Attenuating mitochondrial dysfunction and morphological disruption with PT320 delays dopamine degeneration in MitoPark mice.

BACKGROUND: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. METHODS: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. RESULTS: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. CONCLUSION: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD.

Pulmonary Artery Catheter Usage and Impact on Mortality in Patients With Cardiogenic Shock: Results From a Canadian Single-Centre Registry.

BACKGROUND: Hemodynamic assessment for cardiogenic shock (CS) phenotyping in patients has led to renewed interest in the use of pulmonary artery catheters (PACs). METHODS: We included patients admitted with CS from January 2014 to December 2020 and compared clinical outcomes among patients who received PACs and those who did not. The primary outcome was the rate of in-hospital mortality. Secondary outcomes included use of advanced heart failure therapies and coronary intensive care unit (CICU) and hospital lengths of stay. RESULTS: A total of 1043 patients were analysed and 47% received PACs. Patients selected for PAC-guided management were younger and had lower left ventricular function. They also had higher use of vasopressor and inotropes, and 15.2% of them were already supported with temporary mechanical circulatory support (MCS). In-hospital mortality was lower in patients who received PACs (29.3% vs 36.2%; P = 0.02), mainly driven by a reduction in mortality among those in Society for Cardiovascular Angiography and Interventions (SCAI) stages D and E CS. Patients who received PACs were more likely to receive temporary MCS with Impella, durable ventricular assist devices (VADs), or orthotopic heart transplantation (OHT) (P < 0.001 for all analyses). CICU and hospital lengths of stay were longer in patients who used PACs. CONCLUSIONS: Among patients with CS, the use of PACs was associated with lower in-hospital mortality, especially among those in SCAI stages D and E. Patients who received PACs were also more frequently rescued with temporary MCS or received advanced heart failure therapies, such as durable VADs or OHT.

Improved mortality and haemodynamics with milrinone in cardiogenic shock due to acute decompensated heart failure.

AIMS: Studies in cardiogenic shock (CS) often have a heterogeneous population of patients, including those with acute myocardial infarction and acute decompensated heart failure (ADHF-CS). The therapeutic profile of milrinone may benefit patients with ADHF-CS. We compared the outcomes and haemodynamic trends in ADHF-CS receiving either milrinone or dobutamine. METHODS AND RESULTS: Patients presenting with ADHF-CS (from 2014 to 2020) treated with a single inodilator (milrinone or dobutamine) were included in this study. Clinical characteristics, outcomes, and haemodynamic parameters were collected. The primary endpoint was 30 day mortality, with censoring at the time of transplant or left ventricular assist device implantation. A total of 573 patients were included, of which 366 (63.9%) received milrinone and 207 (36.1%) received dobutamine. Patients receiving milrinone were younger, had better kidney function, and lower lactate at admission. In addition, patients receiving milrinone received mechanical ventilation or vasopressors less frequently, whereas a pulmonary artery catheter was more frequently used. Milrinone use was associated with a lower adjusted risk of 30 day mortality (hazard ratio = 0.52, 95% confidence interval 0.35-0.77). After propensity-matching, the use of milrinone remained associated with a lower mortality (hazard ratio = 0.51, 95% confidence interval 0.27-0.96). These findings were associated with improved pulmonary artery compliance, stroke volume, and right ventricular stroke work index. CONCLUSIONS: The use of milrinone compared with dobutamine in patients with ADHF-CS is associated with lower 30 day mortality and improved haemodynamics. These findings warrant further study in future randomized controlled trials.

