Absence of Tau triggers age-dependent sciatic nerve morphofunctional deficits and motor impairment

Dementia is the cardinal feature of Alzheimer's disease (AD), yet the clinical symptoms of this disorder also include a marked loss of motor function. Tau abnormal hyperphosphorylation and malfunction are well-established key events in AD neuropathology but the impact of the loss of normal Tau function in neuronal degeneration and subsequent behavioral deficits is still debated. While Tau reduction has been increasingly suggested as therapeutic strategy against neurodegeneration, particularly in AD, there is controversial evidence about whether loss of Tau progressively impacts on motor function arguing about damage of CNS motor components. Using a variety of motor-related tests, we herein provide evidence of an age-dependent motor impairment in Tau-/- animals that is accompanied by ultrastructural and functional impairments of the efferent fibers that convey motor-related information. Specifically, we show that the sciatic nerve of old (17-22-months) Tau-/- mice displays increased degenerating myelinated fibers and diminished conduction properties, as compared to age-matched wild-type (Tau+/+) littermates and younger (4-6months) Tau-/- and Tau+/+ mice. In addition, the sciatic nerves of Tau-/- mice exhibit a progressive hypomyelination (assessed by g-ratio) specifically affecting large-diameter, motor-related axons in old animals. These findings suggest that loss of Tau protein may progressively impact on peripheral motor system.The work was supported by grants 'PTDC/SAU-NMC/113934/2009,' 'PTDC/SAU-NSC/118194/2010,' 'SFRH/BPD/97281/2013,' PTDC/SAU-NSC/118194/2010,' 'SFRH/BPD/80118/2011,' 'SFRH/BD/89714/2012' funded by FCT-Portuguese Foundation for Science and Technology and project DoIT-Desenvolvimento e Operacionalizacao da Investigacao de Translacao (No do projeto 13853), funded by Fundo Europeu de Desenvolvimento Regional (FEDER) throughout the Programa Operacional Fatores de Competitividade (POFC). In addition, this work was also co-financed by European Union FP7 project SwitchBox (NS) and the Portuguese North Regional Operational Program (ON.2 - O Novo Norte) under the National Strategic Reference Framework (QREN), through the European Regional Development Fund (FEDER).info:eu-repo/semantics/publishedVersio

Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c

Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose diabetes, but may identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardised proportion of diabetes that was previously undiagnosed, and detected in survey screening, ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the agestandardised proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and surveillance.peer-reviewe

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

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight NCD Risk Factor Collaboration (NCD-RisC)

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions

Subregion-dependent specificities of the hippocampal formation to the acute application of Aβ oligomers

Dissertação de mestrado em Ciências da SaúdeAlzheimer’s disease (AD) is a neurodegenerative disorder and the main cause of dementia worldwide. It is characterized by the presence of extracellular plaques of Amyloid-β (Aβ) and intracellular neurofibrillary tangles of Tau protein. Since the discovery of the mutations leading to the familial form of AD, and their relationship with the overproduction of Aβ, the amyloidogenic hypothesis has been the most accepted theory to explain the neurodegenerative process observed in the disease. Although AD has been intensively studied either by using transgenic animal models or by the application of the Aβ peptides in the hippocampus, in vivo and in vitro, the exact mechanisms leading to neurodegeneration still remain unclear. Probably due to methodological variations, but also because of different intrinsic properties of the different hippocampal subregions, several contradictions are reported in the literature regarding the susceptibility of the CA1 and the dentate gyrus (DG) to Aβ peptides. Indeed, in the presence of two different protocols (theta-burst stimulation and high frequency stimulation), we observed great differences in long term potentiation (LTP) induction between CA1 and the DG, with the DG only presenting LTP in the presence of high frequency stimulation using double stimulation and the GABAA antagonist picrotoxin. Unexpectedly, the application of different neurotoxic concentrations of Aβ (200 nM, 500 nM and 1 μM) in CA1 only resulted in increased paired pulse facilitation in the presence of 1 μM of Aβ. Conversely, in the DG, there were no differences in any of the three measures assessed (input-output relationship, paired pulse facilitation and LTP), in the presence of 200 nM of Aβ. These results showed that, despite the marked intrinsic differences between CA1 and the DG, these two subregions were not differently affected by the application of Aβ oligomers. Possible methodological variations are discussed that could explain the observed results.A Doença de Alzheimer (DA) é uma desordem neurodegenerativa e a causa mais comum de demência em todo o mundo. Esta é caracterizada pela presença de placas extracelulares de proteína β-amiloide (βA) e de tranças neurofibrilares intracelulares de proteína Tau. Com a descoberta das mutações genéticas envolvidas na forma familiar da DA, a hipótese amiloidogénica tem sido a mais aceite para explicar o processo neurodegenerativo observado na doença. Apesar de intensivamente estudada, quer com recurso a modelos animais transgénicos quer com a aplicação de βA in vivo e in vitro, os mecanismos responsáveis pelo processo neurodegenerativo ainda não são claros. Provavelmente devido a variações metodológicas, mas também pelo facto de as diferentes sub-regiões da formação hipocampal apresentarem diferentes características, intrínsecas a cada uma delas, várias contradições estão descritas na literatura no que diz respeito à diferente susceptibilidade de CA1 e do giro denteado (GD) à aplicação de péptidos de βA. De facto, durante a utilização de dois protocolos (estimulação por surtos teta e estimulação de alta frequência), foram observadas diferenças consideráveis na indução de potenciação de longo termo (PLT) no CA1 e no GD, com o GD a apresentar PLT apenas na presença de um protocolo de estimulação de alta frequência quando aplicado com o dobro da estimulação, e com o antagonista de receptores GABAA, pricrotoxina. Inesperadamente, constatou-se que a aplicação de diferentes concentrações neurotóxicas de βA (200 nM, 500 nM e 1 μM) em CA1 só causou diferenças na facilitação por pulsos encadeados aquando da aplicação de 1 μM de βA. Por sua vez, no GD, não foram observadas quaisquer diferenças em nenhum dos três parâmetros avaliados (curva de calibração, facilitação por pulsos encadeados e PLT), na presença de 200 nM de βA. Em suma, estes resultados mostram que, apesar das marcadas diferenças intrínsecas entre CA1 e o GD, estas duas sub-regiões não mostraram ser afectadas de forma diferente quando expostas a oligomeros de βA. Possíveis variações metodológicas são discutidas que podem explicar os resultados observados

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

International audienceAbstract Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29–39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

: Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Heterogeneous contributions of change in population distribution of body mass index to change in obesity and underweight

From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions