Characterization of pSer129-αSyn Pathology and Neurofilament Light-Chain Release across In Vivo, Ex Vivo, and In Vitro Models of Pre-Formed-Fibril-Induced αSyn Aggregation.

Protein aggregation is a predominant feature of many neurodegenerative diseases, including synucleinopathies, which are characterized by cellular inclusions containing α-Synuclein (αSyn) phosphorylated at serine 129 (pSer129). In the present study, we characterized the development of αSyn pre-formed fibril (PFF)-induced pSer129-αSyn pathology in F28tg mice overexpressing human wild-type αSyn, as well as in ex vivo organotypic cultures and in vitro primary cultures from the same mouse model. Concurrently, we collected cerebrospinal fluid (CSF) from mice and conditioned media from ex vivo and in vitro cultures and quantified the levels of neurofilament light chain (NFL), a biomarker of neurodegeneration. We found that the intra-striatal injection of PFFs induces the progressive spread of pSer129-αSyn pathology and microglial activation in vivo, as well as modest increases in NFL levels in the CSF. Similarly, PFF-induced αSyn pathology occurs progressively in ex vivo organotypic slice cultures and is accompanied by significant increases in NFL release into the media. Using in vitro primary hippocampal cultures, we further confirmed that pSer129-αSyn pathology and NFL release occur in a manner that correlates with the fibril dose and the level of the αSyn protein. Overall, we demonstrate that αSyn pathology is associated with NFL release across preclinical models of seeded αSyn aggregation and that the pharmacological inhibition of αSyn aggregation in vitro also significantly reduces NFL release.

Hair cortisol concentrations in pregnant women with bipolar, depressive, or schizophrenic spectrum disorders.

PURPOSE: Maternal cortisol levels in pregnancy may support the growth of or adversely affect fetal organs, including the brain. While moderate cortisol levels are essential for fetal development, excessive or prolonged elevations may have negative health consequences for both the mother and the offspring. Little is known about predictors of altered hypothalamic-pituitary-adrenal (HPA) axis activity during pregnancy. This study examined maternal hair cortisol concentration (HCC) in the 3rd trimester of pregnancy in relation to severe psychopathology. METHODS: Hair samples were collected from 69 women, 32 with a lifetime diagnosis of severe mental disorders (bipolar I or II disorder, moderate or severe depressive disorder, schizophrenic spectrum disorder), and 37 non-clinical controls. Hair samples were collected during the 3rd trimester, and liquid chromatography tandem mass spectrometry was used for cortisol assessment. Psychiatric diagnosis and current level of symptomatic functioning were assessed using the structured clinical interview from the DSM-5 and the global assessment of functioning scale. RESULTS: Women with a lifetime diagnosis of severe mental illness had significantly elevated HCC compared to controls. Poorer current symptomatic functioning was also significantly associated with elevated HCC in pregnancy. CONCLUSIONS: The implications of alterations in HCC on both maternal and infant health need further study.

Key normative, legal, and policy considerations for supporting pregnant and postpartum adolescents in high HIV-burden settings: a critical analysis.

Rates of adolescent pregnancy within sub-Saharan Africa are increasing. Adolescent mothers ages 10-19 years face a distinct set of risks to their own and their children's health, compounded by many economic, social, and epidemiological challenges, such as living with HIV. In navigating this complex developmental period, many adolescent mothers face structural barriers impeding safe transitions to adulthood and motherhood. Drawing on existing literature and emerging data, we outline three normative, legal, and policy issues - violence and gender inequity, access to sexual and reproductive health services, and access to social and structural supports - which affect the health, wellbeing and development of adolescent mothers and their children. We also highlight emergent evidence about programming and policy changes that can better support adolescent mothers and their children. These key proposed responses include removing barriers to SRH and HIV service integration; ensuring implementation of return-to-school policies; and extending social protection systems to cater for adolescent mothers. Despite ongoing global crises and shifts in funding priorities, these normative, legal, and policy considerations remain critical to safeguard the health and wellbeing of adolescent mothers and their children.

The state of adolescent menstrual health in low- and middle-income countries and suggestions for future action and research.

In recognition of the opportunity created by the increasing attention to menstrual health at global, regional, and national levels, the World Health Organization's Department of Sexual and Reproductive Health and Research and the UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction convened a global research collaborative meeting on menstrual health in adolescents in August 2018. Experts considered nine domains of menstrual health (awareness and understanding; stigma, norms, and socio-cultural practices; menstrual products; water and sanitation; disposal; empathy and support; clinical care; integration with other programmes; and financing) and answered the following five questions: (1) What is the current situation? (2) What are the factors contributing to this situation? (3) What should the status of this domain of adolescent menstrual health be in 10 years? (4) What actions are needed to achieve these goals? (5) What research is needed to achieve these goals? This commentary summarizes the consensus reached in relation to these questions during the expert consultation. In doing so, it describes the state of adolescent menstrual health in low- and middle-income countries and sets out suggestions for action and research that could contribute to meeting the holistic menstrual health needs of adolescent girls and others who menstruate worldwide.

The Political, Research, Programmatic, and Social Responses to Adolescent Sexual and Reproductive Health and Rights in the 25 Years Since the International Conference on Population and Development.

Among the ground-breaking achievements of the International Conference on Population and Development (ICPD) was its call to place adolescent sexual and reproductive health (ASRH) on global health and development agendas. This article reviews progress made in low- and middle-income countries in the 25 years since the ICPD in six areas central to ASRH-adolescent pregnancy, HIV, child marriage, violence against women and girls, female genital mutilation, and menstrual hygiene and health. It also examines the ICPD's contribution to the progress made. The article presents epidemiologic levels and trends; political, research, programmatic and social responses; and factors that helped or hindered progress. To do so, it draws on research evidence and programmatic experience and the expertise and experiences of a wide number of individuals, including youth leaders, in numerous countries and organizations. Overall, looking across the six health topics over a 25-year trajectory, there has been great progress at the global and regional levels in putting adolescent health, and especially adolescent sexual and reproductive health and rights, higher on the agenda, raising investment in this area, building the epidemiologic and evidence-base, and setting norms to guide investment and action. At the national level, too, there has been progress in formulating laws and policies, developing strategies and programs and executing them, and engaging communities and societies in moving the agenda forward. Still, progress has been uneven across issues and geography. Furthermore, it has raced ahead sometimes and has stalled at others. The ICPD's Plan of Action contributed to the progress made in ASRH not just because of its bold call in 1994 but also because it provided a springboard for advocacy, investment, action, and research that remains important to this day.

Hair cortisol in the perinatal period mediates associations between maternal adversity and disrupted maternal interaction in early infancy.

Existing literature points to the possibility that cortisol could be one link between maternal adversity and poorer parenting quality, but most studies have examined salivary cortisol concentrations rather than hair cortisol concentrations. The current study examined hair cortisol concentration (HCC) during the third trimester of pregnancy as a mediator between maternal adversity indicators (childhood abuse, severe mental illness, symptomatic functioning) and maternal caregiving behavior at 4 months postpartum. Forty-four women participated in the study: 30 with severe mental disorders, and 14 nonclinical controls. HCC was assessed during the third trimester of pregnancy (HCC-P) and at 4 months postpartum (HCC-4M). Sexual, physical, and emotional abuse were assessed by the Adverse Childhood Experiences Study Questionnaire. Maternal disrupted interaction was reliably coded from mother-infant video interactions during a Still-Face Procedure. Mediation models indicated that maternal HCC-P and HCC-4M mediated associations between maternal psychopathology (severe mental illness, symptomatic functioning) and maternal disrupted interaction at 4 months. Maternal HCC at 4 months also mediated associations between experienced childhood abuse and overall disrupted interaction. Our findings indicate that HCC may be a potential early biomarker for future caregiving challenges among mothers with severe mental illness and histories of childhood abuse.

Antenatal caregiving representations among expectant mothers with severe mental illness: a cross-sectional study.

Objective: The study explores predictors of antenatal caregiving representations among mothers with a history of severe mental illness (SMI). Background: Attachment research has demonstrated that multifactorial assessment of antenatal caregiving representations predicts later maternal behaviour and child attachment. However, the field lacks research among clinical groups. Knowledge of factors influencing caregiving representations during pregnancy can contribute to our understanding of caregiving risk among SMI-mothers and inform intervention decisions. Method: The current study is a cross-sectional subsample of the WARM study. Participants were 65 Danish or Scottish pregnant women with a history of either schizophrenia, bipolar disorder, moderate-severe depression, or non-clinical controls. Caregiving representations, adverse childhood experiences, social support and current symptom severity were assessed during pregnancy. Results: Symptom severity was associated with more non-optimal caregiving representations expecting less parental enjoyment, more difficulties separating from the child, and more feelings of caregiving helplessness. Lack of social support and adverse childhood experiences served as independent predictors of caregiving representations. Parental mental illness during own childhood predicted role reversed expectations. Conclusion: Antenatal caregiving representations can be assessed with a time-efficient self-report measure that assesses caregiving as a multidimensional construct. Prenatal treatment planning should target individual difficulties in undertaking transformation of the caregiving system.

A Phase I/II Clinical Trial of Belinostat (PXD101) in Combination with Doxorubicin in Patients with Soft Tissue Sarcomas.

