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There is an increasing global burden from chikungunya virus (CHIKV). Bangladesh reported a major epidemic in 2017, however, it was unclear if there had been prior widespread transmission. We conducted a nationally representative seroprevalence survey in 70 randomly selected communities immediately prior to the epidemic. We found 69/2,938 (2.4%) of sampled individuals were seropositive to CHIKV. Being seropositive to dengue virus (aOR 3.13 [95% CIs: 1.86-5.27]), male sex (aOR 0.59 [95% CIs: 0.36-0.99]), and community presence of Aedes aegypti mosquitoes (aOR: 1.80, 95% CI: 1.05-3.07) were significantly associated with CHIKV seropositivity. Using a spatial prediction model, we estimated that across the country, 4.99 (95% CI: 4.89 - 5.08) million people had been previously infected. These findings highlight high population susceptibility prior to the major outbreak and that previous outbreaks must have been spatially isolated.
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How the neuromechanics of the lower limb functional muscle groups change with running speed remains to be fully elucidated, with implications for our understanding of human locomotion, conditioning, and injury prevention. This study compared the neuromechanics (ground reaction and joint kinetics, kinematics and muscle activity) of middle-distance athletes running on an instrumented treadmill at six wide-ranging speeds (2.78-8.33 m·s-1). Ground reaction forces and kinematics were analyzed using inverse dynamics to calculate flexor and extensor joint torques, and positive and negative work done by these torques. Contributions of each functional muscle group to the total positive and negative work done by the limb during stance, swing, and the whole stride were quantified. During stance, the ankle plantar flexors were the major energy generator and absorber (>60%) at all speeds, but their contribution to whole stride energy generation and absorption declined with speed. Positive work by the hip extensors rose superlinearly with speed during stance (3-fold) and especially during swing (12-fold), becoming the biggest energy generator across the whole stride at >5 m·s-1. Knee flexor and extensor negative work also rose superlinearly with speed during swing, with the knee flexors becoming the greatest energy absorber over the whole stride at >7.22 m·s-1. Across speeds, plantar flexor peak moment and positive work accounted for 97% and 96% of the variance in step length, and swing hip extension peak moment and positive work accounted for 98% and 99% of the variance in step frequency. There were pronounced speed, phase (stance/swing), and work (positive/negative) dependent contributions of the different functional muscle groups during running, with extensive implications for conditioning and injury prevention.
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Músculo Esquelético , Carrera , Humanos , Carrera/fisiología , Fenómenos Biomecánicos , Músculo Esquelético/fisiología , Masculino , Adulto , Adulto Joven , Electromiografía , Torque , Extremidad Inferior/fisiología , Articulación del Tobillo/fisiología , Femenino , Marcha/fisiología , Articulación de la Rodilla/fisiologíaRESUMEN
Mitochondrial function is maintained by several strictly coordinated mechanisms, collectively termed mitochondrial quality control mechanisms, including fusion and fission, degradation, and biogenesis. As the primary source of energy in cardiomyocytes, mitochondria are the central organelle for maintaining cardiac function. Since adult cardiomyocytes in humans rarely divide, the number of dysfunctional mitochondria cannot easily be diluted through cell division. Thus, efficient degradation of dysfunctional mitochondria is crucial to maintaining cellular function. Mitophagy, a mitochondria specific form of autophagy, is a major mechanism by which damaged or unnecessary mitochondria are targeted and eliminated. Mitophagy is active in cardiomyocytes at baseline and in response to stress, and plays an essential role in maintaining the quality of mitochondria in cardiomyocytes. Mitophagy is mediated through multiple mechanisms in the heart, and each of these mechanisms can partially compensate for the loss of another mechanism. However, insufficient levels of mitophagy eventually lead to mitochondrial dysfunction and the development of heart failure. In this review, we discuss the molecular mechanisms of mitophagy in the heart and the role of mitophagy in cardiac pathophysiology, with the focus on recent findings in the field.
