximately 12.3% of mothers develop some CB-PTSD symptoms (CB-PTSS). To date, there is a dearth of studies on fathers and other coparents. Parental CB-PTSD and CB-PTSS may have a negative impact not only on the parents but also on the infant. Understanding risk and protective factors of CB-PTSD for both parents and its consequences on the family is key to detecting or anticipating it, to developing interventions aimed at reducing its detrimental effects and to supporting parents. METHODS AND ANALYSIS: This study protocol describes an observational, population-based study, consisting of a longitudinal prospective cohort with online surveys at four time points. The population of interest consist of women, in the third trimester of pregnancy or at 6-12 weeks postpartum, and their partner/coparent, who will give birth or gave birth in the French-speaking part of Switzerland. The target sample size is 300-500 women and a proportional number of partners. The primary outcome of this study is the prevalence of CB-PTSD and CB-PTSS. The secondary outcomes focus on: (1) the impact of CB-PTSD and CB-PTSS on the marital and coparental relationships, the bonding with the infant, parental burnout and healthcare seeking behaviours, (2) the role of the childbirth experience in the development of CB-PTSD and CB-PTSS and (3) the social and economic determinants of CB-PTSD and CB-PTSS. ETHICS AND DISSEMINATION: Ethical approval was granted by the human research ethics committee of the Canton de Vaud (study number 2022-00284). All study participants signed an informed consent form. Dissemination of results will occur via national and international conferences, in peer-reviewed journals, public conferences and social media. TRIAL REGISTRATION NUMBER: NCT05865704.

Challenges and opportunities in neonatal sepsis management: insights from a survey among clinicians in 25 Sub-Saharan African countries.

BACKGROUND: Neonatal sepsis (NS) is a global health issue, particularly in Sub-Saharan Africa, where it accounts for a substantial portion of neonatal morbimortality. This multicountry survey aimed to elucidate current practices, challenges and case definitions in managing NS among clinicians in Sub-Saharan Africa. METHODS: The survey targeted physicians and medical practitioners working in neonatal care who participated in a Self-Administered Web Questionnaire. The main objective was to understand NS and infection case definitions and management from the clinician's point of view and to identify challenges and opportunities in sepsis management. Participants were queried on demographics, definitions and diagnostic criteria, treatment approaches, and infection prevention and control (IPC) measures. A total of 136 participants from 93 healthcare structures responded, providing valuable insights into NS management practices. RESULTS: From May to July 2022 across 21 Sub-Saharan African countries, 136 neonatal clinicians with an average from 93 structures with on average 10-year experience took the survey. NS ranked highest among prevalent neonatal conditions. Diagnostic case definitions between sepsis and infection were attributed to clinical signs, anamnesis, C reactive protein, white blood cll count and blood cultures with no statistically significant differences. Early-onset sepsis was defined within 72 hours by 48%, while late-onset varied. Antibiotics were likely on admission (86.4%) and during the stay (82.2%). Treatment abandonment was reported unlikely. The preferred antibiotic regimen for early-onset sepsis was intravenous amoxicillin (or ampicillin), gentamycin and cefotaxime. Blood culture availability and IPC protocols were reported as limited, particularly concerning patient environment, pharmacy protocols and clean-dirty circuits. CONCLUSIONS: This NS survey emphasises clinicians' challenges due to limited access to diagnostic tools and raises concerns about antimicrobial overexposure. IPC also seem limited, according to participants. Addressing these challenges can enhance diagnostic practices, antibiotic stewardship and infection control in the region.

Was retrospective change measurement conducted with Covid-19 containment inconsistent? Comparing prospective and retrospective change measures using data from a national survey on substance use and addictive behaviors.

Single-measurement-point data collection to assess change has increased with studies assessing the impact of the Covid-19 pandemic and of its containment, despite evidence of its lack of validity. Retrospective change is not equivalent to change in repeated self-reported measures giving raise to questions about the validity of the former. This paper purports to investigate inconsistencies between change measures by confronting retrospective change to information from longitudinally self-reported measures from the C-SURF cohort study. The study sample consists of 2,279 young men who participated in C-SURF between 2020 and 2021, and completed between May and June 2021 a survey covering change in alcohol, cigarette, cannabis and other addictive behaviors related to the pandemic. The aforementioned behaviors were assessed longitudinally at two time points using self-reports, and retrospective change since the onset of the Covid-19 crisis was also assessed at the second measurement time. Information from both prospective and retrospective change measures were confronted to identify inconsistent information for each behavior. Additionally, multiple logistic regressions were performed to assess associations between socioeconomic status, impulsivity, depression, and different indicators of motivation to complete the study and inconsistency between both measures for each behavior of interest. Importantly, inconsistent information in at least one of the investigated behaviors was found in about 90% of the participants. Small associations were found between inconsistency and different factors with a consistent effect of impulsivity. In the absence of evidence of the validity of retrospective change measures, studies relying on retrospective change should be interpreted with caution.