Background. Belinostat is a novel histone deacetylase inhibitor. Primary Objectives. Maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) of belinostat (Bel) in combination with doxorubicin (Dox) in solid tumours (phase I) and response rate (RR) in soft tissue sarcomas (phase II). Methods. Bel was administered as a 30-minute IV infusion on days 1-5 and on day 5 with Dox. The dose escalation schedule was as follows: cohort 1: Bel 600 mg/m(2) and 50 mg/m(2) Dox, cohort 2: Bel 600 mg/m(2) and 75 mg/m(2) Dox, cohort 3: Bel 800 mg/m(2) and 75 mg/m(2) Dox, and cohort 4: Bel 1000 mg/m(2) and 75 mg/m(2) Dox. Results. 41 patients were included (25 in phase I, 16 in phase II). Adverse events were fatigue (95%), nausea (76%), and alopecia (63%). There was one DLT, grade 3 rash/hand and foot syndrome. MTD was Bel 1000 mg/m(2)/d and Dox 75 mg/m(2). Four responses were seen: 2 PR in phase I, RR of 8%; in phase II, 1 PR/1 CR, RR of 13%, and 9 patients (56%) with SD. Conclusion. The combination was well tolerated. Response rate was moderate but median time to progression was 6.0 months (95% CI, 1.6-9.7 months) which is superior to some reports of single-agent Dox.

Wellbeing and resilience: mechanisms of transmission of health and risk in parents with complex mental health problems and their offspring--The WARM Study.

UNLABELLED: The WARM study is a longitudinal cohort study following infants of mothers with schizophrenia, bipolar disorder, depression and control from pregnancy to infant 1 year of age. BACKGROUND: Children of parents diagnosed with complex mental health problems including schizophrenia, bipolar disorder and depression, are at increased risk of developing mental health problems compared to the general population. Little is known regarding the early developmental trajectories of infants who are at ultra-high risk and in particular the balance of risk and protective factors expressed in the quality of early caregiver-interaction. METHODS/DESIGN: We are establishing a cohort of pregnant women with a lifetime diagnosis of schizophrenia, bipolar disorder, major depressive disorder and a non-psychiatric control group. Factors in the parents, the infant and the social environment will be evaluated at 1, 4, 16 and 52 weeks in terms of evolution of very early indicators of developmental risk and resilience focusing on three possible environmental transmission mechanisms: stress, maternal caregiver representation, and caregiver-infant interaction. DISCUSSION: The study will provide data on very early risk developmental status and associated psychosocial risk factors, which will be important for developing targeted preventive interventions for infants of parents with severe mental disorder. TRIAL REGISTRATION: NCT02306551, date of registration November 12, 2014.

"A welfare recipient may be drinking, but as long as he does as told--he may drink himself to death": a qualitative analysis of project implementation barriers among Danish job consultants.

BACKGROUND: This paper is embedded in a randomised controlled trial (Alcohol and Employment) that investigated whether welfare-to-work schemes combined with alcohol treatment were more effective than welfare-to-work schemes alone for helping unemployed welfare recipients with alcohol problems get back to employment and reduce their alcohol problems. The implementation of Alcohol and Employment turned out to be challenging, and fewer welfare recipients than expected were enrolled. The aim of this paper was to identify and investigate obstacles to the implementation of Alcohol and Employment. Our main objective was to study the job consultants' role in the implementation process as they were key personnel in conducting the trial. METHODS: The process evaluation was conducted in four Danish municipalities in 2011-2012. Data for identifying factors important for the implementation were collected through observations and focus group interviews with job consultants. Data were analysed thematically and thoroughly discussed among members of the project team; emerging themes were then grouped and read again repeatedly until the themes were consistent. RESULTS: Three themes emerged as the main factors influencing the degree of implementation of Alcohol and Employment: (1) The job consultants' personal attitudes toward alcohol were an important factor. The job consultants generally did not consider a high alcohol intake to be an impediment to employment, or they thought that alcohol problems were only symptoms of more profound problems. (2) The job consultants' perception of their own roles and responsibilities in relation to the welfare recipients was a barrier: they felt that addressing alcohol problems and at the same time sustaining trust with the welfare recipient was difficult. Also, they did not consider alcohol problems to be their responsibility. (3) Shortage of time and resources among the job consultants was determined to be an influential factor. CONCLUSIONS: We identified important factors at the individual level among the job consultants who threatened the implementation of Alcohol and Employment. Future studies in similar settings can take advantage of these findings when preparing interventions that are implemented by job consultants or similar professionals. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01416103.

Transient serotonin toxicity evoked by combination of electroconvulsive therapy and fluoxetine.

The serotonin syndrome has been described only in rare instances for electroconvulsive therapy combined with an antidepressant medication. We describe a case of serotonin toxicity induced by electroconvulsive therapy in combination with fluoxetine.

Can the municipalities prevent medication of mental diseases?