PT320, a Sustained-Release GLP-1 Receptor Agonist, Ameliorates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson's disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks. The late treatment group was given L-DOPA starting at 28 weeks of age and longitudinally observed up to 29 weeks. To explore dopaminergic transmission, fast scan cyclic voltammetry (FSCV) was utilized to measure presynaptic dopamine (DA) dynamics in striatal slices following drug treatments. Early administration of PT320 significantly mitigated the severity L-DOPA-induced abnormal involuntary movements; PT320 particularly improved excessive numbers of standing as well as abnormal paw movements, while it did not affect L-DOPA-induced locomotor hyperactivity. In contrast, late administration of PT320 did not attenuate any L-DOPA-induced dyskinesia measurements. Moreover, early treatment with PT320 was shown to not only increase tonic and phasic release of DA in striatal slices in L-DOPA-naïve MitoPark mice, but also in L-DOPA-primed animals. Early treatment with PT320 ameliorated L-DOPA-induced dyskinesia in MitoPark mice, which may be related to the progressive level of DA denervation in PD.

Augmenting hematoma-scavenging capacity of innate immune cells by CDNF reduces brain injury and promotes functional recovery after intracerebral hemorrhage.

During intracerebral hemorrhage (ICH), hematoma formation at the site of blood vessel damage results in local mechanical injury. Subsequently, erythrocytes lyse to release hemoglobin and heme, which act as neurotoxins and induce inflammation and secondary brain injury, resulting in severe neurological deficits. Accelerating hematoma resorption and mitigating hematoma-induced brain edema by modulating immune cells has potential as a novel therapeutic strategy for functional recovery after ICH. Here, we show that intracerebroventricular administration of recombinant human cerebral dopamine neurotrophic factor (rhCDNF) accelerates hemorrhagic lesion resolution, reduces peri-focal edema, and improves neurological outcomes in an animal model of collagenase-induced ICH. We demonstrate that CDNF acts on microglia/macrophages in the hemorrhagic striatum by promoting scavenger receptor expression, enhancing erythrophagocytosis and increasing anti-inflammatory mediators while suppressing the production of pro-inflammatory cytokines. Administration of rhCDNF results in upregulation of the Nrf2-HO-1 pathway, but alleviation of oxidative stress and unfolded protein responses in the perihematomal area. Finally, we demonstrate that intravenous delivery of rhCDNF has beneficial effects in an animal model of ICH and that systemic application promotes scavenging by the brain's myeloid cells for the treatment of ICH.

Patient Outcomes and Characteristics in a Contemporary Quaternary Canadian Cardiac Intensive Care Unit.

Background: The modern-day cardiac intensive care unit (CICU) has evolved to care for patients with acute critical cardiac illness. We describe the current population of cardiac patients in a quaternary CICU. Methods: Consecutive CICU patients admitted to the CICU at the Toronto General Hospital from 2014 to 2020 were studied. Patient demographics, admission diagnosis, critical care resources, complications, in-hospital mortality, and CICU and hospital length of stay were recorded. Results: A total of 8865 consecutive admissions occurred, with a median age of 64.9 years. The most common primary cardiac diagnoses were acute decompensated heart failure (17.8%), non ST-elevation myocardial infarction (16.8%), ST-elevation myocardial infarction (15.5%), and arrhythmias (14.7%). Cardiogenic shock was seen in 13.2%, and out-of-hospital cardiac arrest in 4.1%. A noncardiovascular admission diagnosis accounted for 13.9% of the cases. Over the period studied, rates of admission were higher for cardiogenic shock (P < 0.001 for trend), with a higher use of critical care resources. Additionally, rates of admission were higher in female patients and those who had chronic kidney disease and diabetes. The in-hospital mortality rate of all CICU admissions was 13.2%, and it was highest in those with noncardiac conditions, compared to the rate in those with cardiac diagnoses (29.4% vs 10.6%, P < 0.001). Conclusions: Given the trends of higher acuity of patients with cardiac critical illness, with higher use of critical care resources, education streams for critical care within cardiology, and alternative pathways of care for patients who have lower-acuity cardiac disease remain imperative to manage this evolving population.

