(S)-S-adenosylmethionine in the treatment of pre-menstrual disorders in adult women: A protocol for an open-label pilot study.

Pre-menstrual disorders, including pre-menstrual syndrome and pre-menstrual dysphoric disorder, are highly prevalent disorders in women of reproductive age. Pre-menstrual disorders are associated with debilitating symptoms that onset in the days prior to menses. A complex interplay between hormonal fluctuations, cellular sensitivity, and psychosocial stressors likely underly the pathophysiology of pre-menstrual disorders. Current treatment options include selective serotonin reuptake inhibitors, hormonal therapies, and psychosocial support. There is growing evidence for oestrogen, progesterone, gonadotropin Releasing Hormone analogues and Complementary and Alternative Medicines in treating Pre-menstrual disorders. (S)-S-adenosylmethionine is a complementary and alternative medicine with postulated roles in the treatment of depression, with a rather rapid onset of action and minimal side effect profile. We propose a protocol for investigating the efficacy of (S)-S-adenosylmethionine in the treatment of pre-menstrual disorders. The proposed study is an open label pilot study, that will recruit thirty women between the ages of 18-45 who experience a pre-menstrual disorder. Daily and interval questionnaires will provide a quantification of symptoms across four menstrual cycles (16 weeks). During two consecutive menstrual cycles it is proposed that participants receive oral (S)-S-adenosylmethionine Complex 400 mg three times a day (total daily dose 1200 mg), during the pre-menstrual time-period (14 days prior to menses). Changes in pre-menstrual disorder symptoms between control and treatment cycles will assist in elucidating the clinical efficacy of (S)-S-adenosylmethionine. This study has the potential to support a larger double blinded, placebo controlled randomised control trial and aims to enrich the knowledge surrounding pre-menstrual disorders.

Inhibitors of the Oncogenic PA2G4-MYCN Protein-Protein Interface.

MYCN is a major oncogenic driver for neuroblastoma tumorigenesis, yet there are no direct MYCN inhibitors. We have previously identified PA2G4 as a direct protein-binding partner of MYCN and drive neuroblastoma tumorigenesis. A small molecule known to bind PA2G4, WS6, significantly decreased tumorigenicity in TH-MYCN neuroblastoma mice, along with the inhibition of PA2G4 and MYCN interactions. Here, we identified a number of novel WS6 analogues, with 80% structural similarity, and used surface plasmon resonance assays to determine their binding affinity. Analogues #5333 and #5338 showed direct binding towards human recombinant PA2G4. Importantly, #5333 and #5338 demonstrated a 70-fold lower toxicity for normal human myofibroblasts compared to WS6. Structure-activity relationship analysis showed that a 2,3 dimethylphenol was the most suitable substituent at the R1 position. Replacing the trifluoromethyl group on the phenyl ring at the R2 position, with a bromine or hydrogen atom, increased the difference between efficacy against neuroblastoma cells and normal myofibroblast toxicity. The WS6 analogues inhibited neuroblastoma cell phenotype in vitro, in part through effects on apoptosis, while their anti-cancer effects required both PA2G4 and MYCN expression. Collectively, chemical inhibition of PA2G4-MYCN binding by WS6 analogues represents a first-in-class drug discovery which may have implications for other MYCN-driven cancers.

Mental health of people of diverse genders and sexualities in Aotearoa/New Zealand: Findings from the New Zealand Mental Health Monitor.