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Cardiopatías , Mitofagia , Humanos , Adulto , Mitofagia/fisiología , Autofagia/fisiología , Mitocondrias/metabolismo , Cardiopatías/metabolismo , Miocitos Cardíacos/metabolismo , Dinámicas MitocondrialesRESUMEN
Molecular mechanisms underlying the diverse therapeutic effects of anti-diabetic metformin, beyond its anti-hyperglycaemic effects, remain largely unclear. Metformin is reported to reduce the long-term complications of diabetes, including cardiovascular fibrosis and remodelling. Our recent investigations show that Discoidin Domain Receptor 2 (DDR2), a Collagen receptor tyrosine kinase, has an obligate regulatory role in Collagen type I gene expression in cardiac and vascular adventitial fibroblasts, and that it may be a molecular link between arterial fibrosis and metabolic syndrome in rhesus monkeys. Using gene knockdown and overexpression approaches, the present study examined whether DDR2 is a target of metformin and whether, by targeting DDR2, it inhibits Fibronectin and Collagen type I expression in rat aortic adventitial fibroblasts exposed to hyperglycaemic conditions. Metformin was found to attenuate hyperglycaemia-induced increase in DDR2 mRNA and protein expression by inhibiting TGF-ß1/SMAD2/3 signalling that mediates the stimulatory effect of hyperglycaemia on DDR2 expression. Metformin also inhibited DDR2-dependent expression of Fibronectin and Collagen type I, indicating that it regulates these matrix proteins via DDR2 inhibition. The findings identify DDR2, a mediator of cardiovascular remodelling, as a molecular target of metformin, thereby uncovering the molecular basis of its protective role in vascular fibrosis and possibly cardiac fibrosis associated with diabetic cardiomyopathy.
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Receptor con Dominio Discoidina 2 , Hiperglucemia , Animales , Ratas , Colágeno Tipo I/metabolismo , Receptor con Dominio Discoidina 2/genética , Receptor con Dominio Discoidina 2/metabolismo , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Fibrosis , Expresión Génica , Hiperglucemia/tratamiento farmacológico , Hiperglucemia/genética , Hiperglucemia/metabolismoRESUMEN
This study probed the largely unexplored regulation and role of fibronectin in Angiotensin II-stimulated cardiac fibroblasts. Using gene knockdown and overexpression approaches, Western blotting, and promoter pull-down assay, we show that collagen type I-activated Discoidin Domain Receptor 2 (DDR2) mediates Angiotensin II-dependent transcriptional upregulation of fibronectin by Yes-activated Protein in cardiac fibroblasts. Furthermore, siRNA-mediated fibronectin knockdown attenuated Angiotensin II-stimulated expression of collagen type I and anti-apoptotic cIAP2, and enhanced cardiac fibroblast susceptibility to apoptosis. Importantly, an obligate role for fibronectin was observed in Angiotensin II-stimulated expression of AT1R, the Angiotensin II receptor, which would link extracellular matrix (ECM) signaling and Angiotensin II signaling in cardiac fibroblasts. The role of fibronectin in Angiotensin II-stimulated cIAP2, collagen type I, and AT1R expression was mediated by Integrin-ß1-integrin-linked kinase signaling. In vivo, we observed modestly reduced basal levels of AT1R in DDR2-null mouse myocardium, which were associated with the previously reported reduction in myocardial Integrin-ß1 levels. The role of fibronectin, downstream of DDR2, could be a critical determinant of cardiac fibroblast-mediated wound healing following myocardial injury. In summary, our findings suggest a complex mechanism of regulation of cardiac fibroblast function involving two major ECM proteins, collagen type I and fibronectin, and their receptors, DDR2 and Integrin-ß1.
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Receptor con Dominio Discoidina 2/deficiencia , Receptor con Dominio Discoidina 2/metabolismo , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Integrina beta1/metabolismo , Miocardio/metabolismo , Receptor de Angiotensina Tipo 1/metabolismo , Angiotensina II/farmacología , Animales , Apoptosis/genética , Proteína 3 que Contiene Repeticiones IAP de Baculovirus/metabolismo , Colágeno Tipo I/antagonistas & inhibidores , Colágeno Tipo I/metabolismo , Receptor con Dominio Discoidina 2/genética , Fibroblastos/efectos de los fármacos , Fibronectinas/genética , Técnicas de Silenciamiento del Gen , Silenciador del Gen , Corazón/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Masculino , Ratones , Ratones Noqueados , Cultivo Primario de Células , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/genética , Transducción de Señal , Proteínas Señalizadoras YAPRESUMEN
Excessive collagen deposition by myofibroblasts during adverse cardiac remodeling leads to myocardial fibrosis that can compromise cardiac function. Unraveling the mechanisms underlying collagen gene expression in cardiac myofibroblasts is therefore an important clinical goal. The collagen receptors, discoidin domain receptor 2 (DDR2), a collagen-specific receptor tyrosine kinase, and integrin-ß1, are reported to mediate tissue fibrosis. Here, we probed the role of DDR2-integrin-ß1 cross-talk in the regulation of collagen α1(I) gene expression in angiotensin II (Ang II)-stimulated cardiac fibroblasts. Results from gene silencing/overexpression approaches, electrophoretic mobility shift assays, and ChIP revealed that DDR2 acts via extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK)-dependent transforming growth factor-ß1 (TGF-ß1) signaling to activate activator protein-1 (AP-1) that in turn transcriptionally enhances the expression of collagen-binding integrin-ß1 in Ang II-stimulated cardiac fibroblasts. The DDR2-integrin-ß1 link was also evident in spontaneously hypertensive rats and DDR2-knockout mice. Further, DDR2 acted via integrin-ß1 to regulate α-smooth muscle actin (α-SMA) and collagen type I expression in Ang II-exposed cardiac fibroblasts. Downstream of the DDR2-integrin-ß1 axis, α-SMA was found to regulate collagen α1(I) gene expression via the Ca2+ channel, transient receptor potential cation channel subfamily C member 6 (TRPC6), and the profibrotic transcription factor, Yes-associated protein (YAP). This finding indicated that fibroblast-to-myofibroblast conversion is mechanistically coupled to collagen expression. The observation that collagen receptor cross-talk underlies α-SMA-dependent collagen type I expression in cardiac fibroblasts expands our understanding of the complex mechanisms involved in collagen gene expression in the heart and may be relevant to cardiac fibrogenesis.
