Dynamic physiological alpha-synuclein S129 phosphorylation is driven by neuronal activity

In Parkinson’s disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity. Neuronal activity triggers a sustained increase of pS129 in cultured neurons (200% within 4 h). In accord, brain pS129 is elevated in environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent α-synuclein phosphorylation is S129-specific, reversible, confers no cytotoxicity, and accumulates at synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with a model in which neuronal stimulation enhances Plk2 kinase activity via a calcium/calcineurin pathway to counteract PP2A phosphatase activity for efficient phosphorylation of membrane-bound α-synuclein. Patch clamping of rat SNCA−/− neurons expressing exogenous wild-type or phospho-incompetent (S129A) α-synuclein suggests that pS129 fine-tunes the balance between excitatory and inhibitory neuronal currents. Consistently, our novel S129A knock-in (S129AKI) mice exhibit impaired hippocampal plasticity. The discovery of a key physiological function for pS129 has implications for understanding the role of α-synuclein in neurotransmission and adds nuance to the interpretation of pS129 as a synucleinopathy biomarker

Theories of schizophrenia: a genetic-inflammatory-vascular synthesis

BACKGROUND: Schizophrenia, a relatively common psychiatric syndrome, affects virtually all brain functions yet has eluded explanation for more than 100 years. Whether by developmental and/or degenerative processes, abnormalities of neurons and their synaptic connections have been the recent focus of attention. However, our inability to fathom the pathophysiology of schizophrenia forces us to challenge our theoretical models and beliefs. A search for a more satisfying model to explain aspects of schizophrenia uncovers clues pointing to genetically mediated CNS microvascular inflammatory disease. DISCUSSION: A vascular component to a theory of schizophrenia posits that the physiologic abnormalities leading to illness involve disruption of the exquisitely precise regulation of the delivery of energy and oxygen required for normal brain function. The theory further proposes that abnormalities of CNS metabolism arise because genetically modulated inflammatory reactions damage the microvascular system of the brain in reaction to environmental agents, including infections, hypoxia, and physical trauma. Damage may accumulate with repeated exposure to triggering agents resulting in exacerbation and deterioration, or healing with their removal. There are clear examples of genetic polymorphisms in inflammatory regulators leading to exaggerated inflammatory responses. There is also ample evidence that inflammatory vascular disease of the brain can lead to psychosis, often waxing and waning, and exhibiting a fluctuating course, as seen in schizophrenia. Disturbances of CNS blood flow have repeatedly been observed in people with schizophrenia using old and new technologies. To account for the myriad of behavioral and other curious findings in schizophrenia such as minor physical anomalies, or reported decreased rates of rheumatoid arthritis and highly visible nail fold capillaries, we would have to evoke a process that is systemic such as the vascular and immune/inflammatory systems. SUMMARY: A vascular-inflammatory theory of schizophrenia brings together environmental and genetic factors in a way that can explain the diversity of symptoms and outcomes observed. If these ideas are confirmed, they would lead in new directions for treatments or preventions by avoiding inducers of inflammation or by way of inflammatory modulating agents, thus preventing exaggerated inflammation and consequent triggering of a psychotic episode in genetically predisposed persons

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background: Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories.Methods: We used data from 1990 to 2019 on people aged 30-79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age.Findings: The number of people aged 30-79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306-359) million women and 317 (292-344) million men in 1990 to 626 (584-668) million women and 652 (604-698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55-62) of women and 49% (46-52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43-51) of women and 38% (35-41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20-27) for women and 18% (16-21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran.Interpretation: Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings.Copyright (C) 2021 World Health Organization; licensee Elsevier.</p

Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants

Background Hypertension can be detected at the primary health-care level and low-cost treatments can effectively control hypertension. We aimed to measure the prevalence of hypertension and progress in its detection, treatment, and control from 1990 to 2019 for 200 countries and territories. Methods We used data from 1990 to 2019 on people aged 30–79 years from population-representative studies with measurement of blood pressure and data on blood pressure treatment. We defined hypertension as having systolic blood pressure 140 mm Hg or greater, diastolic blood pressure 90 mm Hg or greater, or taking medication for hypertension. We applied a Bayesian hierarchical model to estimate the prevalence of hypertension and the proportion of people with hypertension who had a previous diagnosis (detection), who were taking medication for hypertension (treatment), and whose hypertension was controlled to below 140/90 mm Hg (control). The model allowed for trends over time to be non-linear and to vary by age. Findings The number of people aged 30–79 years with hypertension doubled from 1990 to 2019, from 331 (95% credible interval 306–359) million women and 317 (292–344) million men in 1990 to 626 (584–668) million women and 652 (604–698) million men in 2019, despite stable global age-standardised prevalence. In 2019, age-standardised hypertension prevalence was lowest in Canada and Peru for both men and women; in Taiwan, South Korea, Japan, and some countries in western Europe including Switzerland, Spain, and the UK for women; and in several low-income and middle-income countries such as Eritrea, Bangladesh, Ethiopia, and Solomon Islands for men. Hypertension prevalence surpassed 50% for women in two countries and men in nine countries, in central and eastern Europe, central Asia, Oceania, and Latin America. Globally, 59% (55–62) of women and 49% (46–52) of men with hypertension reported a previous diagnosis of hypertension in 2019, and 47% (43–51) of women and 38% (35–41) of men were treated. Control rates among people with hypertension in 2019 were 23% (20–27) for women and 18% (16–21) for men. In 2019, treatment and control rates were highest in South Korea, Canada, and Iceland (treatment >70%; control >50%), followed by the USA, Costa Rica, Germany, Portugal, and Taiwan. Treatment rates were less than 25% for women and less than 20% for men in Nepal, Indonesia, and some countries in sub-Saharan Africa and Oceania. Control rates were below 10% for women and men in these countries and for men in some countries in north Africa, central and south Asia, and eastern Europe. Treatment and control rates have improved in most countries since 1990, but we found little change in most countries in sub-Saharan Africa and Oceania. Improvements were largest in high-income countries, central Europe, and some upper-middle-income and recently high-income countries including Costa Rica, Taiwan, Kazakhstan, South Africa, Brazil, Chile, Turkey, and Iran. Interpretation Improvements in the detection, treatment, and control of hypertension have varied substantially across countries, with some middle-income countries now outperforming most high-income nations. The dual approach of reducing hypertension prevalence through primary prevention and enhancing its treatment and control is achievable not only in high-income countries but also in low-income and middle-income settings. Funding WHO

case-controlled study

Aim: To evaluate platelet function in patients with a history of surgical treatment for hepatic hydatid disease (HD). Methods: This retrospective case-controlled study was performed in a state hospital in Turkey from January 2009 to November 2013. The patients were divided into two groups: those evaluated in the preoperative period (Group 1) and those evaluated in the postoperative period (Group 2). The patient groups were compared with a control group (Group 3). All three groups were evaluated using laboratory records from day 1 of the preoperative period and day 30 of the postoperative period. The haematocrit level (HTC), platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and percentage of eosinophils (EOS) were compared among the groups. Results: Fifty-three patients who had undergone surgical treatment of hepatic HD and 55 healthy controls were included in the study. The mean follow-up time for all patients was 45 (14-70) months. The patients comprised 33 (62%) females and 20 (38%) males. The control group comprised 37 (67%) females and 18 (33%) males. The median age of the patients was 48 (19-78) years, while that of the control group was 42 (16-64) years. No significant differences in the HTC, PLT, or EOS were present among the groups. The MPV and PDW indicated that platelet function was significantly different between Group 1 and Groups 2 and 3. Additionally, nine patients had undergone previous surgical treatment for HD. In a separate long-term follow-up, these patients exhibited no statistically significant differences in MPV or PDW between the preoperative and postoperative periods. Conclusions: MPV and PDW can be used in the initial follow-up of patients with hepatic HD, but have limited use in long-term follow-up

case-controlled study

Aim: To evaluate platelet function in patients with a history of surgical treatment for hepatic hydatid disease (HD). Methods: This retrospective case-controlled study was performed in a state hospital in Turkey from January 2009 to November 2013. The patients were divided into two groups: those evaluated in the preoperative period (Group 1) and those evaluated in the postoperative period (Group 2). The patient groups were compared with a control group (Group 3). All three groups were evaluated using laboratory records from day 1 of the preoperative period and day 30 of the postoperative period. The haematocrit level (HTC), platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and percentage of eosinophils (EOS) were compared among the groups. Results: Fifty-three patients who had undergone surgical treatment of hepatic HD and 55 healthy controls were included in the study. The mean follow-up time for all patients was 45 (14-70) months. The patients comprised 33 (62%) females and 20 (38%) males. The control group comprised 37 (67%) females and 18 (33%) males. The median age of the patients was 48 (19-78) years, while that of the control group was 42 (16-64) years. No significant differences in the HTC, PLT, or EOS were present among the groups. The MPV and PDW indicated that platelet function was significantly different between Group 1 and Groups 2 and 3. Additionally, nine patients had undergone previous surgical treatment for HD. In a separate long-term follow-up, these patients exhibited no statistically significant differences in MPV or PDW between the preoperative and postoperative periods. Conclusions: MPV and PDW can be used in the initial follow-up of patients with hepatic HD, but have limited use in long-term follow-up

Platelet function parameters in management of hepatic hydatid disease: a case-controlled study.

AIM: To evaluate platelet function in patients with a history of surgical treatment for hepatic hydatid disease (HD). METHODS: This retrospective case-controlled study was performed in a state hospital in Turkey from January 2009 to November 2013. The patients were divided into two groups: those evaluated in the preoperative period (Group 1) and those evaluated in the postoperative period (Group 2). The patient groups were compared with a control group (Group 3). All three groups were evaluated using laboratory records from day 1 of the preoperative period and day 30 of the postoperative period. The haematocrit level (HTC), platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and percentage of eosinophils (EOS) were compared among the groups. RESULTS: Fifty-three patients who had undergone surgical treatment of hepatic HD and 55 healthy controls were included in the study. The mean follow-up time for all patients was 45 (14-70) months. The patients comprised 33 (62%) females and 20 (38%) males. The control group comprised 37 (67%) females and 18 (33%) males. The median age of the patients was 48 (19-78) years, while that of the control group was 42 (16-64) years. No significant differences in the HTC, PLT, or EOS were present among the groups. The MPV and PDW indicated that platelet function was significantly different between Group 1 and Groups 2 and 3. Additionally, nine patients had undergone previous surgical treatment for HD. In a separate long-term follow-up, these patients exhibited no statistically significant differences in MPV or PDW between the preoperative and postoperative periods. CONCLUSIONS: MPV and PDW can be used in the initial follow-up of patients with hepatic HD, but have limited use in long-term follow-up

Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity

Abstract In Parkinson’s disease and other synucleinopathies, the elevation of α-synuclein phosphorylated at Serine129 (pS129) is a widely cited marker of pathology. However, the physiological role for pS129 has remained undefined. Here we use multiple approaches to show for the first time that pS129 functions as a physiological regulator of neuronal activity. Neuronal activity triggers a sustained increase of pS129 in cultured neurons (200% within 4 h). In accord, brain pS129 is elevated in environmentally enriched mice exhibiting enhanced long-term potentiation. Activity-dependent α-synuclein phosphorylation is S129-specific, reversible, confers no cytotoxicity, and accumulates at synapsin-containing presynaptic boutons. Mechanistically, our findings are consistent with a model in which neuronal stimulation enhances Plk2 kinase activity via a calcium/calcineurin pathway to counteract PP2A phosphatase activity for efficient phosphorylation of membrane-bound α-synuclein. Patch clamping of rat SNCA −/− neurons expressing exogenous wild-type or phospho-incompetent (S129A) α-synuclein suggests that pS129 fine-tunes the balance between excitatory and inhibitory neuronal currents. Consistently, our novel S129A knock-in (S129AKI) mice exhibit impaired hippocampal plasticity. The discovery of a key physiological function for pS129 has implications for understanding the role of α-synuclein in neurotransmission and adds nuance to the interpretation of pS129 as a synucleinopathy biomarker