Associations of binge gaming (5 or more consecutive hours played) with gaming disorder and mental health in young men.

Background: Video gaming is a popular activity among young people. Time spent with gaming was found to be only moderately associated with gaming disorder. However, patterns of binge gaming (playing more than 5 h consecutively) were rarely considered in research on gaming. This study explores how binge gaming frequency is related with gaming disorder and mental health. Methods: The sample came from the Cohort study on substance use risk factors (C-SURF) and comprised 5,358 young men aged 28.26 years (SD = 1.27). ANCOVA was conducted to estimate the association between binge gaming frequency (gaming at least 5 h consecutively) and gaming disorder (measured with the Game Addiction Scale) as well as indicators of mental health. Results: A total of 33.3% of the sample engaged in binge gaming at least once in the previous year, and 6.1% at least weekly. Frequency of binge gaming was associated with gaming disorder score in a linear dose-response relationship (linear trend = 2.30 [2.14, 2.46]) even if adjusted for time spent gaming (linear trend = 1.24 [1.03, 1.45). More frequent binge gaming was associated with lower life satisfaction and sleep quality, and with more major depression and social anxiety disorder symptoms. Conclusions: Binge gaming patterns, especially daily or almost daily binge gaming, are important to consider with regard to gaming disorder and mental health. Asking about binge gaming may be a promising screening question for gaming related problems. Encouraging regular breaks from gaming may be a valuable prevention strategy to reduce negative outcomes of gaming.

Economic and Social Costs of Noma: Design and Application of an Estimation Model to Niger and Burkina Faso.

BACKGROUND: While noma affects hundreds of thousands of children every year, taking their lives, disfiguring them and leaving them permanently disabled, the economic and social costs of the disease have not been previously estimated. An understanding of the nature and levels of these costs is much needed to formulate and implement strategies for the prevention and control of this disease, or to mitigate its burden. The objectives of our study were to develop a model for estimating the economic and social costs of noma and to provide estimates by applying this model to the specific contexts of two countries in the "noma belt", namely Burkina Faso and Niger. METHODS: Three main approaches were used. The estimation of prevalence levels of potential noma cases and of cases that should receive and actually do receive medical care was carried out using a literature review. The documentary approach made it possible to estimate the direct costs of noma by analyzing the database of a non-governmental organization operating in this field and present in both countries. Indirect costs were estimated using the human capital method and the cost component analysis technique. RESULTS: The direct costs of care and management of noma survivors amount to approximately USD 30 million per year in Burkina Faso, compared to approximately USD 31 million in Niger. They mainly include costs for medical treatment, surgery, hospital stays, physiological care, psychological care, social assistance, schooling, vocational training and care abroad. Indirect costs are estimated at around 20 million in lost production costs in Burkina and around 16 million in Niger. Costs related to premature deaths are estimated at more than USD 3.5 billion in Burkina Faso and USD 3 billion in Niger. Finally, the costs to survivors who are unable to marry are around USD 13.4 million in Burkina and around USD 15 million in Niger. Intangible costs were not calculated. CONCLUSIONS: The neglect of noma and inaction in terms of prevention and control of the disease have enormous economic and social costs for households, communities and states. Future studies of this kind are necessary and useful to raise awareness and eradicate this disease, which impacts the health and well-being of children and results in lifelong suffering and severe economic and social costs to survivors and their families.

Noma: Experiences of Survivors, Opinion Leaders and Healthcare Professionals in Burkina Faso.

