Two-Year observational study of autonomic skin function in patients with Parkinson's disease compared to healthy individuals.

BACKGROUND AND PURPOSE: We characterized autonomic pilomotor and sudomotor skin function in early Parkinson's disease (PD) longitudinally. METHODS: We enrolled PD patients (Hoehn and Yahr 1-2) and healthy controls from movement disorder centers in Germany, Hungary, and the United States. We evaluated axon-reflex responses in adrenergic sympathetic pilomotor nerves and in cholinergic sudomotor nerves and assessed sympathetic skin response (SSR), predominantly parasympathetic neurocardiac function via heart rate variability, and disease-related symptoms at baseline, after 2 weeks, and after 1 and 2 years. CLINICALTRIALS: gov: NCT03043768. RESULTS: We included 38 participants: 26 PD (60% females, aged 62.4 ± 7.4 years, mean ± SD) and 12 controls (75% females, aged 59.5 ± 5.8 years). Pilomotor function was reduced in PD compared to controls at baseline when quantified via spatial axon-reflex spread (78 [43-143], median [interquartile range] mm2 vs. 175 [68-200] mm2 , p = 0.01) or erect hair follicle count in the axon-reflex region (8 [6-10] vs. 11 [6-16], p = 0.008) and showed reliability absent any changes from baseline to Week 2 (p = not significant [ns]). Between-group differences increased over the course of 2 years (p < 0.05), although no decline was observed within groups (p = ns). Pilomotor impairment in PD correlated with motor symptoms (rho = -0.59, p = 0.017) and was not lateralized (p = ns). Sudomotor axon-reflex and neurocardiac function did not differ between groups (p = ns), but SSR was reduced in PD (p = 0.0001). CONCLUSIONS: Impairment of adrenergic sympathetic pilomotor function and SSR in evolving PD is not paralleled by changes to cholinergic sudomotor function and parasympathetic neurocardiac function, suggesting a sympathetic pathophysiology. A pilomotor axon-reflex test might be useful to monitor PD-related pathology.

Quantifying and mathematical modelling of the influence of soluble adenylate cyclase on cell cycle in human endothelial cells with Bayesian inference.

Adenosine-3', 5'-cyclic monophosphate (cAMP) produced by adenylate cyclases (ADCYs) is an established key regulator of cell homoeostasis. However, its role in cell cycle control is still controversially discussed. This study focussed on the impact of soluble HCO3 - -activated ADCY10 on cell cycle progression. Effects are quantified with Bayesian inference integrating a mathematical model and experimental data. The activity of ADCY10 in human umbilical vein endothelial cells (HUVECs) was either pharmacologically inhibited by KH7 or endogenously activated by HCO3 - . Cell numbers of individual cell cycle phases were assessed over time using flow cytometry. Based on these numbers, cell cycle dynamics were analysed using a mathematical model. This allowed precise quantification of cell cycle dynamics with model parameters that describe the durations of individual cell cycle phases. Endogenous inactivation of ADCY10 resulted in prolongation of mean cell cycle times (38.7 ± 8.3 h at 0 mM HCO3 - vs 30.3 ± 2.7 h at 24 mM HCO3 - ), while pharmacological inhibition resulted in functional arrest of cell cycle by increasing mean cell cycle time after G0 /G1 synchronization to 221.0 ± 96.3 h. All cell cycle phases progressed slower due to ADCY10 inactivation. In particular, the G1 -S transition was quantitatively the most influenced by ADCY10. In conclusion, the data of the present study show that ADCY10 is a key regulator in cell cycle progression linked specifically to the G1 -S transition.

Preventive Approaches for Post-Stroke Depression: Where Do We Stand? A Systematic Review.

PURPOSE: Post-stroke depression (PSD) occurs in one-third of stroke survivors, leading to a substantial decrease in quality of life as well as delayed functional and neurological recovery. Early detection of patients at risk and initiation of tailored preventive measures may reduce the medical and socioeconomic burden associated with PSD. We sought to review the current evidence on pharmacological and non-pharmacological prevention of PSD. MATERIALS AND METHODS: We conducted a systematic review using PubMed/MEDLINE and bibliographies of identified papers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, including randomized controlled studies. Eligible studies were included when performed within 1 year after the index cerebrovascular event. Animal and basic research studies, studies lacking a control group, review papers, and case reports were excluded. RESULTS: Out of 150 studies screened, 37 met our criteria. Among the strategies identified, administration of antidepressants displayed the most robust evidence for preventing PSD, whereas non-pharmacological interventions such as psychotherapy appear to be the most frequently used approaches to prevent depression after stroke. Research suggests that the efficacy of PSD prevention increases with the duration of preventive treatment. Seven out of 11 studies (63%) that used pharmacological and eight out of 16 (50%) that used non-pharmacological interventions reported a positive preventive effect on PSD. CONCLUSION: Overall, the current literature on PSD prevention shows heterogeneity, substantiating a need for well-designed randomized controlled trials to test the safety and efficacy of pharmacological as well as non-pharmacological and composite prevention regimens to minimize the risk of PSD in stroke survivors. Integrative strategies combining personalized non-pharmacological interventions such as educational, mental, and physical health support, and pharmacological strategies such as SSRIs may be the most promising approach to prevent PSD.

