Reproductive Profile of Neuronal Androgen Receptor Knockout Female Mice With a Low Dose of DHT.

Hyperandrogenism and polycystic ovarian syndrome result from the imbalance or increase of androgen levels in females. Androgen receptor (AR) mediates the effects of androgens, and this study examines whether neuronal AR plays a role in reproduction under normal and increased androgen conditions in female mice. The neuron-specific AR knockout (KO) mouse (SynARKO) was generated from a female mouse (synapsin promoter driven Cre) and a male mouse (Ar fl/y). Puberty onset and the levels of reproductive hormones such as LH, FSH, testosterone, and estradiol were comparable between the control and the SynARKO mice. There were no differences in cyclicity and fertility between the control and SynARKO mice, with similar impairment in both groups on DHT treatment. Neuronal AR KO, as in this SynARKO mouse model, did not alleviate the infertility associated with DHT treatment. These studies suggest that neuronal AR KO neither altered reproductive function under physiological androgen levels, nor restored fertility under hyperandrogenic conditions.

Neuronal AR Regulates Glucose Homeostasis and Energy Expenditure in Lean Female Mice With Androgen Excess.

Hyperandrogenemia and polycystic ovary syndrome are a result of the imbalance of androgen levels in females. Androgen receptor (Ar) mediates the effect of androgen, and this study examines how neuronal Ar in the central nervous system mediates metabolism under normal and increased androgen conditions in female mice. The neuron-specific ARKO mouse (SynARKO) was created from female (Ar fl/wt; synapsin promoter driven Cre) and male (Ar fl/y) mice. A glucose tolerance test revealed impaired glucose tolerance that was partially alleviated in the SynARKO-dihydrotestosterone (DHT) mice compared with Con-DHT mice after 4 months of DHT treatment. Heat production and food intake was higher in Con-DHT mice than in Con-veh mice; these effects were not altered between SynARKO-veh and SynARKO-DHT mice, indicating that excess androgens may partially alter calorie intake and energy expenditure in females via the neuronal Ar. The pAkt/Akt activity was higher in the hypothalamus in Con-DHT mice than in Con-veh mice, and this effect was attenuated in SynARKO-DHT mice. Western blot studies show that markers of inflammation and microglia activation, such as NF-kB p-65 and IBA1, increased in the hypothalamus of Con-DHT mice compared with Con-veh. These studies suggest that neuronal Ar mediates the metabolic impacts of androgen excess in females.

Eliminating morbidity caused by neglected tropical diseases by 2030.

The objective of this manuscript is to provide selective examples of the work of the Pan American Health Organization/World Health Organization (PAHO/WHO) Collaborating Centre for Research and Training in Parasite Epidemiology and Control which contribute to the WHO goal of eliminating neglected tropical diseases by 2030. This PAHO/WHO CC specifically aligns its activities with the Sustainable Development Goals and with the goals outlined in the WHO Road Map for Neglected Tropical Diseases 2021-2030. Its role is to contribute to advancing global action on NTDs, primarily through policy development and knowledge translation. Three important projects have recently been completed: 1. Finalizing the Monitoring and Evaluation Framework for the NTD Road Map (published May 2021; this PAHO/WHO CC was a member of the working group); 2. Developing new guidelines for the preventive chemotherapy of Taenia solium taeniasis (published September 2021; this PAHO/WHO CC was co-Chair; and 3. Formulating a policy brief on deworming for adolescent girls and women of reproductive age (published January 2022; this PAHO/WHO CC is co-lead). These projects are the result of the integration of expertise and experience from multiple partners, including from PAHO and WHO (where both organizations provided key leadership), this PAHO/WHO CC, government ministries, civil society organizations and universities, among others. In conclusion, this PAHO/WHO CC contributes timely guidance to country-led evidence-informed public health policy, to cost-effective program implementation and to the identification of priority research topics - all focused, ultimately, on eliminating NTD-attributable morbidity by 2030.

El objetivo de este artículo es proporcionar ejemplos seleccionados de la labor del centro colaborador de investigación y capacitación en epidemiología y control de parásitos de la Organización Panamericana de la Salud/Organización Mundial de la Salud (OPS/OMS), que contribuye al objetivo de la OMS de eliminar las enfermedades tropicales desatendidas para el 2030. Este centro colaborador de la OPS/OMS alinea sus actividades específicamente con los Objetivos de Desarrollo Sostenible y con los objetivos descritos en la Hoja de ruta sobre enfermedades tropicales desatendidas 2021-2030 de la OMS. Su función es contribuir al avance de las medidas mundiales sobre las enfermedades tropicales desatendidas, principalmente mediante la elaboración de políticas y la traducción de conocimiento. Recientemente se han completado tres proyectos importantes: 1) finalización del marco de seguimiento y evaluación de la Hoja de ruta sobre enfermedades tropicales desatendidas (publicado en mayo del 2021; este centro colaborador de la OPS/OMS formó parte del grupo de trabajo); 2) elaboración de nuevas directrices para la quimioterapia preventiva de la teniasis por Taenia solium (publicado en septiembre del 2021; este centro colaborador fue copresidente); y 3) formulación de un informe de políticas sobre la desparasitación de las adolescentes y las mujeres en edad reproductiva (publicado en enero del 2022; este centro colaborador fue coautor). Estos proyectos son el resultado de la integración del conocimiento y la experiencia de múltiples asociados, como la OPS y la OMS (ambas organizaciones ofrecieron un liderazgo clave), este centro colaborador de la OPS/OMS, así como varios ministerios gubernamentales, organizaciones de la sociedad civil y universidades, entre otros. En conclusión, este centro colaborador de la OPS/OMS ofrece orientaciones oportunas para las políticas de salud pública basadas en la evidencia lideradas por los países, la ejecución de programas costo-efectivos y la determinación de los temas de investigación prioritarios, todo ello destinado, en última instancia, a eliminar la morbilidad atribuible a las enfermedades tropicales desatendidas para el 2030.