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Actinas/metabolismo , Angiotensina II/farmacología , Fibroblastos/metabolismo , Miocardio/citología , Receptores de Colágeno/metabolismo , Animales , Colágeno/metabolismo , Medios de Cultivo Condicionados , Fibroblastos/efectos de los fármacos , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Integrina beta1/metabolismo , Integrinas/metabolismo , Masculino , Ratones , Ratones Noqueados , Músculo Liso/metabolismo , Interferencia de ARN , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Canales Catiónicos TRPC/metabolismo , Canal Catiónico TRPC6/metabolismoRESUMEN
Relative resistance to apoptosis and the ability to proliferate and produce a collagen-rich scar determine the critical role of cardiac fibroblasts in wound healing and tissue remodeling following myocardial injury. Identification of cardiac fibroblast-specific factors and mechanisms underlying these aspects of cardiac fibroblast function is therefore of considerable scientific and clinical interest. In the present study, gene knockdown and overexpression approaches and promoter binding assays showed that discoidin domain receptor 2 (DDR2), a mesenchymal cell-specific collagen receptor tyrosine kinase localized predominantly in fibroblasts in the heart, acts via ERK1/2 MAPK-activated serum response factor (SRF) transcription factor to enhance the expression of antiapoptotic cIAP2 in cardiac fibroblasts, conferring resistance against oxidative injury. Furthermore, DDR2 was found to act via ERK1/2 MAPK-activated SRF to transcriptionally upregulate Skp2 that in turn facilitated post-translational degradation of p27, the cyclin-dependent kinase inhibitor that causes cell cycle arrest, to promote G1-S transition, as evidenced by Rb phosphorylation, increased proliferating cell nuclear antigen (PCNA) levels, and flow cytometry. DDR2-dependent ERK1/2 MAPK activation also suppressed forkhead box O 3a (FoxO3a)-mediated transcriptional induction of p27. Inhibition of the binding of collagen type I to DDR2 using WRG-28 indicated the obligate role of collagen type I in the activation of DDR2 and its regulatory role in cell survival and cell cycle protein expression. Notably, DDR2 levels positively correlated with SRF, cIAP2, and PCNA levels in cardiac fibroblasts from spontaneously hypertensive rats. To conclude, DDR2-mediated ERK1/2 MAPK activation facilitates coordinated regulation of cell survival and cell cycle progression in cardiac fibroblasts via SRF.NEW & NOTEWORTHY Relative resistance to apoptosis and the ability to proliferate and produce a collagen-rich scar enable cardiac fibroblasts to play a central role in myocardial response to injury. This study reports novel findings that mitogen-stimulated cardiac fibroblasts exploit a common regulatory mechanism involving collagen receptor (DDR2)-dependent activation of ERK1/2 MAPK and serum response factor to achieve coordinated regulation of apoptosis resistance and cell cycle progression, which could facilitate their survival and function in the injured myocardium.