ISSUES ADDRESSED: To examine the mental health inequities, and social exclusion and isolation and protective factor differences between people of diverse genders and sexualities (lesbian/gay, bisexual, gender diverse and takatapui) and cisgender and heterosexual people in Aotearoa/New Zealand. METHODS: We employed data from the pooled probability sample of 2016 and 2018 New Zealand Mental Health Monitor. The sample comprised of 2938 people at least 15 years old, of which 93 had diverse gender and sexuality identities. Generalised linear models were used to test for differences in mental health (current and lifetime mental distress, depression, anxiety, self-harm and suicide), social exclusion and isolation, and friend and family support for people of diverse genders and sexualities. We also conducted exploratory linear regression analyses to examine whether mental health difficulties were associated with social exclusion and isolation and friend/family support. RESULTS: People of diverse genders and sexualities had high rates of mental health difficulties across all variables we examined. For example, people identifying as diverse genders and sexualities had three times the risk of considering self-harm and suicide than their cisgender and heterosexual counterparts (22% vs 5%; RR = 3.12). People of diverse genders and sexualities also scored an average of 6.08 points higher on the 27-point PHQ-9 depression scale when they had experienced social isolation, and 4.01 points higher when they experienced social exclusion. CONCLUSION: Our results are consistent with current literature on the large mental health inequities faced by people of diverse genders and sexualities. SO WHAT?: Policy makers and health care providers in Aotearoa/New Zealand should consider the negative mental health consequences of social exclusion and isolation for people of diverse genders and sexualities.

The Relationship Between Childhood Circumstances and Late Life Physical and Mental Health: The Role of Adult Socioeconomic Status.

OBJECTIVES: Socioeconomic status and health in childhood are linked to health outcomes in later life. Health outcomes may also be shaped by socioeconomic circumstances in adulthood and later life. This paper examined the relationship between childhood conditions and later life health and tested whether this relationship was mediated by later life economic living standards. METHODS: Data from a longitudinal study of aging was combined with retrospective life history data from 787 participants from the New Zealand Health, Work and Retirement Study. RESULTS: Significant relationships were found between childhood conditions and later life health. These relationships were mediated by economic living standards in older age, but the partial direct effect of childhood conditions on health found in early older age became fully meditated 10 years later. CONCLUSION: While childhood circumstances are part of this complex relationship, socioeconomic conditions in later life are vital to ensuring ongoing health into older age.

A structural view of PA2G4 isoforms with opposing functions in cancer.

The role of proliferation-associated protein 2G4 (PA2G4), alternatively known as ErbB3-binding protein 1 (EBP1), in cancer has become apparent over the past 20 years. PA2G4 expression levels are correlated with prognosis in a range of human cancers, including neuroblastoma, cervical, brain, breast, prostate, pancreatic, hepatocellular, and other tumors. There are two PA2G4 isoforms, PA2G4-p42 and PA2G4-p48, and although both isoforms of PA2G4 regulate cellular growth and differentiation, these isoforms often have opposing roles depending on the context. Therefore, PA2G4 can function either as a contextual tumor suppressor or as an oncogene, depending on the tissue being studied. However, it is unclear how distinct structural features of the two PA2G4 isoforms translate into different functional outcomes. In this review, we examine published structures to identify important structural and functional components of PA2G4 and consider how they may explain its crucial role in the malignant phenotype. We will highlight the lysine-rich regions, protein-protein interaction sites, and post-translational modifications of the two PA2G4 isoforms and relate these to the functional cellular role of PA2G4. These data will enable a better understanding of the function and structure relationship of the two PA2G4 isoforms and highlight the care that will need to be undertaken for those who wish to conduct isoform-specific structure-based drug design campaigns.

Drugging MYCN Oncogenic Signaling through the MYCN-PA2G4 Binding Interface.

MYCN is a major driver for the childhood cancer, neuroblastoma, however, there are no inhibitors of this target. Enhanced MYCN protein stability is a key component of MYCN oncogenesis and is maintained by multiple feedforward expression loops involving MYCN transactivation target genes. Here, we reveal the oncogenic role of a novel MYCN target and binding protein, proliferation-associated 2AG4 (PA2G4). Chromatin immunoprecipitation studies demonstrated that MYCN occupies the PA2G4 gene promoter, stimulating transcription. Direct binding of PA2G4 to MYCN protein blocked proteolysis of MYCN and enhanced colony formation in a MYCN-dependent manner. Using molecular modeling, surface plasmon resonance, and mutagenesis studies, we mapped the MYCN-PA2G4 interaction site to a 14 amino acid MYCN sequence and a surface crevice of PA2G4. Competitive chemical inhibition of the MYCN-PA2G4 protein-protein interface had potent inhibitory effects on neuroblastoma tumorigenesis in vivo. Treated tumors showed reduced levels of both MYCN and PA2G4. Our findings demonstrate a critical role for PA2G4 as a cofactor in MYCN-driven neuroblastoma and highlight competitive inhibition of the PA2G4-MYCN protein binding as a novel therapeutic strategy in the disease. SIGNIFICANCE: Competitive chemical inhibition of the PA2G4-MYCN protein interface provides a basis for drug design of small molecules targeting MYC and MYCN-binding partners in malignancies driven by MYC family oncoproteins.