O objetivo deste manuscrito é fornecer exemplos seletivos do trabalho do Centro Colaborador de Pesquisa e Treinamento em Epidemiologia e Controle de Parasitos da Organização Pan-Americana da Saúde/Organização Mundial da Saúde (OPAS/OMS) que contribuem para a meta da OMS de eliminar até 2030 as doenças tropicais negligenciadas. Este CC da OPAS/OMS alinha especificamente suas atividades com os Objetivos de Desenvolvimento Sustentável e com as metas delineadas no Roteiro da OMS para Doenças Tropicais Negligenciadas 2021-2030. Seu papel é contribuir para o avanço da ação global contra doenças tropicais negligenciadas, principalmente por meio do desenvolvimento de políticas e da tradução de conhecimentos. Três importantes projetos foram concluídos recentemente: 1. Finalização da Estrutura de Monitoramento e Avaliação do Roteiro para as DTN (publicada em maio de 2021 ­ este CC da OPAS/OMS foi membro do grupo de trabalho); 2. Desenvolvimento de novas diretrizes para a quimioprofilaxia da teníase por Taenia solium (publicado em setembro de 2021 ­ este CC da OPAS/OMS foi copresidente); e 3. Formulação de orientação para políticas de desparasitação para adolescentes e mulheres em idade reprodutiva (publicado em janeiro de 2022 ­ este CC da OPAS/OMS foi cogestor). Esses projetos são o resultado da integração de conhecimentos e experiência de múltiplos parceiros, incluindo a OPAS e a OMS (onde ambas as organizações forneceram liderança essencial), este CC da OPAS/OMS, ministérios governamentais, organizações da sociedade civil e universidades, entre outros. Em suma, este CC da OPAS/OMS contribui com orientações oportunas para uma política de saúde pública liderada pelos países e informada com base em evidências, para a implementação de programas com boa relação custo-benefício e para a identificação de tópicos prioritários de pesquisa ­ todos focados, em última análise, na eliminação da morbidade atribuível às DTN até 2030.

Eliminating morbidity caused by neglected tropical diseases by 2030

[ABSTRACT]. The objective of this manuscript is to provide selective examples of the work of the Pan American Health Orga- nization/World Health Organization (PAHO/WHO) Collaborating Centre for Research and Training in Parasite Epidemiology and Control which contribute to the WHO goal of eliminating neglected tropical diseases by 2030. This PAHO/WHO CC specifically aligns its activities with the Sustainable Development Goals and with the goals outlined in the WHO Road Map for Neglected Tropical Diseases 2021-2030. Its role is to contribute to advancing global action on NTDs, primarily through policy development and knowledge translation. Three important projects have recently been completed: 1. Finalizing the Monitoring and Evaluation Framework for the NTD Road Map (published May 2021; this PAHO/WHO CC was a member of the working group); 2. Devel- oping new guidelines for the preventive chemotherapy of Taenia solium taeniasis (published September 2021; this PAHO/WHO CC was co-Chair; and 3. Formulating a policy brief on deworming for adolescent girls and women of reproductive age (published January 2022; this PAHO/WHO CC is co-lead). These projects are the result of the integration of expertise and experience from multiple partners, including from PAHO and WHO (where both organizations provided key leadership), this PAHO/WHO CC, government ministries, civil society organizations and universities, among others. In conclusion, this PAHO/WHO CC contributes timely guidance to country-led evidence-informed public health policy, to cost-effective program implementation and to the identification of priority research topics – all focused, ultimately, on eliminating NTD-attributable morbidity by 2030.

[RESUMEN]. El objetivo de este artículo es proporcionar ejemplos seleccionados de la labor del centro colaborador de investigación y capacitación en epidemiología y control de parásitos de la Organización Panamericana de la Salud/Organización Mundial de la Salud (OPS/OMS), que contribuye al objetivo de la OMS de eliminar las enfermedades tropicales desatendidas para el 2030. Este centro colaborador de la OPS/OMS alinea sus actividades específicamente con los Objetivos de Desarrollo Sostenible y con los objetivos descritos en la Hoja de ruta sobre enfermedades tropicales desatendidas 2021-2030 de la OMS. Su función es contribuir al avance de las medidas mundiales sobre las enfermedades tropicales desatendidas, principalmente mediante la elaboración de políticas y la traducción de conocimiento. Recientemente se han completado tres proyectos importantes: 1) finalización del marco de seguimiento y evaluación de la Hoja de ruta sobre enfermedades tropicales desatendidas (publicado en mayo del 2021; este centro colaborador de la OPS/OMS formó parte del grupo de trabajo); 2) elaboración de nuevas directrices para la quimioterapia preventiva de la teniasis por Taenia solium (publicado en septiembre del 2021; este centro colaborador fue copresidente); y 3) formulación de un informe de políticas sobre la desparasitación de las adolescentes y las mujeres en edad reproductiva (publicado en enero del 2022; este centro colaborador fue coautor). Estos proyectos son el resultado de la integración del conocimiento y la experiencia de múltiples asociados, como la OPS y la OMS (ambas organi- zaciones ofrecieron un liderazgo clave), este centro colaborador de la OPS/OMS, así como varios ministerios gubernamentales, organizaciones de la sociedad civil y universidades, entre otros. En conclusión, este centro colaborador de la OPS/OMS ofrece orientaciones oportunas para las políticas de salud pública basadas en la evidencia lideradas por los países, la ejecución de programas costo-efectivos y la determinación de los temas de investigación prioritarios, todo ello destinado, en última instancia, a eliminar la morbilidad atribuible a las enfermedades tropicales desatendidas para el 2030.