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Ciclo Celular/fisiología , Supervivencia Celular/fisiología , Receptor con Dominio Discoidina 2/metabolismo , Fibroblastos/metabolismo , Miocardio/metabolismo , Factores de Transcripción/metabolismo , Animales , Apoptosis/fisiología , Proliferación Celular/fisiología , Regulación de la Expresión Génica , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Sprague-DawleyRESUMEN
BACKGROUND & AIMS: The number of people living with previous hepatitis C infection that have attained a sustained viral response (SVR) is expected to grow rapidly. So far, the prognosis of this group relative to the general population is unclear. METHODS: Individuals attaining SVR in Scotland in 1996-2011 were identified using a national database. Through record-linkage, we obtained cause-specific mortality data complete to Dec 2013. We calculated standardised mortality ratios (SMRs) to compare the frequency of mortality in SVR patients to the general population. In a parallel analysis, we used Cox regression to identify modifiable patient characteristics associated with post-SVR mortality. RESULTS: We identified 1824 patients, followed on average for 5.2years after SVR. In total, 78 deaths were observed. Overall, all-cause mortality was 1.9 times more frequent for SVR patients than the general population (SMR: 1.86; 95% confidence interval (CI): 1.49-2.32). Significant cause-specific elevations were seen for death due to primary liver cancer (SMR: 23.50; 95% CI: 12.23-45.16), and death due to drug-related causes (SMR: 6.58, 95% CI: 4.15-10.45). Together these two causes accounted for 66% of the total excess death observed. All of the modifiable characteristics associated with increased mortality were markers either of heavy alcohol use or injecting drug use. Individuals without these behavioural markers (32.8% of cohort) experienced equivalent survival to the general population (SMR: 0.70; 95% CI: 0.41-1.18) CONCLUSIONS: Mortality in Scottish SVR patients is higher overall than the general population. The excess was driven by death from drug-related causes and liver cancer. Health risk behaviours emerged as important modifiable determinants of mortality in this population. LAY SUMMARY: Patients cured of hepatitis C through treatment had a higher mortality rate overall than the general population. Most of the surplus mortality was due to drug-related causes and death from liver cancer. A history of heavy alcohol and injecting drug use were associated with a higher mortality risk.
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Antivirales , Hepatitis C Crónica , Respuesta Virológica Sostenida , Adulto , Anciano , Antivirales/efectos adversos , Antivirales/uso terapéutico , Causas de Muerte , Bases de Datos Factuales , Femenino , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/mortalidad , Hepatitis C Crónica/virología , Humanos , Neoplasias Hepáticas/epidemiología , Masculino , Persona de Mediana Edad , Mortalidad , Pronóstico , Factores de Riesgo , Escocia/epidemiologíaRESUMEN
UNLABELLED: Sustained viral response (SVR) is the optimal outcome of hepatitis C virus (HCV) therapy, yet more detailed data are required to confirm its clinical value. Individuals receiving treatment in 1996-2011 were identified using the Scottish HCV clinical database. We sourced data on 10 clinical events: liver, nonliver, and all-cause mortality; first hospitalisation for severe liver morbidity (SLM); cardiovascular disease (CVD); respiratory disorders; neoplasms; alcohol-intoxication; drug intoxication; and violence-related injury (note: the latter three events were selected a priori to gauge ongoing chaotic lifestyle behaviours). We determined the association between SVR attainment and each outcome event, in terms of the relative hazard reduction and absolute risk reduction (ARR). We tested for an interaction between SVR and liver disease severity (mild vs. nonmild), defining mild disease as an aspartate aminotransferase-to-platelet ratio index (APRI) <0.7. Our cohort comprised 3,385 patients (mean age: 41.6 years), followed-up for a median 5.3 years (interquartile range: 3.3-8.2). SVR was associated with a reduced risk of liver mortality (adjusted hazard ratio [AHR]: 0.24; P < 0.001), nonliver mortality (AHR, 0.68; P = 0.026), all-cause mortality (AHR, 0.49; P < 0.001), SLM (AHR, 0.21; P < 0.001), CVD (AHR, 0.70; P = 0.001), alcohol intoxication (AHR, 0.52; P = 0.003), and violence-related injury (AHR, 0.51; P = 0.002). After 7.5 years, SVR was associated with significant ARRs for liver mortality, all-cause mortality, SLM, and CVD (each 3.0%-4.7%). However, we detected a strong interaction, in that ARRs were considerably higher for individuals with nonmild disease than for individuals with mild disease. CONCLUSIONS: The conclusions are 3-fold: (1) Overall, SVR is associated with reduced hazard for a range of hepatic and nonhepatic events; (2) an association between SVR and behavioral events is consistent with SVR patients leading healthier lives; and (3) the short-term value of SVR is greatest for those with nonmild disease.