Reconciling Work and Caregiving Responsibilities among Older Workers in New Zealand.

There are 432,000 individuals in New Zealand who provide unpaid care for someone who is ill or disabled and 65% of these carers are also in paid employment. The number of older people in the paid workforce is projected to increase in the next two decades. With the median age of carers in 2013 at 49 years, the ageing of both the population and workforce suggests that many carers may still be in paid work as they themselves age. Family care is an essential part of the health care system. Informal care provides many benefits including improved patient outcomes, reduced unnecessary re-hospitalisations and residential care placements, and considerable savings in health care expenditure. However, combining paid work and informal care is problematic for many carers and can impact on their health and wellbeing, and on work-related outcomes by way of reduced work hours, absenteeism, and employment exit. Recent policy initiatives have been implemented to support family carers in New Zealand to remain in or re-enter the workforce. This paper explores the challenges presented to older New Zealanders who combine paid work with caregiving responsibilities. We provide a profile of older workers (aged 55+) who are providing care and analyse the impact of combining paid work and care on their health, wellbeing and economic living standards. Finally, we situate these findings within the policy framework in New Zealand.

Quality of life in indigenous and non-indigenous older adults: assessing the CASP-12 factor structure and identifying a brief CASP-3.

PURPOSE: We assessed whether the original three-factor structure of the older adult CASP-12 Quality of Life (QOL) scale was stable for both indigenous and non-indigenous older adult populations in the same non-European country (i.e. New Zealand). METHOD: A total of 3076 New Zealanders aged 50-84 (Maori = 1,130; non-Maori sample = 1,946) completed a postal survey for the first data collection wave of the New Zealand Longitudinal Study of Ageing in 2010. The survey included the CASP-12, a chronic health conditions checklist, CES-D-10, de Jong Gierveld loneliness scale, and the WHOQOL single-item QOL indicator. RESULTS: Exploratory factor analysis revealed that the CASP-12 responses resulted in a revised two-factor structure for both Maori and non-Maori we called the NZCASP-11, which included a new three-item global indicator of QOL (CASP-3) that consistently cross-loaded on both factors. Confirmatory factor analysis supported the NZCASP-11 factor structure over the original CASP-12 model, and further assessment validated both the utility of the NZCASP-11 as an indicator of QOL in New Zealand and illustrated the utility of the CASP-3 as a brief screen for global QOL. CONCLUSION: While CASP items coalesce to provide a robust QOL indicator of indigenous and non-indigenous QOL in a single-country setting, the actual factor structure underpinning this CASP indicator (i.e. the NZCASP-11) is not entirely reflective of that found in the United Kingdom. Furthermore, we revealed that three CASP items (i.e. the CASP-3) may reflect a stable brief indicator of QOL applicable for assessing QOL across cultures within a single setting.

Accounting for differences in cognitive health between older adults in New Zealand and the USA.