[RESUMO]. O objetivo deste manuscrito é fornecer exemplos seletivos do trabalho do Centro Colaborador de Pesquisa e Treinamento em Epidemiologia e Controle de Parasitos da Organização Pan-Americana da Saúde/Organi- zação Mundial da Saúde (OPAS/OMS) que contribuem para a meta da OMS de eliminar até 2030 as doenças tropicais negligenciadas. Este CC da OPAS/OMS alinha especificamente suas atividades com os Objetivos de Desenvolvimento Sustentável e com as metas delineadas no Roteiro da OMS para Doenças Tropicais Negligenciadas 2021-2030. Seu papel é contribuir para o avanço da ação global contra doenças tropicais negligenciadas, principalmente por meio do desenvolvimento de políticas e da tradução de conhecimentos. Três importantes projetos foram concluídos recentemente: 1. Finalização da Estrutura de Monitoramento e Avaliação do Roteiro para as DTN (publicada em maio de 2021 – este CC da OPAS/OMS foi membro do grupo de trabalho); 2. Desenvolvimento de novas diretrizes para a quimioprofilaxia da teníase por Taenia solium (publicado em setembro de 2021 – este CC da OPAS/OMS foi copresidente); e 3. Formulação de orientação para políticas de desparasitação para adolescentes e mulheres em idade reprodutiva (publicado em janeiro de 2022 – este CC da OPAS/OMS foi cogestor). Esses projetos são o resultado da integração de conhecimen- tos e experiência de múltiplos parceiros, incluindo a OPAS e a OMS (onde ambas as organizações forneceram liderança essencial), este CC da OPAS/OMS, ministérios governamentais, organizações da sociedade civil e universidades, entre outros. Em suma, este CC da OPAS/OMS contribui com orientações oportunas para uma política de saúde pública liderada pelos países e informada com base em evidências, para a implementação de programas com boa relação custo-benefício e para a identificação de tópicos prioritários de pesquisa – todos focados, em última análise, na eliminação da morbidade atribuível às DTN até 2030.

Eliminating morbidity caused by neglected tropical diseases by 2030 / Eliminar la morbilidad causada por las enfermedades tropicales desatendidas para el 2030 / Eliminação até 2030 da morbidade causada pelas doenças tropicais negligenciadas

ABSTRACT The objective of this manuscript is to provide selective examples of the work of the Pan American Health Organization/World Health Organization (PAHO/WHO) Collaborating Centre for Research and Training in Parasite Epidemiology and Control which contribute to the WHO goal of eliminating neglected tropical diseases by 2030. This PAHO/WHO CC specifically aligns its activities with the Sustainable Development Goals and with the goals outlined in the WHO Road Map for Neglected Tropical Diseases 2021-2030. Its role is to contribute to advancing global action on NTDs, primarily through policy development and knowledge translation. Three important projects have recently been completed: 1. Finalizing the Monitoring and Evaluation Framework for the NTD Road Map (published May 2021; this PAHO/WHO CC was a member of the working group); 2. Developing new guidelines for the preventive chemotherapy of Taenia solium taeniasis (published September 2021; this PAHO/WHO CC was co-Chair; and 3. Formulating a policy brief on deworming for adolescent girls and women of reproductive age (published January 2022; this PAHO/WHO CC is co-lead). These projects are the result of the integration of expertise and experience from multiple partners, including from PAHO and WHO (where both organizations provided key leadership), this PAHO/WHO CC, government ministries, civil society organizations and universities, among others. In conclusion, this PAHO/WHO CC contributes timely guidance to country-led evidence-informed public health policy, to cost-effective program implementation and to the identification of priority research topics - all focused, ultimately, on eliminating NTD-attributable morbidity by 2030.