Introduction: L'unité de soins intensifs de cardiologie (USIC) d'aujourd'hui a évolué vers des soins aux patients atteints d'une maladie cardiaque aiguë en phase critique. Nous décrivons la population actuelle de patients cardiaques d'une USIC quaternaires. Méthodes: Les patients consécutifs d'USIC admis à l'USIC de l'Hôpital général de Toronto de 2014 à 2020 ont fait l'objet de l'étude. Les données démographiques des patients, le diagnostic à l'admission, les ressources en soins aux patients en phase critique, les complications, la mortalité intrahospitalière, et la durée de séjour à l'hôpital et à l'USIC ont été enregistrés. Résultats: Il y a eu un total de 8 865 admissions consécutives dont les patients avaient un âge médian de 64,9 ans. Les diagnostics principaux les plus fréquents de maladies cardiaques étaient l'insuffisance cardiaque aiguë décompensée (17,8 %), l'infarctus du myocarde sans élévation du segment ST (16,8 %), l'infarctus du myocarde avec élévation du segment ST (15,5 %) et les arythmies (14,7 %). Le choc cardiogénique a été observé chez 13,2 %, et l'arrêt cardiaque hors de l'hôpital, chez 4,1 %. Un diagnostic d'admission de maladie non cardiovasculaire représente 13,9 % des cas. Durant la période étudiée, les taux d'admission en raison d'un choc cardiogénique étaient plus élevés (P < 0,001 pour la tendance), et entraînaient une utilisation plus élevée de ressources en soins aux patients en phase critique. De plus, les taux d'admission étaient plus élevés chez les patientes, et chez ceux qui avaient une insuffisance rénale chronique et un diabète. Le taux de mortalité intrahospitalière de toutes les admissions à l'USIC était de 13,2 %, et il constituait le taux le plus élevé chez ceux qui avaient des maladies non cardiaques comparativement au taux chez ceux qui avaient des diagnostics de maladies cardiaques (29,4 % vs 10,6 %, P < 0,001). Conclusions: Compte tenu des tendances d'accroissement de la gravité de l'état des patients atteints d'une maladie cardiaque en phase critique et de la plus grande utilisation des ressources en soins aux patients en phase critique, des volets de formation en soins aux patients en phase critique en cardiologie et d'autres protocoles de soins des patients qui ont une maladie cardiaque de plus faible gravité demeurent essentiels à la prise en charge de cette population grandissante.

Tetrabenazine Mitigates Aberrant Release and Clearance of Dopamine in the Nigrostriatal System, and Alleviates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

BACKGROUND: L-DOPA-induced dyskinesia (LID), occurring with aberrant processing of exogenous L-DOPA in the dopamine-denervated striatum, is a main complication of levodopa treatment in Parkinson's disease. OBJECTIVE: To characterize the effects of the vesicular antagonist tetrabenazine (TBZ) on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease. METHODS: 20-week-old MitoPark mice were co-treated or separately administered TBZ and L-DOPA for 14 days. Abnormal involuntary movements (AIMs) and locomotor activity were analyzed. To explore dopamine (DA) transmission, fast scan cyclic voltammetry was used to assess presynaptic DA dynamics in striatal slices following treatments. PET imaging with 4-[18F]-PE2I, ADAM and immunoblotting assays were used to detect receptor protein changes in the DA-denervated striatum. Finally, nigrostriatal tissues were collected for HPLC measures of DA, serotonin and their metabolites. RESULTS: A single injection of TBZ given in the interval between the two L-DOPA/Carbidopa treatments significantly attenuated L-DOPA-induced AIMs expression and locomotor hyperactivity. TBZ was shown to reduce tonic and phasic release of DA following L-DOPA treatment in DA-denervated striatal tissue. In the DA-depleted striatum, TBZ decreased the expression of L-DOPA-enhanced D1 receptors and the serotonin reuptake transporter. Neurochemical analysis indicated that TBZ attenuated L-DOPA-induced surges of DA levels by promoting DA turnover in the nigrostriatal system. CONCLUSIONS: Our findings demonstrate that TBZ diminishes abnormal striatal DA transmission, which involves the ability of TBZ to modulate the presymptomatic dynamics of DA, and then mitigate aberrant release of exogenous L-DOPA from nerve terminals. The results support the potential of repositioning TBZ to counteract LID development.