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Causas de Muerte , Hepatitis C Crónica/tratamiento farmacológico , Hepatitis C Crónica/mortalidad , Cirrosis Hepática/virología , Fallo Hepático/virología , Adulto , Anciano , Antivirales/uso terapéutico , Bases de Datos Factuales , Progresión de la Enfermedad , Femenino , Hepatitis C Crónica/fisiopatología , Humanos , Cirrosis Hepática/mortalidad , Cirrosis Hepática/fisiopatología , Fallo Hepático/mortalidad , Fallo Hepático/fisiopatología , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Conducta de Reducción del Riesgo , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Carga Viral/efectos de los fármacosRESUMEN
BACKGROUND & AIMS: The global burden associated with hepatitis C virus (HCV) infection has prompted a scale-up of antiviral therapy. Hitherto, no data exist on the impact of scaling-up, on the characteristics of treated populations, or on sustained viral response (SVR) rates. We assessed the country-wide scale-up of antiviral therapy in Scotland, a country which nationally monitors uptake of and response to HCV treatment. METHODS: Data for patients, initiated on combined pegylated interferon and ribavirin therapy at 13 specialist HCV clinics in 2001-2010, were extracted from the Scottish HCV Clinical Database (n=3895). Patient characteristics included age, genotype, PWID (people who inject drugs) status, prison referral, and diagnosed cirrhosis. Temporal trends in covariates and adjusted effects on a SVR were examined via mixed-effects regression. RESULTS: The number of patients starting treatment increased from 237 in 2001-2002 to 1560 in 2009-2010, with an increasing trend in SVR from 44% to 57% over this period. For a given clinic, between 2001/2 and 2010 there was a decrease in the odds of those treated being diagnosed with cirrhosis (odds ratio [OR]=0.84 per year), and increasing temporal trends for those treated being PWID (OR=1.08) and prison referrals (OR=1.06). Adjusting for covariates, the proportion of a given clinic's patients achieving SVR was positively associated with the percentage of PWID (OR=1.01 per percent increase; 95% confidence interval [CI]: 1.00-1.02) and genotype 2/3 (OR=1.03; 95% CI: 1.02-1.04). CONCLUSIONS: Despite changes in patient characteristics, a country-wide scale-up of antiviral therapy did not compromise SVR rates. Results are highly relevant to countries planning on scaling-up treatment, given the forthcoming availability of new interferon-free therapies.
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Hepacivirus/genética , Hepatitis C Crónica/tratamiento farmacológico , Interferón-alfa/uso terapéutico , Polietilenglicoles/uso terapéutico , ARN Viral/genética , Ribavirina/uso terapéutico , Adulto , Antivirales/uso terapéutico , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Genotipo , Hepatitis C Crónica/virología , Humanos , Masculino , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Resultado del Tratamiento , Carga ViralRESUMEN
There is a marked difference between males and females in sprint running performance, yet a comprehensive investigation of sex differences in the muscle morphology of sprinters, which could explain the performance differences, remains to be completed. This study compared muscle volumes of 23 individual leg muscles and 5 functional muscle groups, assessed with 3 T magnetic resonance imaging, between male (n = 31) and female (n = 22) sprinters, as well as subgroups of elite males (EM, n = 5), elite females (EF, n = 5), and performance-matched (to elite females) males (PMMEF, n = 6). Differences in muscle volume distribution between EM, EF, and unathletic male (UM) controls were also assessed. For the full cohorts, male sprinters were more muscular than their female counterparts, but the differences were nonuniform and anatomically variable, with the largest differences in the hip extensors and flexors. However, among elite sprinters the sex differences in the volume of the functional muscle groups were almost uniform (absolute volume +47-53%), and the muscle volume distribution of EM was more similar to EF than to UM (P < 0.039). For PMMEF, relative hip extensor volume, but not stature or percent body fat, differentiated for performance (PMMEF and EF < EM) rather than sex. In conclusion, although the full cohorts of sprinters showed a marked sex difference in the amount and distribution of muscle mass, elite sprinters appeared to be selected for a common muscle distribution phenotype that for these elite subgroups was a stronger effect than that of sex. Relative hip extensor muscle volume, rather than stature, percent body fat, or total relative muscle volume, appeared to be the primary determinant of the sex difference in performance.NEW & NOTEWORTHY We present novel evidence suggesting muscle volume, specifically relative hip extensor volume, may be a primary deterministic variable for the sex difference in sprint performance, such that with matched sprint times, male and female sprinters may be expected to have equivalent muscle morphology. We highlight striking similarities in distribution of leg muscle mass between elite male and female sprinters and provide evidence for the existence of a muscular distribution phenotype specific to elite sprinters, irrespective of sex.