RESUMEN El objetivo de este artículo es proporcionar ejemplos seleccionados de la labor del centro colaborador de investigación y capacitación en epidemiología y control de parásitos de la Organización Panamericana de la Salud/Organización Mundial de la Salud (OPS/OMS), que contribuye al objetivo de la OMS de eliminar las enfermedades tropicales desatendidas para el 2030. Este centro colaborador de la OPS/OMS alinea sus actividades específicamente con los Objetivos de Desarrollo Sostenible y con los objetivos descritos en la Hoja de ruta sobre enfermedades tropicales desatendidas 2021-2030 de la OMS. Su función es contribuir al avance de las medidas mundiales sobre las enfermedades tropicales desatendidas, principalmente mediante la elaboración de políticas y la traducción de conocimiento. Recientemente se han completado tres proyectos importantes: 1) finalización del marco de seguimiento y evaluación de la Hoja de ruta sobre enfermedades tropicales desatendidas (publicado en mayo del 2021; este centro colaborador de la OPS/OMS formó parte del grupo de trabajo); 2) elaboración de nuevas directrices para la quimioterapia preventiva de la teniasis por Taenia solium (publicado en septiembre del 2021; este centro colaborador fue copresidente); y 3) formulación de un informe de políticas sobre la desparasitación de las adolescentes y las mujeres en edad reproductiva (publicado en enero del 2022; este centro colaborador fue coautor). Estos proyectos son el resultado de la integración del conocimiento y la experiencia de múltiples asociados, como la OPS y la OMS (ambas organizaciones ofrecieron un liderazgo clave), este centro colaborador de la OPS/OMS, así como varios ministerios gubernamentales, organizaciones de la sociedad civil y universidades, entre otros. En conclusión, este centro colaborador de la OPS/OMS ofrece orientaciones oportunas para las políticas de salud pública basadas en la evidencia lideradas por los países, la ejecución de programas costo-efectivos y la determinación de los temas de investigación prioritarios, todo ello destinado, en última instancia, a eliminar la morbilidad atribuible a las enfermedades tropicales desatendidas para el 2030.

RESUMO O objetivo deste manuscrito é fornecer exemplos seletivos do trabalho do Centro Colaborador de Pesquisa e Treinamento em Epidemiologia e Controle de Parasitos da Organização Pan-Americana da Saúde/Organização Mundial da Saúde (OPAS/OMS) que contribuem para a meta da OMS de eliminar até 2030 as doenças tropicais negligenciadas. Este CC da OPAS/OMS alinha especificamente suas atividades com os Objetivos de Desenvolvimento Sustentável e com as metas delineadas no Roteiro da OMS para Doenças Tropicais Negligenciadas 2021-2030. Seu papel é contribuir para o avanço da ação global contra doenças tropicais negligenciadas, principalmente por meio do desenvolvimento de políticas e da tradução de conhecimentos. Três importantes projetos foram concluídos recentemente: 1. Finalização da Estrutura de Monitoramento e Avaliação do Roteiro para as DTN (publicada em maio de 2021 - este CC da OPAS/OMS foi membro do grupo de trabalho); 2. Desenvolvimento de novas diretrizes para a quimioprofilaxia da teníase por Taenia solium (publicado em setembro de 2021 - este CC da OPAS/OMS foi copresidente); e 3. Formulação de orientação para políticas de desparasitação para adolescentes e mulheres em idade reprodutiva (publicado em janeiro de 2022 - este CC da OPAS/OMS foi cogestor). Esses projetos são o resultado da integração de conhecimentos e experiência de múltiplos parceiros, incluindo a OPAS e a OMS (onde ambas as organizações forneceram liderança essencial), este CC da OPAS/OMS, ministérios governamentais, organizações da sociedade civil e universidades, entre outros. Em suma, este CC da OPAS/OMS contribui com orientações oportunas para uma política de saúde pública liderada pelos países e informada com base em evidências, para a implementação de programas com boa relação custo-benefício e para a identificação de tópicos prioritários de pesquisa - todos focados, em última análise, na eliminação da morbidade atribuível às DTN até 2030.

Sodium dichloroacetate stimulates cardiac mitochondrial metabolism and improves cardiac conduction in the ovine fetus during labor.

Previous studies in our laboratory have suggested that the increase in stillbirth in pregnancies complicated by chronic maternal stress or hypercortisolemia is associated with cardiac dysfunction in late stages of labor and delivery. Transcriptomics analysis of the overly represented differentially expressed genes in the fetal heart of hypercortisolemic ewes indicated involvement of mitochondrial function. Sodium dichloroacetate (DCA) has been used to improve mitochondrial function in several disease states. We hypothesized that administration of DCA to laboring ewes would improve both cardiac mitochondrial activity and cardiac function in their fetuses. Four groups of ewes and their fetuses were studied: control, cortisol-infused (1 g/kg/day from 115 to term; CORT), DCA-treated (over 24 h), and DCA + CORT-treated; oxytocin was delivered starting 48 h before the DCA treatment. DCA significantly decreased cardiac lactate, alanine, and glucose/glucose-6-phosphate and increased acetylcarnitine/isobutyryl-carnitine. DCA increased mitochondrial activity, increasing oxidative phosphorylation (PCI, PCI + II) per tissue weight or per unit of citrate synthase. DCA also decreased the duration of the QRS, attenuating the prolongation of the QRS observed in CORT fetuses. The effect to reduce QRS duration with DCA treatment correlated with increased glycerophosphocholine and serine and decreased phosphorylcholine after DCA treatment. There were negative correlations of acetylcarnitine/isobutyryl-carnitine to both heart rate (HR) and mean arterial pressure (MAP). These results suggest that improvements in mitochondrial respiration with DCA produced changes in the cardiac lipid metabolism that favor improved conduction in the heart. DCA may therefore be an effective treatment of fetal cardiac metabolic disturbances in labor that can contribute to impairments of fetal cardiac conduction.