Development of a Chemical Cocktail That Rescues Mouse Brain Demyelination in a Cuprizone-Induced Model.

Oligodendrocytes are glial cells located in the central nervous system (CNS) that play essential roles in the transmission of nerve signals and in the neuroprotection of myelinated neurons. The dysfunction or loss of oligodendrocytes leads to demyelinating diseases such as multiple sclerosis (MS). To treat demyelinating diseases, the development of a therapy that promotes remyelination is required. In the present study, we established an in vitro method to convert human fibroblasts into induced oligodendrocyte-like cells (iOLCs) in 3 days. The induced cells displayed morphologies and molecular signatures similar to oligodendrocytes after treatment with valproic acid and exposure to the small molecules Y27632, SU9516, and forskolin (FSK). To pursue the development of a cell-free remyelination therapy in vivo, we used a cuprizone-induced demyelinated mouse model. The small molecules (Y27632, SU9516, and FSK) were directly injected into the demyelinated corpus callosum of the mouse brain. This combination of small molecules rescued the demyelination phenotype within two weeks as observed by light and electron microscopy. These results provide a foundation for exploring the development of a treatment for demyelinating diseases via regenerative medicine.

CALL-K score: predicting the need for renal replacement therapy in cardiogenic shock.

AIMS: The clinical predictors and outcomes of patients with cardiogenic shock (CS) requiring renal replacement therapy (RRT) have not been studied previously. This study assesses the impact of RRT on mortality in patients with CS and aims to identify clinical factors that contribute to the need of RRT. METHODS AND RESULTS: Consecutive patients presenting with CS were included from a prospective registry of cardiac intensive care unit admissions at a single institution between 2014 and 2020. Of the 1030 patients admitted with CS, 123 (11.9%) received RRT. RRT was associated with higher 1-year mortality [adjusted hazard ratio = 1.62, 95% confidence interval (CI) 1.02-2.14], and a higher in-hospital incidence of sepsis [risk ratio = 2.76, P < 0.001], and pneumonia (risk ratio = 2.9, P = 0.001). Those who received RRT were less likely to receive guideline-directed medical treatment at time of discharge, undergo heart transplantation (2.4% vs. 11.5%, P = 0.002) or receive a durable left ventricular assist device (0.0% vs. 11.6%, P < 0.001). Five variables at admission best predicted the need for RRT (age, lactate, haemoglobin, use of pre-admission loop diuretics, and admission estimated glomerular filtration rate) and were used to generate the CALL-K 9-point risk score, with better discrimination than creatinine alone (P = 0.008). The score was internally validated (area under the curve = 0.815, 95% CI 0.739-0.835) with good calibration (Hosmer-Lemeshow P = 0.827). CONCLUSIONS: RRT is associated with worse outcomes, including a lower likelihood to receive advanced heart failure therapies in patients with CS. A risk score comprising five variables routinely collected at admission can accurately estimate the risk of needing RRT.

Post-stroke Delivery of Valproic Acid Promotes Functional Recovery and Differentially Modifies Responses of Peri-Infarct Microglia.

The specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. In this study, we first determined whether a single dose of VPA after stroke could decrease infarction area or improve functional recovery. Next, we investigated the number and morphological characteristic of peri-infarct microglia at different time points and elucidated the mechanism of microglial response by VPA treatment. Male Sprague-Dawley rats were subjected to distal middle cerebral artery occlusion (dMCAo) for 90 min, followed by reperfusion. Some received a single injection of VPA (200 mg/kg) 90 min after the induction of ischemia, while vehicle-treated animals underwent the same procedure with physiological saline. Infarction volume was calculated at 48 h after reperfusion, and neurological symptoms were evaluated. VPA didn't significantly reduce infarct volume but did ameliorate neurological deficit at least partially compared with vehicle. Meanwhile, VPA reduced dMCAo-induced elevation of IL-6 at 24 h post-stroke and significantly decreased the number of CD11b-positive microglia within peri-infarct cortex at 7 days. Morphological analysis revealed that VPA therapy leads to higher fractal dimensions, smaller soma size and lower circularity index of CD11b-positive cells within peri-infarct cortex at both 2 and 7 days, suggesting that VPA has core effects on microglial morphology. The modulation of microglia morphology caused by VPA might involve HDAC inhibition-mediated suppression of galectin-3 production. Furthermore, qPCR analysis of CD11b-positive cells at 3 days post-stroke suggested that VPA could partially enhance M2 subset polarization of microglia in peri-infarct cortex. Analysis of VPA-induced changes to gene expressions at 3 days post-stroke implies that these alternations of the biomarkers and microglial responses are implicated in the upregulation of wound healing, collagen trimmer, and extracellular matrix genes within peri-infarct cortex. Our results are the first to show that a low dose of VPA promotes short-term functional recovery but does not alter infarct volume. The decreases in the expression of both IL-6 and galectin-3 might influence the morphological characteristics and transcriptional profiles of microglia and extracellular matrix remodeling, which could contribute to the improved recovery.

Sustained Release GLP-1 Agonist PT320 Delays Disease Progression in a Mouse Model of Parkinson's Disease.

GLP-1 agonists have become increasingly interesting as a new Parkinson's disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model. A clinically translatable biweekly PT320 dose was administered starting at 5 weeks of age and longitudinally evaluated to 24 weeks, and multiple behavioral/cellular parameters were measured. PT320 significantly improved spontaneous locomotor activity and rearing in MitoPark PD mice. "Motivated" behavior also improved, evaluated by accelerating rotarod performance. Behavioral improvement was correlated with enhanced cellular and molecular indices of dopamine (DA) midbrain function. Fast scan cyclic voltammetry demonstrated protection of striatal and nucleus accumbens DA release and reuptake in PT320 treated MitoPark mice. Positron emission tomography showed protection of striatal DA fibers and tyrosine hydroxylase protein expression was augmented by PT320 administration. Early PT320 treatment may hence provide an important neuroprotective therapeutic strategy in PD.

Management of Acute Decompensated Heart Failure in the Cardiac Intensive Care Unit: The Importance of Co-management With a Heart Failure Specialist.

BACKGROUND: Heart failure (HF) is a common reason for admission to the cardiac intensive care unit. We sought to identify the role of an HF consultation service in improving the management of this patient population. METHODS: We identified all adult patients admitted to the cardiac intensive care unit (2014-2015) at the University Health Network with a diagnosis of acute decompensated HF ± cardiogenic shock (CS). Clinical characteristics and course were recorded. We calculated a propensity score-adjusted association between HF consultation and in-hospital mortality. RESULTS: A total of 285 unique patients were identified in our cohort. Of these, 82 (28.7%) died. A total of 150 patients (52.6%) were co-managed by an HF service, and 135 patients (47.3%) were not. Patients who were managed by an HF team were younger (52.5 vs 68.0 years, P < 0.0001), were more likely to be admitted with CS (61.3 vs 41.5%, P < 0.0009), and had higher rates of vasoactive medications during their admission (69.3% vs 52.6%, P < 0.005). At discharge, there were higher rates of discharge to a HF clinic (52.0% vs 27.5%, P < 0.0001) and prescription of guideline-directed medical therapy. In-hospital mortality was lower in those co-managed by a HF team (16.7% vs 42.2%, P < 0.0001). HF consultation reduced the odds of readmission by 76% (odds ratio, 0.24; 95% confidence interval, 0.13-0.47). CONCLUSIONS: Patients managed by a HF team were more likely to be in CS at admission, to survive to discharge from hospital, and to be initiated on guideline-directed medical therapy with HF follow-up.