BACKGROUND: National differences in cognitive health of older adults provide an opportunity to shed light on etiological factors. We compared the cognitive health of older adults in New Zealand and the USA, and examined differences in known risk factors. METHODS: Two nationally representative samples were derived from the 2010 waves of the New Zealand Longitudinal Study of Ageing (n = 953) and the US Health and Retirement Study (HRS) (n = 3,746). Data from comparable measures of cognitive function, gender, age, income, education, prevalence of cancer, diabetes, heart disease, hypertension and stroke, exercise, alcohol consumption, smoker status, depression, and self-reported health were subjected to hierarchical regression analysis to examine how national differences in cognitive function might be explained by differences in these risk factors. RESULTS: The New Zealand sample scored 4.4 points higher on average than the US sample on the 43 point cognitive scale. Regression analyses of the combined samples showed that poorer cognitive health is more likely in those who are male, older, less educated, have suffered a stroke, consume alcohol less frequently, are more depressed, and report worse overall health. Controlling for age and sex reduced the mean difference to 2.6 and controlling for risk factors further reduced it to 2.3. CONCLUSIONS: Older New Zealand adults displayed better cognitive function than those in a US sample. This advantage can be partially explained by age and sex differences and, to some extent, by differences in known risk factors. However, the national advantage remained even when all measured risk factors are statistically controlled.

The influence of ethnicity and gender on caregiver health in older New Zealanders.

OBJECTIVES: We examined the interrelationships between ethnicity, gender, and caregiving on the health of older New Zealanders. We hypothesized that those providing higher levels of care and more care across time would have poorer health outcomes and that these relationships would be moderated by ethnicity and gender. METHOD: A representative sample of participants (N = 2,155) aged 54-70 years from the first 2 waves of the New Zealand Health, Work and Retirement study completed postal surveys in 2006 and 2008. Caregiving questions were adapted from the Australian Women's Health study, and health measures were derived from the SF36 Health Survey. RESULTS: Women and Maori (indigenous New Zealanders) were more likely to provide care than men and non-Maori. Respondents providing higher levels of care reported poorer mental health and this was particularly true of Maori and female caregivers. Male Maori caregivers providing the highest level of care reported the poorest mental health. Level of care was unrelated to physical health. There was minimal evidence for changes in health over time based on caregiver status. DISCUSSION: The poorer health of caregivers supports previous findings on the detrimental health effects of caregiving. Caregiving may have more detrimental effects on Maori health outcomes due to existing inequalities in health, barriers to formal support services, and the multiple roles of elder Maori.

The effects of types of social networks, perceived social support, and loneliness on the health of older people: accounting for the social context.

OBJECTIVES: To use an ecological model of ageing (Berkman, Glass, Brissette, & Seeman, 2000) which includes upstream social context factors and downstream social support factors to examine the effects of social networks on health. METHOD: Postal survey responses from a representative population sample of New Zealanders aged 55 to 70 years (N = 6,662). RESULTS: Correlations and multiple regression analyses provided support for a model in which social context contributes to social network type, which affects perceived social support and loneliness, and consequent mental and physical health. Ethnicity was related to social networks and health but this was largely accounted for by other contextual variables measuring socioeconomic status. Gender and age were also significant variables in the model. DISCUSSION: Social network type is a useful way to assess social integration within this model of cascading effects. More detailed information could be gained through the development of our network assessment instruments for older people.

SF-36v2 norms for New Zealanders aged 55-69 years.

Owing to an ageing population there is growing interest in research to improve the health of older New Zealanders. To facilitate the use of the internationally used SF-36 (version 2) measure of health and quality of life for this work in New Zealand we provide norms and comparative data from the first wave in a longitudinal study of a representative sample of New Zealanders aged 55-69 years. The use of the normative data from this study will facilitate comparisons of results from small clinical samples of older people with the general New Zealand population and international populations. The norms are also available for use in calculating summary physical and mental health summary scores for data from clinical trials and national surveys.

Independence, well-being, and social participation in an aging population.

In 2005 the Health, Work, and Retirement (HWR) Longitudinal Study was established at Massey University in order to identify the later-midlife factors that lay the basis for community participation, independence, and health in later life. Information was collected via postal questionnaire on physical and mental health, psychosocial factors, work and retirement attitudes, and socioeconomic and demographic indicators of a sample of 6662 community-dwelling adults aged 55-70 years. This report provides an overview of these results, and highlights the impact that the transition from work to retirement has on the health and retirement adjustment of older people with respect to independence, well-being, and social participation.