Androgen-induced insulin resistance is ameliorated by deletion of hepatic androgen receptor in females.

Androgen excess is one of the most common endocrine disorders of reproductive-aged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear. Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies. We conditionally disrupted hepatocyte AR in female mice developmentally (LivARKO) or acutely by tail vein injection of an adeno-associated virus with a liver-specific promoter for Cre expression in ARfl/fl mice (adLivARKO). We observed normal metabolic function in littermate female Control (ARfl/fl ) and LivARKO (ARfl/fl ; Cre+/- ) mice. Following chronic DHT treatment, female Control mice treated with DHT (Con-DHT) developed impaired glucose tolerance, pyruvate tolerance, and insulin tolerance, not observed in LivARKO mice treated with DHT (LivARKO-DHT). Furthermore, during an euglycemic hyperinsulinemic clamp, the glucose infusion rate was improved in LivARKO-DHT mice compared to Con-DHT mice. Liver from LivARKO, and primary hepatocytes derived from LivARKO, and adLivARKO mice were protected from DHT-induced insulin resistance and increased gluconeogenesis. These data support a paradigm in which elevated androgens in females disrupt metabolic function via hepatic AR and insulin sensitivity was restored by deletion of hepatic AR.

Maternal hypercortisolemia alters placental metabolism: a multiomics view.

Previous studies have suggested that increases in maternal cortisol or maternal stress in late pregnancy increase the risk of stillbirth at term. In an ovine model with increased maternal cortisol over the last 0.20 of gestation, we have previously found evidence of disruption of fetal serum and cardiac metabolomics and altered expression of genes related to mitochondrial function and metabolism in biceps femoris, diaphragm, and cardiac muscle. The present studies were designed to test for effects of chronically increased maternal cortisol on gene expression and metabolomics in placentomes near term. We hypothesized that changes in placenta might underlie or contribute to the alterations in fetal serum metabolomics and thereby contribute to changes in striated muscle metabolism. Placentomes were collected from pregnancies in early labor (143 ± 1 days gestation) of control ewes (n = 7) or ewes treated with cortisol (1 mg·kg-1·day-1 iv; n = 5) starting at day 115 of gestation. Transcriptomics and metabolomics were performed using an ovine gene expression microarray (Agilent 019921) and HR-MAS NMR, respectively. Multiomic analysis indicates that amino acid metabolism, particularly of branched-chain amino acids and glutamate, occur in placenta; changes in amino acid metabolism, degradation, or biosynthesis in placenta were consistent with changes in valine, isoleucine, leucine, and glycine in fetal serum. The analysis also indicates changes in glycerophospholipid metabolism and suggests changes in endoplasmic reticulum stress and antioxidant status in the placenta. These findings suggest that changes in placental function occurring with excess maternal cortisol in late gestation may contribute to metabolic dysfunction at birth.

Fetal ovine skeletal and cardiac muscle transcriptomics are differentially altered by increased maternal cortisol during gestation.

We have previously found that in utero exposure to excess maternal cortisol (1 mg/kg/day) in late gestation increases the incidence of stillbirth during labor and produces fetal bradycardia at birth. In the interventricular septum, mitochondrial DNA (mt-DNA) was decreased, and transcriptomics and metabolomics were consistent with altered mitochondrial metabolism. The present study uses transcriptomics to model effects of increased maternal cortisol on fetal biceps femoris. Transcriptomic modeling revealed that pathways related to mitochondrial metabolism were downregulated, whereas pathways for regulation of reactive oxygen species and activation of the apoptotic cascade were upregulated. Mt-DNA and the protein levels of cytochrome C were significantly decreased in the biceps femoris. RT-PCR validation of the pathways confirmed a significant decrease in SLC2A4 mRNA levels and a significant increase in PDK4, TXNIP, ANGPTL4 mRNA levels, suggesting that insulin sensitivity of the biceps femoris muscle may be reduced in cortisol offspring. We also tested for changes in gene expression in diaphragm by rt-PCR. PDK4, TXNIP, and ANGPTL4 mRNA were also increased in the diaphragm, but SLC2A4, cytochrome C protein, and mt-DNA were unchanged. Comparison of the change in gene expression in biceps femoris to that in cardiac interventricular septum and left ventricle showed few common genes and little overlap in specific metabolic or signaling pathways, despite reduction in mt-DNA in both heart and biceps femoris. Our results suggest that glucocorticoid exposure alters expression of nuclear genes important to mitochondrial activity and oxidative stress in both cardiac and skeletal muscle tissues, but that these effects are tissue-specific.

Pharmacokinetic and Biochemical Profiling of Sodium Dichloroacetate in Pregnant Ewes and Fetuses.