CONTEXTE: L'insuffisance cardiaque (IC) est un motif fréquent d'admission à l'unité de soins intensifs de cardiologie. Cette étude visait à cerner le rôle d'un service de consultation spécialisé en IC dans l'amélioration de la prise en charge de la population de patients atteinte de cette affection. MÉTHODOLOGIE: Un recensement de tous les patients adultes admis en 2014-2015 à l'unité de soins intensifs de cardiologie du Réseau universitaire de santé et ayant reçu un diagnostic d'IC aiguë décompensée avec ou sans choc cardiogénique a été effectué. Les caractéristiques cliniques et l'évolution de l'atteinte avaient été consignées pour ces patients. L'association, ajustée en fonction du score de propension, entre la consultation pour IC et la mortalité hospitalière a été calculée. RÉSULTATS: Au total, 285 patients uniques ont été recensés dans la cohorte. De ce nombre, 82 (28,7 %) patients sont décédés. Sur les 285 patients, 150 (52,6 %) avaient été pris en charge conjointement par un service spécialisé en IC, tandis que les 135 (47,3 %) autres ne l'avaient pas été. Les patients pris en charge par une équipe spécialisée en IC étaient plus jeunes (52,5 vs 68,0 ans, p < 0,0001), étaient plus susceptibles d'être en proie à un choc cardiogénique à l'admission (61,3 vs 41,5 %, p < 0,0009) et étaient plus nombreux à avoir reçu un agent vasoactif à l'admission (69,3 % vs 52,6 %, p < 0,005). Ils ont aussi été plus nombreux à être orientés vers une clinique spécialisée en IC à leur sortie de l'hôpital (52,0 % vs 27,5 %, p < 0,0001) et à se voir prescrire un traitement médical recommandé dans des lignes directrices. La mortalité hospitalière était plus faible chez les patients qui ont fait l'objet d'une prise en charge conjointe par une équipe spécialisée en IC (16,7 % vs 42,2 %, p < 0,0001). La consultation d'une équipe spécialisée en IC a en outre réduit le risque de réadmission de 76 % (rapport de cotes de 0,24; intervalle de confiance à 95 % : 0,13-0,47). CONCLUSIONS: Les patients pris en charge par une équipe spécialisée en IC étaient plus susceptibles d'être en proie à un choc cardiogénique à l'admission, de survivre à leur sortie de l'hôpital, de se voir prescrire un traitement médical recommandé dans des lignes directrices et de faire l'objet d'un suivi dans une clinique spécialisée en IC.

Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice.

This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson's disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior. The degeneration of the nigrostriatal DA system in MP mice is earlier and more marked than that of the mesolimbic DA system, with male MP mice again being more strongly affected than female MP mice. After ovariectomy, DA presynaptic and behavioral changes in female mice become very similar to those of male animals. Our results suggest that estrogen, either directly or indirectly, is neuroprotective in the midbrain DA system. Our results are compatible with epidemiological data on incidence and symptom progression in PD, showing that men are more strongly affected than women at early ages.

Early decline in functional ovarian reserve in young women with low (CGGn < 26) FMR1 gene alleles.

Mouse fmr1 models, and recent cross-sectional human data, suggest that different triple CGGn ranges of the fragile X mental retardation 1 (FMR1) gene are associated with variations in ovarian aging and infertility treatment outcomes. The FMR1 mutation affecting reproductive function most negatively in humans is the so-called low mutation, characterized by CGGn < 26. We here present a first longitudinal study of selected young women with normal functional ovarian reserve (FOR). In a prospective cohort study, we selected among 233 young oocyte donors (mean age 24.8 ± 3.3 years) as study population of 66 who had more than 1 anti-Müllerian hormone (AMH) level drawn over a 4-year period. AMH curves, as reflection of FOR, were then statistically compared between women with and without low FMR1 alleles. Biallelic low FMR1 (hom-low/low) donors already at initial presentation demonstrated significantly lower FOR than donors with biallelic normal (norm) FMR1 (CGGn = 26-34; P = 0.001). Although monoallelic low FMR1 at initial presentation was not yet associated with decreased FOR, it over 4 years did demonstrate significantly enhanced declines in FOR (P = 0.046). Including repeat measurements, low/low (P = 0.006) and high/high (CGGn > 34) alleles (P < 0.001) demonstrated lower FOR by AMH than norm donors. Even monoallelic low FMR1 alleles are, thus, already at young female ages associated with accelerated declines in FOR. Low FMR1 alleles, therefore, potentially represent a screening tool for women at genetic risk toward premature ovarian senescence, representing in all races circa 10% of the female population.

