Increased NOS coupling by the metabolite tetrahydrobiopterin (BH4) reduces preeclampsia/IUGR consequences.

Preeclampsia (PE) is a high-prevalence pregnancy disease characterized by placental insufficiency, gestational hypertension, and proteinuria. Overexpression of the A isoform of the STOX1 transcription factor (STOX1A) recapitulates PE in mice, and STOX1A overexpressing trophoblasts recapitulate PE patients hallmarks in terms of gene expression and pathophysiology. STOX1 overexpression induces nitroso-redox imbalance and mitochondrial hyper-activation. Here, by a thorough analysis on cell models, we show that STOX1 overexpression in trophoblasts alters inducible nitric oxide synthase (iNOS), nitric oxide (NO) content, the nitroso-redox balance, the antioxidant defense, and mitochondrial function. This is accompanied by specific alterations of the Krebs cycle leading to reduced l-malate content. By increasing NOS coupling using the metabolite tetrahydrobiopterin (BH4) we restore this multi-step pathway in vitro. Moving in vivo on two different rodent models (STOX1 mice and RUPP rats, alike early onset and late onset preeclampsia, respectively), we show by transcriptomics that BH4 directly reverts STOX1-deregulated gene expression including glutathione metabolism, oxidative phosphorylation, cholesterol metabolism, inflammation, lipoprotein metabolism and platelet activation, successfully treating placental hypotrophy, gestational hypertension, proteinuria and heart hypertrophy. In the RUPP rats we show that the major fetal issue of preeclampsia, Intra Uterine Growth Restriction (IUGR), is efficiently corrected. Our work posits on solid bases BH4 as a novel potential therapy for preeclampsia.

Medication exposure and predictors of first mood episode in offspring of parents with bipolar disorder: a prospective study

Objectives: To prospectively investigate whether baseline clinical characteristics and medication exposure predict development of major depressive disorder or bipolar disorder in offspring of parents with bipolar disorder. Methods: Youth aged 9-20 years with at least one biological parent with bipolar disorder and no prior history of mood or psychotic episodes (n=93) were prospectively evaluated and treated naturalistically during the study. Participants were divided into two groups: converters, defined as those who met DSM-IV criteria for a mood episode during follow-up (n=19); or non-converters (n=74). Logistic regression models were used to investigate associations between baseline clinical variables and medication exposure during follow-up and risk of developing a first mood episode (conversion). Results: Multivariate regression analyses showed that baseline anxiety disorders and subsyndromal mood disorders were associated with increased risk of conversion during follow-up. Adding medication exposure to the multivariate model showed that exposure to antidepressants during follow-up was associated with increased risk of conversion. Conclusions: Caution should be used when treating bipolar offspring with anxiety and/or emerging depressive symptoms using antidepressant agents, given the increased risk of developing a major mood disorder.

Medication exposure and predictors of first mood episode in offspring of parents with bipolar disorder: a prospective study.

OBJECTIVES: To prospectively investigate whether baseline clinical characteristics and medication exposure predict development of major depressive disorder or bipolar disorder in offspring of parents with bipolar disorder. METHODS: Youth aged 9-20 years with at least one biological parent with bipolar disorder and no prior history of mood or psychotic episodes (n=93) were prospectively evaluated and treated naturalistically during the study. Participants were divided into two groups: converters, defined as those who met DSM-IV criteria for a mood episode during follow-up (n=19); or non-converters (n=74). Logistic regression models were used to investigate associations between baseline clinical variables and medication exposure during follow-up and risk of developing a first mood episode (conversion). RESULTS: Multivariate regression analyses showed that baseline anxiety disorders and subsyndromal mood disorders were associated with increased risk of conversion during follow-up. Adding medication exposure to the multivariate model showed that exposure to antidepressants during follow-up was associated with increased risk of conversion. CONCLUSIONS: Caution should be used when treating bipolar offspring with anxiety and/or emerging depressive symptoms using antidepressant agents, given the increased risk of developing a major mood disorder.

Survival analysis of 219 dogs with hyperadrenocorticism attending primary care practice in England.

BACKGROUND: Hyperadrenocorticism is an endocrine disease routinely encountered within primary care practice; however, few studies evaluating survival beyond diagnosis have studied this population. METHODS: This retrospective cohort study analysed the electronic patient records of 219 cases of hyperadrenocorticism from a sample of dogs attending primary care practices in England. Kaplan-Meier plots examined the cumulative survival and Cox proportional hazard regression modelling identified factors associated with the hazard of all-cause mortality. RESULTS: In the analysis, 179/219 (81.7 per cent) hyperadrenocorticism cases died during the study period with a median survival time from first diagnosis of 510 days (95% CI 412 to 618 days). Trilostane was used in 94.1 per cent of cases and differentiation between pituitary-dependent and adrenal-dependent disease was made in 20.1 per cent of cases. In the multivariable analysis, dogs weighing greater than or equal to 15 kg (HR 1.51, 95% CI 1.06 to 2.15, P=0.023) and those diagnosed greater than or equal to 13 years of age (HR 3.74, 95% CI 2.29 to 6.09, P<0.001) had increased hazards of all-cause mortality. Dogs that had their initial trilostane dose increased had a favourable prognosis (HR 0.49, 95% CI 0.32 to 0.76, P=0.015). CONCLUSION: This study shows that survival from diagnosis of hyperadrenocorticism appears fair for many dogs and provides primary care practitioners with relatable benchmark prognostic figures.