Sodium dichloroacetate (DCA) is an investigational drug that shows promise in the treatment of acquired and congenital mitochondrial diseases, including myocardial ischemia and failure. DCA increases glucose utilization and decreases lactate production, so it may also have clinical utility in reducing lactic acidosis during labor. In the current study, we tested the ability of DCA to cross the placenta and be measured in fetal blood after intravenous administration to pregnant ewes during late gestation and labor. Sustained administration of DCA to the mother over 72 hours achieved pharmacologically active levels of DCA in the fetus and decreased fetal plasma lactate concentrations. Multicompartmental pharmacokinetics modeling indicated that drug metabolism in the fetal and maternal compartments is best described by the DCA inhibiting lactate production in both compartments, consistent with our finding that the hepatic expression of the DCA-metabolizing enzyme glutathione transferase zeta1 was decreased in the ewes and their fetuses exposed to the drug. We provide the first evidence that DCA can cross the placental compartment to enter the fetal circulation and inhibit its own hepatic metabolism in the fetus, leading to increased DCA concentrations and decreased fetal plasma lactate concentrations during its parenteral administration to the mother. SIGNIFICANCE STATEMENT: This study was the first to administer sodium dichloroacetate (DCA) to pregnant animals (sheep). It showed that DCA administered to the mother can cross the placental barrier and achieve concentrations in fetus sufficient to decrease fetal lactate concentrations. Consistent with findings reported in other species, DCA-mediated inhibition of glutathione transferase zeta1 was also observed in ewes, resulting in reduced metabolism of DCA after prolonged administration.

Transcriptomic evidence that cortisol alters perinatal epicardial adipose tissue maturation.

Cortisol administration during late gestation in ewes, modeling maternal stress, resulted in transcriptomic changes suggesting altered maturation and metabolic changes to the offspring heart. This study investigates the effects of cortisol on epicardial adipose tissue (EAT), a visceral fat pad associated with adverse cardiovascular conditions in adults. Pregnant ewes were treated with either 1 mg·kg-1·day-1 cortisol from 115 days gestation to term and EAT collected from term fetuses (control: n = 8, maternal cortisol 1 mg·kg-1·day-1: n = 6). To compare the effects of cortisol to the normal maturation in EAT, we also modeled the normal changes in gene expression in EAT at the transition from in utero to postnatal life using the EAT from control fetuses and from two-week-old lambs (control: n = 7). Transcriptomic modeling was used to identify pathways altered by maternal cortisol overexposure. Transcriptomic modeling confirmed the brown fat phenotype of EAT at term and a transition toward white fat at 2 wk of age in EAT of control fetuses/lambs and highlighted a role of immune responses, including complement coagulation, and serotonin in this transition. Maternal cortisol (1 mg·kg-1·day-1) increased the lipid peroxidation product 4-hydroxynonenal in EAT of term fetuses but did not affect the number of activated macrophages or size of the lipid droplets in the depot; transcriptomics suggested an earlier metabolic maturation of EAT via, in part, increased immune responses.

Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-transmitted helminths: A systematic review, meta-analysis and individual patient data analysis.

BACKGROUND: The soil-transmitted helminths (STH), Ascaris lumbricoides, Trichuris trichiura and hookworms, infect 1.5 billion people worldwide and cause an estimated burden of 3.3 million disability-adjusted life years (DALYs). Current control strategies focus on morbidity reduction through preventive chemotherapy (PC) but the most commonly used recommended drugs (albendazole and mebendazole) are particularly inefficacious against T. trichiura. This, together with the threat of emerging drug resistance, calls for new control strategies, including co-administration with other anthelminthics. Ivermectin plus albendazole is widely used against lymphatic filariasis, but its efficacy and safety against STH infections has not yet been fully understood. METHODS AND FINDINGS: We conducted a systematic literature review and meta-analysis on the efficacy and safety of ivermectin-albendazole co-administration in five different databases (i.e. PubMed, ISI Web of Science, ScienceDirect, CENTRAL and clinicaltrials.gov) from 1960 to January 2018. Four studies reporting efficacy of ivermectin-albendazole against STH infections and five studies on its safety met the selection criteria and were included for quantitative analysis. Ivermectin-albendazole was significantly associated with lower risk (risk ratio (RR) = 0.44, 95% confidence interval (CI) = 0.31-0.62) for T. trichiura infection after treatment compared to albendazole alone. The co-administration revealed no or only a marginal benefit on cure and egg reduction rates over albendazole alone for A. lumbricoides and hookworm infections. Adverse events (AEs) occurring after ivermectin-albendazole co-administration were mostly mild and transient. Overall, the number of individuals reporting any AE was not different (RR = 1.09, 95% CI = 0.87-1.36) in co-treated and albendazole-treated patients. However, although not statistically significant, sub-group analysis showed a tendency for slightly more AEs in patients with filariasis treated with ivermectin-albendazole compared to those treated with albendazole alone (RR = 1.29, 95% CI = 0.81-2.05). CONCLUSIONS: Our findings suggest a good tolerability and higher efficacy of ivermectin-albendazole against T. trichiura compared to the current standard single-dose albendazole treatment, which supports the use of this co-administration in PC programs. Large-scale definitive randomized controlled trials are required to confirm our results.

Determinants of time from HIV infection to linkage-to-care in rural KwaZulu-Natal, South Africa.