Augmenting psychoeducation with a mobile intervention for bipolar disorder: a randomized controlled trial.

BACKGROUND: Psychosocial interventions for bipolar disorder are frequently unavailable and resource intensive. Mobile technology may improve access to evidence-based interventions and may increase their efficacy. We evaluated the feasibility, acceptability and efficacy of an augmentative mobile ecological momentary intervention targeting self-management of mood symptoms. METHODS: This was a randomized single-blind controlled trial with 82 consumers diagnosed with bipolar disorder who completed a four-session psychoeducational intervention and were assigned to 10 weeks of either: 1) mobile device delivered interactive intervention linking patient-reported mood states with personalized self-management strategies, or 2) paper-and-pencil mood monitoring. Participants were assessed at baseline, 6 weeks (mid-point), 12 weeks (post-treatment), and 24 weeks (follow up) with clinician-rated depression and mania scales and self-reported functioning. RESULTS: Retention at 12 weeks was 93% and both conditions were associated with high satisfaction. Compared to the paper-and-pencil condition, participants in the augmented mobile intervention condition showed significantly greater reductions in depressive symptoms at 6 and 12 weeks (Cohen׳s d for both were d=0.48). However, these effects were not maintained at 24-weeks follow up. Conditions did not differ significantly in the impact on manic symptoms or functional impairment. LIMITATIONS: This was not a definitive trial and was not powered to detect moderators and mediators. CONCLUSIONS: Automated mobile-phone intervention is feasible, acceptable, and may enhance the impact of brief psychoeducation on depressive symptoms in bipolar disorder. However, sustainment of gains from symptom self-management mobile interventions, once stopped, may be limited.

Sexual health and function in later life: a population-based study of 606 older adults with a partner.

BACKGROUND: Sexual health and function is an important yet understudied aspect of overall health and well-being in older adults. There are limited data on the relative strength of associations between various aspects of sexual health with the physical, emotional, and cognitive function in older adults. Additionally, there is little information on how these associations differ by age and sex. METHODS: In this Successful Aging Evaluation (SAGE) study, 606 community-dwelling adults in San Diego County, aged 50-99 years and who had a partner, were included in the analysis. Evaluations included a phone-based cognitive screening followed by a comprehensive mail-in survey including rating scales of sexual health, depression, anxiety, and physical function. RESULTS: The mean age of the sample was 75.2 years. Over 80% of respondents had engaged in sexual activity in the past year, over 70% engaged in sexual activity weekly or more than once a week, and over 60% were somewhat or very satisfied with their sex lives. No sex differences were evident on dimensions of sexual health except for a higher rate of rejection of sexual overtures by women. Depressive symptoms were negatively associated with all assessed aspects of sexual health, even after adjusting for age, physical functioning, anxiety, cognitive ability, or perceived stress in both men and women. CONCLUSIONS: In this population-based study older men and women who had a partner reported frequent engagement in and satisfaction with sexual activity. Depressive symptoms were broadly associated with worse sexual health, more so than physical function, anxiety or stress, or age itself.

Reduced activity restriction buffers the relations between chronic stress and sympathetic nervous system activation.