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Músculo Esquelético , Carrera , Caracteres Sexuales , Humanos , Masculino , Femenino , Músculo Esquelético/fisiología , Músculo Esquelético/anatomía & histología , Músculo Esquelético/diagnóstico por imagen , Carrera/fisiología , Adulto Joven , Adulto , Imagen por Resonancia Magnética/métodos , Atletas , Rendimiento Atlético/fisiología , Pierna/fisiología , Pierna/anatomía & histología , Factores SexualesRESUMEN
Site-specific information about local water sources is an important part of a community-driven effort to improve environmental conditions. The purpose of this assessment was to gather this information for residents of rural villages in Ghana. Sanitary surveys and bacteriological testing for total coliforms and Escherichia coli (EC) using Colilert(®) were conducted at nearly 80 water sources serving eight villages. A focus group was carried out to assess the desirability and perceived quality of water sources. Standpipes accounted for almost half of the available water sources; however, a third of them were not functioning at the time of the survey. EC bacteria were found in the majority of shallow wells (80%), rivers (67%), and standpipes (61%), as well as 28% of dug wells. Boreholes were free of EC. Residents felt that the standpipes and boreholes produced safe drinking water. Intermittent service and poor water quality from the piped supply has led to limited access to drinking water. The perception of residents, that the water from standpipes is clean and does not need to be treated at home, is particularly troubling in light of the poor bacteriological quality of water from the standpipes.
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Agua Potable/microbiología , Agua Potable/normas , Abastecimiento de Agua/normas , Ghana , Humanos , Población RuralRESUMEN
Nicotinamide adenine dinucleotide (NAD+) kinase (NADK) phosphorylates NAD+, thereby producing nicotinamide adenine dinucleotide phosphate (NADP). Both NADK genes and the NADP(H)-producing mechanism are evolutionarily conserved among archaea, bacteria, plants and mammals. In mammals, NADK is activated by phosphorylation and protein-protein interaction. Recent studies conducted using genetically altered models validate the essential role of NADK in cellular redox homeostasis and metabolism in multicellular organisms. Here, we describe the evolutionary conservation, molecular properties, and signaling mechanisms and discuss the pathophysiological significance of NADK.
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NAD , Plantas , Animales , NAD/metabolismo , NADP/metabolismo , Plantas/metabolismo , Transducción de Señal , Mamíferos/metabolismoRESUMEN
Modification of cysteine residues by oxidative and nitrosative stress affects structure and function of proteins, thereby contributing to the pathogenesis of cardiovascular disease. Although the major function of thioredoxin 1 (Trx1) is to reduce disulfide bonds, it can also act as either a denitrosylase or transnitrosylase in a context-dependent manner. Here we show that Trx1 transnitrosylates Atg7, an E1-like enzyme, thereby stimulating autophagy. During ischemia, Trx1 was oxidized at Cys32-Cys35 of the oxidoreductase catalytic center and S-nitrosylated at Cys73. Unexpectedly, Atg7 Cys545-Cys548 reduced the disulfide bond in Trx1 at Cys32-Cys35 through thiol-disulfide exchange and this then allowed NO to be released from Cys73 in Trx1 and transferred to Atg7 at Cys402. Experiments conducted with Atg7 C402S-knockin mice showed that S-nitrosylation of Atg7 at Cys402 promotes autophagy by stimulating E1-like activity, thereby protecting the heart against ischemia. These results suggest that the thiol-disulfide exchange and the NO transfer are functionally coupled, allowing oxidized Trx1 to mediate a salutary effect during myocardial ischemia through transnitrosylation of Atg7 and stimulation of autophagy.
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Isquemia Miocárdica , Tiorredoxinas , Animales , Ratones , Autofagia , Proteína 7 Relacionada con la Autofagia/genética , Proteína 7 Relacionada con la Autofagia/metabolismo , Cisteína/metabolismo , Disulfuros , Isquemia Miocárdica/genética , Oxidación-Reducción , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMEN
INTRODUCTION: A paucity of research exists examining the importance of muscle morphological and functional characteristics for elite female sprint performance. PURPOSE: This study aimed to compare lower body muscle volumes and vertical jumping power between elite and subelite female sprinters and assess the relationships of these characteristics with sprint race and acceleration performance. METHODS: Five elite (100 m seasons best [SBE 100 ], 11.16 ± 0.06 s) and 17 subelite (SBE 100 , 11.84 ± 0.42 s) female sprinters underwent: 3T magnetic resonance imaging to determine the volume of 23 individual leg muscles/compartments and five functional muscle groups; countermovement jump and 30 m acceleration tests. RESULTS: Total absolute lower body muscle volume was higher in elite versus subelite sprinters (+15%). Elite females exhibited greater muscle volume of the hip flexors (absolute, +28%; relative [to body mass], +19%), hip extensors (absolute, +22%; relative, +14%), and knee extensors (absolute, +21%), demonstrating pronounced anatomically specific muscularity, with relative hip flexor volume alone explaining 48% of sprint performance variability. The relative volume of five individual muscles (sartorius, gluteus maximus, adductor magnus, vastus lateralis, illiopsoas) were both distinct between groups (elite > subelite) and related to SBE 100 ( r = 0.553-0.639), with the combination of the sartorius (41%) and the adductor magnus (17%) explaining 58% of the variance in SBE 100 . Elite female sprinters demonstrated greater absolute countermovement jump power versus subelite, and absolute and relative power were related to both SBE 100 ( r = -0.520 to -0.741) and acceleration performance ( r = 0.569 to 0.808). CONCLUSIONS: This investigation illustrates the distinctive, anatomically specific muscle volume distribution that facilitates elite sprint running in females, and emphasizes the importance of hip flexor and extensor relative muscle volume.