OBJECTIVE: To estimate time from HIV infection to linkage-to-care and its determinants. Linkage-to-care is usually assessed using the date of HIV diagnosis as the starting point for exposure time. However, timing of diagnosis is likely endogenous to linkage, leading to bias in linkage estimation. DESIGN: We used longitudinal HIV serosurvey data from a large population-based HIV incidence cohort in KwaZulu-Natal (2004-2013) to estimate time of HIV infection. We linked these data to patient records from a public-sector HIV treatment and care program to determine time from infection to linkage (defined using the date of the first CD4 cell count). METHODS: We used Cox proportional hazards models to estimate time from infection to linkage and the effects of the following covariates on this time: sex, age, education, food security, socioeconomic status, area of residence, distance to clinics, knowledge of HIV status, and whether other household members have initiated antiretroviral therapy. RESULTS: We estimated that it would take an average of 4.9 years for 50% of HIV seroconverters to be linked to care (95% confidence intervals: 4.2-5.7). Among all cohort members who were linked to care, the median CD4 cell count at linkage was 350 cells/µl (95% confidence interval: 330-380). Men and participants aged less than 30 years were found to have the slowest rates of linkage-to-care. Time to linkage became shorter over calendar time. CONCLUSION: Average time from HIV infection to linkage-to-care is long and needs to be reduced to ensure that HIV treatment-as-prevention policies are effective. Targeted interventions for men and young individuals have the largest potential to improve linkage rates.

Preventive chemotherapy in one year reduces by over 80% the number of individuals with soil-transmitted helminthiases causing morbidity: results from meta-analysis.

The morbidity due to Ascaris lumbricoides and Trichuris trichiura is caused by infections of moderate and heavy intensity while hookworm infections of all intensities are recognized to cause morbidity. This study aims to evaluate the effect of repeated rounds of preventive chemotherapy on the proportion of soil-transmitted helminth (STH) infections causing morbidity. We identified studies from 17 countries, reporting changes in the proportion of STH infection causing morbidity between baseline and follow-up. In the studies identified, the average proportion of individuals with STH infections of moderate and heavy intensity was of 14% at baseline and was on average reduced to 2% by the intervention (i.e., 85% reduction). There was an average reduction of 73% after the first year of treatment, which reached almost 80% after 5 years and over 95% in 10 years of deworming interventions. The reduction in hookworm prevalence was 57% after 12 months reaching 78% after 5 years. We consider the results presented in this study especially useful for decision makers as it demonstrates the effectiveness of preventive chemotherapy in reducing STH prevalence and morbidity. We encourage the implementation of deworming programs to achieve the goal, set by WHO for 2020, to eliminate STH morbidity in children.

Adverse Events from a Randomized, Multi-Arm, Placebo-Controlled Trial of Mebendazole in Children 12-24 Months of Age.

Large-scale deworming interventions, using anthelminthic drugs, are recommended in areas where the prevalence of soil-transmitted helminth infection is high. Anthelminthic safety has been established primarily in school-age children. Our objective was to provide evidence on adverse events from anthelminthic use in early childhood. A randomized multi-arm, placebo-controlled trial of mebendazole, administered at different times and frequencies, was conducted in children 12 months of age living in Iquitos, Peru. Children were followed up to 24 months of age. The association between mebendazole administration and the occurrence of a serious or minor adverse event was determined using logistic regression. There was a total of 1,686 administrations of mebendazole and 1,676 administrations of placebo to 1,760 children. Eighteen serious adverse events (i.e., 11 deaths and seven hospitalizations) and 31 minor adverse events were reported. There was no association between mebendazole and the occurrence of a serious adverse event (odds ratio [OR] = 1.21; 95% confidence interval [CI] = 0.47, 3.09) or a minor adverse event (OR = 0.84; 95% CI = 0.41, 1.72). Results from our trial support evidence of safety in administering mebendazole during early childhood. These results support World Health Organization deworming policy and the scaling up of interventions to reach children as of 12 months of age in endemic areas.

The Effect of Deworming on Growth in One-Year-Old Children Living in a Soil-Transmitted Helminth-Endemic Area of Peru: A Randomized Controlled Trial.

BACKGROUND: Appropriate health and nutrition interventions to prevent long-term adverse effects in children are necessary before two years of age. One such intervention may include population-based deworming, recommended as of 12 months of age by the World Health Organization in soil-transmitted helminth (STH)-endemic areas; however, the benefit of deworming has been understudied in early preschool-age children. METHODOLOGY/PRINCIPAL FINDINGS: A randomized, double-blind, placebo-controlled trial was conducted to determine the effect of deworming (500 mg single-dose crushed mebendazole tablet) on growth in one-year-old children in Iquitos, Peru. Children were enrolled during their routine 12-month growth and development clinic visit and followed up at their 18 and 24-month visits. Children were randomly allocated to: Group 1: deworming at 12 months and placebo at 18 months; Group 2: placebo at 12 months and deworming at 18 months; Group 3: deworming at both 12 and 18 months; or Group 4: placebo at both 12 and 18 months (i.e. control group). The primary outcome was weight gain at the 24-month visit. An intention-to-treat approach was used. A total of 1760 children were enrolled between September 2011 and June 2012. Follow-up of 1563 children (88.8%) was completed by July 2013. STH infection was of low prevalence and predominantly light intensity in the study population. All groups gained between 1.93 and 2.05 kg on average over 12 months; the average difference in weight gain (kg) compared to placebo was: 0.05 (95% CI: -0.05, 0.17) in Group 1; -0.07 (95%CI: -0.17, 0.04) in Group 2; and 0.04 (95%CI: -0.06, 0.14) in Group 3. There was no statistically significant difference in weight gain in any of the deworming intervention groups compared to the control group. CONCLUSIONS: Overall, with one year of follow-up, no effect of deworming on growth could be detected in this population of preschool-age children. Low baseline STH prevalence and intensity and/or access to deworming drugs outside of the trial may have diluted the potential effect of the intervention. Additional research is required to overcome these challenges and to contribute to strengthening the evidence base on deworming. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01314937).