OBJECTIVES: Caregivers of dementia patients are at risk for developing cardiovascular disease (CVD), and this risk increases the longer they provide care. Greater perceptions that caregiving restricts social/recreational activities (i.e., activity restriction [AR]) has been associated with poorer health, and AR may exacerbate the relations between stress and health outcomes. The current study examined the interactive role of greater exposure to stress and increased AR on plasma catecholamine (CAT) levels: norepinephrine (NE) and epinephrine (EPI). METHOD: A total of 84 dementia caregivers completed a standard assessment battery, and a nurse collected blood, which was assayed for NE and EPI. Separate regressions for NE and EPI were used to determine whether the relations between years caregiving and CATs were greater in those with high versus low AR. RESULTS: A significant interaction was found between years caregiving and AR in predicting resting EPI (p = .032) but not resting NE (p = .103). Post hoc analyses indicated that years caregiving was significantly associated with EPI when AR was high (p = .008) but not when AR was low (p = .799). Additionally, years caregiving was not significantly associated with NE when AR was high or low. DISCUSSION: The subjective experience of AR can play an important role in determining risk for detrimental physical health outcomes, particularly CVD risk.

The effect of endogenous estrogen on Doppler-estimated right ventricular systolic pressure during exercise.

We evaluated the effect of endogenous estrogen levels on exercise-related changes in right ventricular systolic pressure (RVSP) of healthy, eumenorrheic, sedentary women. Volunteers were studied at two separates phases of the menstrual cycle (LO and HI estrogen phases), exercised on a semi-supine ergometer with escalating workload and monitored continuously by 12-lead ECG and automated blood pressure cuff. At each exercise stage, Doppler echocardiography measurements were obtained and analyzed to determine RVSP. Fourteen subjects (age 24 ± 5) were studied. Exercise duration was significantly higher on the HI estrogen day, but no significant differences in hemodynamic response to exercise were found between the two study days. There were also no significant differences with respect to heart rate (HR) acceleration during early exercise, as well as resting and peak RVSP, HR, blood pressure, and rate pressure product. Doppler-estimated RVSP demonstrated a linear relationship to HR at a ratio of 1 mm Hg (1 mm Hg = 133.3224 Pa) for every 5 bpm (beats per minute) increase in HR. There were no differences in the slope of this relationship between HI and LO estrogen phases of the menstrual cycle. Our findings did not demonstrate any effect of endogenous estrogen levels on the modulation of the pulmonary vascular response to exercise in healthy women.

A Pilot Study of Mood Ratings Captured by Mobile Phone Versus Paper-and-Pencil Mood Charts in Bipolar Disorder.

OBJECTIVE: Patient reported mood charts are frequently used in management of bipolar disorder. Although mood charts have recently been programmed in electronic devices such as mobile phones, little is known about the impact of the method of data capture on the psychometric properties and validity of these data. METHODS: In an ongoing pilot study, a sample of outpatients with bipolar disorder were randomized to either complete mood charts on a mobile phone or a standard paper-and-pencil mood chart as part of a 12 week-intervention (primary outcomes for the trial await study completion). We compared these conditions across single item rating of mood state, and we hypothesized that mobile phone based data capture would produce greater compliance to mood ratings, variability between and within participants, and concurrent validity with blinded clinician-rated affective symptom severity. RESULTS: A total of 56 participants were randomized and 40 participants were included in the analyses. There were no significant differences between conditions on demographic or clinical variables. The rate of compliance was significantly higher in paper-and-pencil versus mobile phone ratings. Ratings demonstrated significantly more variability within individuals in the mobile phone condition. Mobile phone mood ratings were significantly correlated with clinician-rated depressive symptom severity across the study and with manic symptom severity at the Week 6 assessment, whereas paper-and-pencil ratings were not significantly associated with clinician-rated depression or mania. CONCLUSIONS: Although preliminary, our results suggest a lower rate of compliance with mobile phones compared to paper-and-pencil daily mood rating in bipolar disorder, yet a greater ability to capture variability and concurrent validity in quantifying affective symptoms. This clinical trial is registered at http://www.clinicaltrials.gov as NCT01670123.