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Rendimiento Atlético , Carrera , Humanos , Femenino , Carrera/fisiología , Músculo Esquelético/fisiología , Músculo Cuádriceps/fisiología , Pierna , Extremidad Inferior/fisiología , Rendimiento Atlético/fisiologíaRESUMEN
The motion of the swing leg of elite sprinters at maximum speed is markedly different from that of slower sprinters, but the mechanisms by which this difference influences performance are unknown. The aim of this study was to establish whether and, if so, how the motion of the swing leg influences maximum achievable running speed using computer simulation. A seven-segment planar computer model was constructed to simulate the stance phase of sprinting. Optimisation was used to maximise the running speed of the model using two different swing leg techniques, one representative of an elite sprint athlete, and the other of a sub-elite athlete. The maximum speed of the model increased when using the swing leg technique of the elite athlete compared with the technique of the sub-elite athlete (10.2 m s-1 vs 9.3 m s-1). This improvement in performance was due to greater horizontal displacement of the mass centre during stance (0.861 m vs 0.814 m), and an increase in average vertical ground force of 51 N (0.06 bodyweights). The increase in vertical force was due to a larger impact peak caused by more negative vertical momentum of the stance leg at touchdown, and subsequently greater torques in the joints of the stance leg which were placed in faster eccentric conditions and at angles closer to optimum during the first half of stance. It is likely that force increases in early stance associated with swing leg technique contribute to the asymmetrical vertical ground reaction force traces observed in elite sprinters.
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Pierna , Fenómenos Biomecánicos , Simulación por Computador , Humanos , TorqueRESUMEN
PURPOSE: This study aimed to investigate the changes in lower limb kinematics, kinetics, and muscle activation during a high-intensity run to fatigue (HIRF). METHODS: Eighteen male and female competitive middle-distance runners performed a HIRF on an instrumented treadmill at a constant but unsustainable middle-distance speed (~3 min) based on a preceding maximum oxygen uptake (VËO2max) test. Three-dimensional kinematics and kinetics were collected and compared between the start, 33%, 67%, and the end of the HIRF. In addition, the activation of eight lower limb muscles of each leg was measured with surface EMG (sEMG). RESULTS: Time to exhaustion was 181 ± 42 s. By the end of the HIRF (i.e., vs the start), ground contact time increased (+4.0%), whereas flight time (-3.2%), peak vertical ground reaction force (-6.1%), and vertical impulse (-4.1%) decreased (all P < 0.05), and joint angles at initial contact became more (dorsi)flexed (ankle, +1.9°; knee, +2.1°; hip, +3.6°; all P < 0.05). During stance, by the end of the HIRF: peak ankle plantarflexion moment decreased by 0.4 N·m·kg-1 (-9.0%), whereas peak knee extension moment increased by 0.24 N·m·kg-1 (+10.3%); similarly, positive ankle plantarflexion work decreased by 0.19 J·kg-1 (-13.9%), whereas positive knee extension work increased by 0.09 J·kg-1 (+33.3%; both P < 0.05) with no change in positive hip extension work. Hip extensor surface EMG amplitude increased during the late swing phase (+20.9-37.3%; P < 0.05). CONCLUSION: Running at a constant middle-distance pace led primarily to the fatigue of the plantarflexors with a compensatory increase in positive work done at the knee. Improving the fatigue resistance of the plantarflexors might be beneficial for middle-distance running performance.
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Extremidad Inferior/fisiología , Fatiga Muscular/fisiología , Músculo Esquelético/fisiología , Carrera/fisiología , Adulto , Articulación del Tobillo/fisiología , Rendimiento Atlético/fisiología , Fenómenos Biomecánicos , Electromiografía , Femenino , Marcha/fisiología , Articulación de la Cadera/fisiología , Humanos , Cinética , Articulación de la Rodilla/fisiología , Masculino , Adulto JovenRESUMEN
Sprinting ability is important for successful performance in sports. The aim of this study was to examine the correlation between force-velocity-power relationship of a whole-body movement and sprint performance. Twelve male participants performed maximal squat jumps with additional loads ranging from 0% to 100% body weight to obtain force-velocity profiles. The mean force and velocity were calculated during the push-off phase for each jump, which resulted in a force-velocity curve. The theoretical maximal force (F0), theoretical maximal velocity (V0) and theoretical maximum power (P0) were computed via extrapolation of the force and velocity data. In the second session, participants performed two 60 m sprints and the time to cover 20 m (t20), time to cover 60 m (t60), and maximum sprint velocity (Vmax) were calculated from the best 60 m trial. Correlation analyses revealed strong and significant correlations between V0 and t20 (r = -0.60), V0 and t60 (r = -0.60), P0 and t20 (r = -0.75) and P0 and t60 (r = -0.78). Multiple linear regression indicated that P0 explained 56%, 61% and 60% of the variability in t20, t60 and Vmax, respectively. Our results emphasise the importance of developing power production capabilities to improve sprint performance.