The effect of deworming on early childhood development in Peru: A randomized controlled trial.

BACKGROUND: There is a knowledge gap on the effect of early childhood deworming on development in low- and middle-income countries. This evidence is important in the critical window of growth and development before two years of age. METHODS: A randomized controlled trial of the benefit, and optimal timing and frequency, of deworming on development was conducted in Iquitos, Peru. Children were enrolled during routine 12-month growth and development visits and randomly allocated to: (1) deworming at the 12-month visit and placebo at the 18-month visit; (2) placebo at the 12-month visit and deworming at the 18-month visit; (3) deworming at the 12 and 18-month visits; or (4) placebo at the 12 and 18-month visits. The Bayley Scales of Infant Development III was used to assess cognitive, language and motor skills at the 12 and 24-month visits. One-way ANOVA analyses used an intention-to-treat approach. RESULTS: Between September 2011 and June 2012, 1760 children were enrolled. Attendance at the 24-month visit was 88.8% (n=1563). Raw scores on all subtests increased over 12 months; however, cognitive and expressive language scaled scores decreased. There was no statistically significant benefit of deworming, or effect of timing or frequency, on any of the development scores. Baseline height and weight and maternal education were associated with development scores at 24 months. CONCLUSIONS: After 12 months of follow-up, an overall benefit of deworming on cognition, language or fine motor development was not detected. Additional integrated child and maternal interventions should be considered to prevent developmental deficits in this critical period.

Risk factors associated with malnutrition in one-year-old children living in the Peruvian Amazon.

BACKGROUND: Children under two years of age are in the most critical window for growth and development. As mobility increases, this time period also coincides with first exposure to soil-transmitted helminth (STH) infections in tropical and sub-tropical environments. The association between malnutrition and STH infection, however, has been understudied in this vulnerable age group. METHODOLOGY/PRINCIPAL FINDINGS: A nested cross-sectional survey was conducted in 12 and 13-month old children participating in a deworming trial in Iquitos, an STH-endemic area of the Peruvian Amazon. An extensive socio-demo-epi questionnaire was administered to the child's parent. Length and weight were measured, and the Bayley Scales of Infant and Toddler Development were administered to measure cognition, language, and fine motor development. Stool specimens were collected to determine the presence of STH. The association between malnutrition (i.e. stunting and underweight) and STH infection, and other child, maternal, and household characteristics, was analyzed using multivariable Poisson regression. A total of 1760 children were recruited between September 2011 and June 2012. Baseline data showed a prevalence of stunting and underweight of 24.2% and 8.6%, respectively. In a subgroup of 880 randomly-allocated children whose specimens were analyzed by the Kato-Katz method, the prevalence of any STH infection was 14.5%. Risk factors for stunting in these 880 children included infection with at least one STH species (aRR = 1.37; 95% CI 1.01, 1.86) and a lower development score (aRR = 0.97; 95% CI: 0.95, 0.99). A lower development score was also a significant risk factor for underweight (aRR = 0.92; 95% CI: 0.89, 0.95). CONCLUSIONS: The high prevalence of malnutrition, particularly stunting, and its association with STH infection and lower developmental attainment in early preschool-age children is of concern. Emphasis should be placed on determining the most cost-effective, integrated interventions to reduce disease and malnutrition burdens in this vulnerable age group.

Timing of umbilical cord-clamping and infant anaemia: the role of maternal anaemia.

BACKGROUND: Evidence from randomized controlled trials has shown that delayed cord-clamping is beneficial to infant iron status. The role of maternal anaemia in this relationship, however, has not been established. OBJECTIVE: To determine the effect of maternal anaemia at delivery on the association between timing of umbilical cord-clamping and infant anaemia at 4 and 8 months of age. METHODS: A cohort of pregnant women admitted to the labour room of Hospital Iquitos (Iquitos, Peru) and their newborns were recruited into the study during two time periods (18 May to 3 June and 6-20 July 2009). Between the two recruitment periods, the hospital's policy changed from early to delayed umbilical cord-clamping. Maternal haemoglobin levels were measured before delivery, and the time between delivery and cord-clamping was recorded at delivery for the entire cohort. Mother-infant pairs were followed-up at 4 (n = 207) and 8 months (n = 184) post partum. Infant haemoglobin levels were measured at follow-up visits. Data were analysed using logistic regression models. RESULTS: The prevalence of maternal anaemia (Hb <11.0 g/dl) at delivery was 22%. Infant haemoglobin levels at 4 and 8 months of age were 10.4 g/dl and 10.3 g/dl, respectively. Infant haemoglobin levels did not differ significantly between infants born to anaemic mothers and those born to non-anaemic mothers at either 4 or 8 months of age. However, the association between the timing of cord-clamping and infant anaemia was modified by the mother's anaemia status. Significant benefits of delayed cord-clamping in preventing anaemia were found in infants born to anaemic mothers at both 4 months (aOR = 0.59, 95% CI 0.36-0.99) and 8 months (aOR = 0.38, 95% CI 0.19-0.76) of age. CONCLUSION: The study contributes additional evidence in support of delayed cord-clamping. This intervention is likely to have most public health impact in areas with a high prevalence of anaemia during pregnancy.