The scientific literature on noma (Cancrum Oris) has clearly increased in recent decades, but there seems to have been limited analysis of issues around the psycho-social impacts of this disease. Even when these issues have been addressed, the focus has tended to be on patient experiences, whereas the community dimension of the disease and the role of healthcare professionals and community leaders in mitigating these impacts remain largely unexplored. A study in the form of semi-directed interviews with 20 noma survivors and 10 healthcare professionals and community leaders was conducted between January and March 2021 in Burkina Faso with the aim of describing the experiences of noma survivors, generating knowledge about living with the burden of the disease and understanding the attitudes of community leaders towards the disease. The results reveal that noma is a disease that affects economically vulnerable populations and leads to extreme household poverty. As far as treatment is concerned, patients tend to turn to practitioners of both traditional and modern medicine. Within communities, noma survivors face discrimination and stigma. The study highlighted a lack of information and knowledge about noma. However, surgical operations lead to patient satisfaction and these remain one of the coping strategies used to tackle the stigma and discrimination. The recommendations set out in this article are aimed firstly at stepping up research into the psycho-social impacts of noma, and secondly at considering these impacts in regional programmes and national plans to combat the disease.

The NAD biosynthesis inhibitor APO866 has potent antitumor activity against hematologic malignancies.

APO866 inhibits nicotinamide phosphoribosyltransferase (NMPRTase), a key enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis from the natural precursor nicotinamide. Intracellular NAD is essential for cell survival, and NAD depletion resulting from APO866 treatment elicits tumor cell death. Here, we determine the in vitro and in vivo sensitivities of hematologic cancer cells to APO866 using a panel of cell lines (n = 45) and primary cells (n = 32). Most cancer cells (acute myeloid leukemia [AML], acute lymphoblastic leukemia [ALL], mantle cell lymphoma [MCL], chronic lymphocytic leukemia [CLL], and T-cell lymphoma), but not normal hematopoietic progenitor cells, were sensitive to low concentrations of APO866 as measured in cytotoxicity and clonogenic assays. Treatment with APO866 decreased intracellular NAD and adenosine triphosphate (ATP) at 24 hours and 48 to72 hours, respectively. The NAD depletion led to cell death. At 96 hours, APO866-mediated cell death occurred in a caspase-independent mode, and was associated with mitochondrial dysfunction and autophagy. Further, in vivo administration of APO866 as a single agent prevented and abrogated tumor growth in animal models of human AML, lymphoblastic lymphoma, and leukemia without significant toxicity to the animals. The results support the potential of APO866 for treating hematologic malignancies.

Anti-cancer activity of 5-O-alkyl 1,4-imino-1,4-dideoxyribitols.

New derivatives of 1,4-dideoxy-1,4-imino-D-ribitol have been prepared and evaluated for their cytotoxicity on solid and haematological malignancies. 1,4-Dideoxy-5-O-[(9Z)-octadec-9-en-1-yl]-1,4-imino-D-ribitol (13, IC(50) ∼2 µM) and its C(18)-analogues (IC(50) <10 µM) are cytotoxic toward SKBR3 (breast cancer) cells. 13 also inhibits (IC(50) ∼8 µM) growth of JURKAT cells.

Resistance to FasL and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in Sezary syndrome T-cells associated with impaired death receptor and FLICE-inhibitory protein expression.

Because of the low proliferative potential of tumor cells in patients with Sézary syndrome (SzS), their accumulation has been suggested to be due to defective regulation of apoptosis. We analyzed the sensitivity to soluble Fas-ligand (FasL) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), 2 members of the TNF superfamily in peripheral blood leukocytes (PBL) from patients with SzS. Compared with healthy donors, CD4(+) cells from patients with SzS were completely resistant to FasL in 9 of 16 cases. Of these 9 FasL-resistant cases, 4 revealed a loss in Fas (CD95) expression, whereas the remaining 5 exhibited normal or enhanced Fas expression. In the latter 5 cases, the apoptosis inhibitor cFLIP was overexpressed in CD4(+)/CD26(-) tumor cells compared with CD4(+)/CD26(-) cells from Fas-expressing FasL-sensitive patients and healthy donors. Furthermore, resistance to TRAIL and tumor cell-restricted loss of TRAIL-receptor 2 were observed in 16 of 16 SzS PBLs. It is noteworthy that resistance to FasL could be overcome by the use of a hexameric FasL or upon exposure of SzS cells to interferon-alpha (IFN-alpha) or IFN-gamma, the latter by an increase of Fas expression. Our data on primary SzS lymphocytes reveal frequent resistance to apoptosis induced by FasL and TRAIL, which may contribute to their accumulation in patients with SzS and be relevant at a therapeutic level.

Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as alpha-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies.

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.