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PURPOSE: This study aimed to investigate the differences in muscle volumes and strength between male elite sprinters, sub-elite sprinters, and untrained controls and to assess the relationships of muscle volumes and strength with sprint performance. METHODS: Five elite sprinters (100-m season's best equivalent [SBE100], 10.10 ± 0.07 s), 26 sub-elite sprinters (SBE100, 10.80 ± 0.30 s), and 11 untrained control participants underwent 1) 3-T magnetic resonance imaging scans to determine the volume of 23 individual lower limb muscles/compartments and 5 functional muscle groups and 2) isometric strength assessment of lower body muscle groups. RESULTS: Total lower body muscularity was distinct between the groups (controls < sub-elite +20% < elite +48%). The hip extensors exhibited the largest muscle group differences/relationships (elite, +32% absolute and +15% relative [per kg] volume, vs sub-elite explaining 31%-48% of the variability in SBE100), whereas the plantarflexors showed no differences between sprint groups. Individual muscle differences showed pronounced anatomical specificity (elite vs sub-elite absolute volume range, +57% to -9%). Three hip muscles were consistently larger in elite vs sub-elite (tensor fasciae latae, sartorius, and gluteus maximus; absolute, +45%-57%; relative volume, +25%-37%), and gluteus maximus volume alone explained 34%-44% of the variance in SBE100. The isometric strength of several muscle groups was greater in both sprint groups than controls but similar for the sprint groups and not related to SBE100. CONCLUSIONS: These findings demonstrate the pronounced inhomogeneity and anatomically specific muscularity required for fast sprinting and provides novel, robust evidence that greater hip extensor and gluteus maximus volumes discriminate between elite and sub-elite sprinters and are strongly associated with sprinting performance.
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Atletas , Fuerza Muscular/fisiología , Músculo Esquelético/anatomía & histología , Músculo Esquelético/fisiología , Carrera , Adulto , Nalgas , Cadera , Humanos , Contracción Isométrica , Extremidad Inferior/anatomía & histología , Extremidad Inferior/diagnóstico por imagen , Extremidad Inferior/fisiología , Imagen por Resonancia Magnética , Masculino , Músculo Esquelético/diagnóstico por imagen , Muslo , Adulto JovenRESUMEN
The influence of anthropometry and body composition on running economy is unclear, with previous investigations involving small relatively homogeneous groups of runners and limited anthropometric/composition measurements. PURPOSE: To comprehensively investigate the relationships of anthropometry and body composition with running economy within a large heterogeneous sample of runners. METHODS: Eighty-five runners (males [M], n = 45; females [F], n = 40), of diverse competitive standard, performed a discontinuous protocol of incremental treadmill running (4-min stages, 1 km·h increments) to establish locomotory energy cost (LEc) of running at submaximal speeds (averaged across 10-12 km·h; the highest common speed < lactate turnpoint). Measurements of anthropometry, including segment lengths, perimeters, masses and moments of inertia, and body composition were obtained using tape-based measurements and dual-energy x-ray absorptiometry. RESULTS: Absolute LEc (ABSLEc, kcal·km) was positively correlated with 21 (of 27) absolute anthropometric variables in both male and female cohorts. Multiple-regression analyses revealed that one variable (mean perimeter z score) explained 49.4% (M) and 68.9% (F) of the variance in ABSLEc. Relative LEc (RELLEc, kcal·kg·km) was also correlated with five (M) and seven (F) normalized anthropometric variables, and regression analyses explained 31.6% (M; percentage bone mass and normalized hip perimeter) and 33.3% (F, normalized forearm perimeter) of the variance in RELLEc. CONCLUSIONS: These findings provide novel and robust evidence that anthropometry and body composition variables, predominantly indicative of relative slenderness, explain a considerable proportion of the variance in running economy (i.e., more slender, lower energy cost). We, therefore, recommend that runners and coaches are attentive to relative slenderness in selecting and training athletes with the aim of enhancing running economy, and improving distance running performance.