BACKGROUND: In extension of a large municipality reform in 2007, which reduced the number of Danish municipalities from 275 to 98, it was the intention that the municipalities should assume responsibility for a part of the expenditure connected to secondary sector health care treatment. Furthermore, the municipalities were assigned the responsibility for--and equipped with a number of opportunities for--exerting primary preventive initiatives. AIM OF THE STUDY: To investigate, whether the municipalities by applying these opportunities have been able to prevent medication of mental diseases. Specifically, this is resolved by analysing whether there are significant relationships between measures of municipal policy opportunities and the proportion of population medicated for mental diseases. METHODS: We apply a variety of statistical regression models. Initially, simple linear regression is applied. Next, a Seemingly Unrelated Regression approach, which accounts for intra-municipal behavioural correlation, is brought in play. Finally, this approach is extended to regressions which are adjusted for spatial spillover effects. RESULTS: The initial simple linear specification indicates a potential significant relationship between municipal policy opportunities and medication. However, when applying a specification which is adjusted for intra-municipal correlation, this relationship vanishes. Finally, there seem to be indications of spatial spillover effects. Thus, the relationship between municipal preventive initiatives and medication seems to be a structural, intra-municipal relationship, rather than a cause-response effect. IMPLICATIONS FOR HEALTH POLICIES: Our results show that potential linkages between municipal preventive initiatives and medication for mental diseases are not of a simple nature. Specifically, sophisticated and targeted interventions are needed rather than broad and general public health initiatives. IMPLICATIONS FOR FURTHER RESEARCH: Though the approach is promising, the data underlying the study is at present relatively weak. Future studies should involve more variables as well as longer times series in order to obtain proper understandings of the potential linkages between municipal policy efforts and medication.

Low nanomolar GABA effects at extrasynaptic α4ß1/ß3δ GABA(A) receptor subtypes indicate a different binding mode for GABA at these receptors.

Ionotropic GABA(A) receptors are a highly heterogenous population of receptors assembled from a combination of multiple subunits. The aims of this study were to characterize the potency of GABA at human recombinant δ-containing extrasynaptic GABA(A) receptors expressed in Xenopus oocytes using the two-electrode voltage clamp technique, and to investigate, using site-directed mutagenesis, the molecular determinants for GABA potency at α4ß3δ GABA(A) receptors. α4/δ-Containing GABA(A) receptors displayed high sensitivity to GABA, with mid-nanomolar concentrations activating α4ß1δ (EC50=24 nM) and α4ß3δ (EC50=12 nM) receptors. In the majority of oocytes expressing α4ß3δ subtypes, GABA produced a biphasic concentration-response curve, and activated the receptor with low and high concentrations (EC50(1)=16 nM; EC50(2)=1.2 µM). At α4ß2δ, GABA had low micromolar activity (EC50=1 µM). An analysis of 10 N-terminal singly mutated α4ß3δ receptors shows that GABA interacts with amino acids different to those reported for α1ß2γ2 GABA(A) receptors. Residues Y205 and R207 of the ß3-subunit significantly affected GABA potency, while the residue F71 of the α4- and the residue Y97 of the ß3-subunit did not significantly affect GABA potency. Mutating the residue R218 of the δ-subunit, equivalent to the GABA binding residue R207 of the ß2-subunit, reduced the potency of GABA by 670-fold, suggesting a novel GABA binding site at the δ-subunit interface. Taken together, GABA may have different binding modes for extrasynaptic δ-containing GABA(A) receptors compared to their synaptic counterparts.

Prolonged signal-averaged P wave duration as a prognostic marker for morbidity and mortality in patients with congestive heart failure.

OBJECTIVE: To evaluate the prognostic roles of prolonged signal-averaged P wave duration (SAPWD), raised levels of natriuretic peptides, and clinical characteristics in patients with stable congestive heart failure (CHF). DESIGN: The SAPWD was assessed from a signal-averaged electrocardiogram (SAECG), and the plasma levels of N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP) were measured in 43 consecutive patients with stable CHF without prior supraventricular arrhythmia. Echocardiographic and clinical data were also recorded. Time to death, hospitalization due to deteriorated CHF, or ECG-documented atrial fibrillation (AF) was recorded over a 438-day median follow-up. RESULTS: During follow-up, 17 patients met an endpoint defined as death, AF, or hospitalization due to deteriorated CHF. Proportional hazard regression including the variables high age, prolonged SAPWD, raised levels of Nt-proANP and Nt-proBNP, and low ejection fraction (EF) showed that only prolonged SAPWD > or =149 ms was associated with an increased risk of meeting an early endpoint; the hazard ratio 3.94 with 95% confidence interval 1.50-10.42; p = 0.006. CONCLUSION: Prolonged SAPWD appears to predict early death, AF development, or hospitalization due to deterioration of CHF in patients with stable CHF.