Effects of digitalized university curriculum-associated teaching on the equilibrium of autonomic neurophysiology and disposition of learners in medical school (EDUCATE-AND-LEARN): protocol for a randomized crossover study.

BACKGROUND: Homoeostasis of the autonomic nervous system (ANS) contributes to cognitive functional integrity in learners and can be greatly influenced by emotions and stress. While moderate stress can enhance learning and memory processes, long-term stress compromises learning performance in a face-to-face classroom environment. Integrative online learning and communication tools were shown to be beneficial for visualization and comprehension but their effects on the ANS are poorly understood. We aim to assess the effects of video conference-supported live lectures compared to on-site classroom teaching on autonomic functions and their association with learning performance. METHODS AND DESIGN: Fifty mentally and physically healthy medical students will be enrolled in a randomized two-period crossover study. Subjects will attend a seminar, which is held in face-to-face and simultaneously transmitted via videoconference. Subjects will be allocated in two arms in a randomized sequence determining the order in which both seminar settings will be attended. At baseline and throughout the interactive seminar subjects will undergo detailed autonomic testing comprising neurocardiac (heart rate variability), sudomotor (sympathetic skin response), neurovascular (laser Doppler flowmetry) and pupillomotor (pupillography) function. Furthermore, learning progress will be evaluated using pre- and post-tests on the seminar subject and emotions will be assessed using profile of mood state (POMS) questionnaire. STATISTICAL ANALYSIS: Carryover effects will be handled using a two-way repeated measures (mixed model). Between-group differences (baseline vs face-to-face vs videoconference) will be determined using one-way analysis of variance ANOVA followed by Student-Newman-Keul test. LIMITATIONS AND STRENGTHS: This study may elucidate complex interactions between autonomic and emotional dynamics during conventional on-site and video conference-based teaching, thus providing a basis for customized learning and teaching methods. Understanding and utilizing advanced distance learning strategies is particularly important during the current pandemic, which has been limiting on-site teaching dramatically in nearly all countries of the world.

Significant role of female sex hormones in cardiac myofilament activation in angiotensin II-mediated hypertensive rats.

Ovariectomy leads to suppression of cardiac myofilament activation in healthy rats implicating the physiological essence of female sex hormones on myocardial contraction. However, the possible function of these hormones during pathologically induced myofilament adaptation is not known. In this study, sham-operated and ovariectomized female rats were chronically exposed to angiotensin II (AII), which has been shown to cause myocardial adaptation. In the shams, AII induced cardiac adaptation by increasing myofilament Ca(2+) sensitivity. Interestingly, this hypersensitivity was further enhanced in AII-infused ovariectomized rats. Ovariectomy increased the phosphorylation levels of cardiac tropomyosin, which may underlie the mechanism of hypersensitivity. On the other hand, AII infusion did not alter maximal tension that was suppressed after ovariectomy. This finding coincided with a comparable increase in ß-isoform of myosin heavy chains in both ovariectomized groups. Together, it is conceivable that female sex hormones serve as predominant factors that regulate cardiac myofilament activation. Furthermore, they may prevent stress-induced myofilament maladaptation.

Testosterone regulates cardiac contractile activation by modulating SERCA but not NCX activity.

Alterations in intracellular Ca(2+) transients of cardiomyocytes in orchidectomized (ORX) rats could be a cause of cardiac dysfunction in the hypogonadal condition. To investigate the role of male sex hormones in intracellular Ca(2+) homeostasis during relaxation, Ca(2+)-handling activities by sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) and the Na(+)/Ca(2+) exchanger (NCX) were evaluated in the ventricular muscle of 10-wk-old ORX rats with and without testosterone supplementation (2.5 mg/kg testosterone propionate, 2 times/wk). ORX induced a 50% decrease in contraction force accompanied by a prolonged time to achieve 50% relaxation (T(50)) in isolated intact ventricular trabeculae, which was partially corrected by testosterone administration. Maximum active tension was also suppressed in ORX rats without changes in myofilament Ca(2+) sensitivity and passive stiffness of the heart. Using a sarcoplasmic reticulum-enriched membrane preparation, the maximum thapsigargin-sensitive SERCA activity of the ORX rat was 27% lower with an increased Ca(2+) sensitivity, which was prevented by testosterone treatment. However, neither changes in SERCA content nor its modulating components, sarcolipin and heat shock protein 20, were detected in the ORX rat, but there was a significant decrease in the phosphorylated Thr(17) form of phospholamban. Despite a lower level of NCX protein in the heart of ORX rats, prolonged T(50) disappeared after an incubation with thapsigargin (10 µM), implying a lack of effect of male sex hormone deficiency on NCX function. These findings indicate that male sex hormones can regulate cardiac relaxation by acting mainly through SERCA. However, a detailed mechanism of SERCA modulation under male sex hormone deficiency status remains to be explored.