RESUMEN

BACKGROUND: The occurrence of neonatal abstinence syndrome (NAS) mirrors the growing opioid epidemic in the United States. As Medicaid covers a majority of cases, the commercially insured population has largely been ignored for NAS risk. OBJECTIVE: The objective of this study was to examine Medicaid and commercially insured mother-infant pairs to determine demographic and clinical characteristics associated with NAS length of stay (LOS). RESEARCH DESIGN: This observational, descriptive case-series study utilized administrative claims from HealthCore Integrated Research Database to measure maternal characteristics for 6 months before delivery, and neonatal characteristics and health care service utilization for 3 months after NAS diagnosis. Bootstrapped regressions were used to model LOS. RESULTS: The sample included 1807 mother-infant pairs. Most infants (79%) had Medicaid coverage (Medicaid: N=1419; Commercial: N=388). Although all infants had NAS, Medicaid-insured mothers had more prevalent drug abuse (70.8% vs. 41.0%; P<0.0001), but fewer used prescription opioids (45.3% vs. 60.8%; P<0.0001) compared with commercially insured mothers. Commercially insured infants were sicker, with a higher prevalence of complex chronic conditions, and yet Medicaid-insured infants were admitted to neonatal intensive care unit at a much higher rate (91.1% vs. 78.9%; P<0.0001). After adjustment, neonatal intensive care unit admission (+6.7 d, 95% confidence interval: 4.5-9.3) and chronic complex conditions (+5.2 d, 95% confidence interval: 3.8-6.6) contributed most to LOS. CONCLUSION: A re-evaluation of obstetrical management towards a focus on the history of possible opioid and substance use regardless of insurance type and demographic background might inform efforts to reduce LOS.

Asunto(s)

Cobertura del Seguro/estadística & datos numéricos , Seguro de Salud/estadística & datos numéricos , Tiempo de Internación/estadística & datos numéricos , Medicaid/estadística & datos numéricos , Síndrome de Abstinencia Neonatal/epidemiología , Adulto , Comorbilidad , Femenino , Humanos , Recién Nacido , Unidades de Cuidado Intensivo Neonatal/estadística & datos numéricos , Madres , Índice de Severidad de la Enfermedad , Factores Socioeconómicos , Trastornos Relacionados con Sustancias/clasificación , Trastornos Relacionados con Sustancias/complicaciones , Estados Unidos

RESUMEN

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by loss of α-motor neurons, leading to profound skeletal muscle atrophy. Patients also suffer from decreased bone mineral density and increased fracture risk. The majority of treatments for SMA, approved or in clinic trials, focus on addressing the underlying cause of disease, insufficient production of full-length SMN protein. While restoration of SMN has resulted in improvements in functional measures, significant deficits remain in both mice and SMA patients following treatment. Motor function in SMA patients may be additionally improved by targeting skeletal muscle to reduce atrophy and improve muscle strength. Inhibition of myostatin, a negative regulator of muscle mass, offers a promising approach to increase muscle function in SMA patients. Here we demonstrate that muSRK-015P, a monoclonal antibody which specifically inhibits myostatin activation, effectively increases muscle mass and function in two variants of the pharmacological mouse model of SMA in which pharmacologic restoration of SMN has taken place either 1 or 24 days after birth to reflect early or later therapeutic intervention. Additionally, muSRK-015P treatment improves the cortical and trabecular bone phenotypes in these mice. These data indicate that preventing myostatin activation has therapeutic potential in addressing muscle and bone deficiencies in SMA patients. An optimized variant of SRK-015P, SRK-015, is currently in clinical development for treatment of SMA.

Asunto(s)

Atrofia Muscular Espinal/genética , Miostatina/genética , Miostatina/fisiología , Animales , Anticuerpos Monoclonales , Modelos Animales de Enfermedad , Ratones , Neuronas Motoras/metabolismo , Fuerza Muscular/fisiología , Músculo Esquelético/metabolismo , Atrofia Muscular Espinal/fisiopatología , Miostatina/antagonistas & inhibidores , Proteína 1 para la Supervivencia de la Neurona Motora/genética , Proteína 2 para la Supervivencia de la Neurona Motora/genética

RESUMEN

Daytime light exposure has been reported to impact or have no influence on energy metabolism in humans. Further, whether inter-individual differences in wake, sleep, 24 h energy expenditure, and RQ during circadian entrainment and circadian misalignment are stable across repeated 24 h assessments is largely unknown. We present data from two studies: Study 1 of 15 participants (7 females) exposed to three light exposure conditions: continuous typical room ~100 lx warm white light, continuous ~750 lx warm white light, and alternating hourly ~750 lx warm white and blue-enriched white light on three separate days in a randomized order; and Study 2 of 14 participants (8 females) during circadian misalignment induced by a simulated night shift protocol. Participants were healthy, free of medical disorders, medications, and illicit drugs. Participants maintained a consistent 8 h per night sleep schedule for one week as an outpatient prior to the study verified by wrist actigraphy, sleep diaries, and call-ins to a time stamped recorder. Participants consumed an outpatient energy balance research diet for three days prior to the study. The inpatient protocol for both studies consisted of an initial sleep disorder screening night. For study 1, this was followed by three standard days with 16 h scheduled wakefulness and 8 h scheduled nighttime sleep. For Study 2, it was followed by 16 h scheduled wake and 8 h scheduled sleep at habitual bedtime followed by three night shifts with 8 h scheduled daytime sleep. Energy expenditure was measured using whole-room indirect calorimetry. Constant posture bedrest conditions were maintained to control for energy expenditure associated with activity and the baseline energy balance diet was continued with the same exact meals across days to control for thermic effects of food. No significant impact of light exposure was observed on metabolic outcomes in response to daytime light exposure. Inter-individual variability in energy expenditure was systematic and ranged from substantial to almost perfect consistency during both nighttime sleep and circadian misalignment. Findings show robust and stable trait-like individual differences in whole body 24 h, waking, and sleep energy expenditure, 24 h respiratory quotient-an index of a fat and carbohydrate oxidation-during repeated assessments under entrained conditions, and also in 24 h and sleep energy expenditure during repeated days of circadian misalignment.

RESUMEN

Sex hormones appear to play a role in the regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. The objective was to isolate the effects of estradiol (E2) on central activation of the HPA axis. We hypothesized that the HPA axis response to corticotropin-releasing hormone (CRH) under dexamethasone (Dex) suppression would be exaggerated in response to chronic ovarian hormone suppression and that physiologic E2 add-back would mitigate this response. Thirty premenopausal women underwent 20 wk of gonadotropin-releasing hormone agonist therapy (GnRHAG) and transdermal E2 (0.075 mg per day, GnRHAG + E2, n = 15) or placebo (PL) patch (GnRHAG + PL, n = 15). Women in the GnRHAG + PL and GnRHAG + E2 groups were of similar age (38 (SD 5) yr vs. 36 (SD 7) yr) and body mass index (27 (SD 6) kg/m2 vs. 27 (SD 6) kg/m2). Serum E2 changed differently between the groups ( P = 0.01); it decreased in response to GnRHAG + PL (77.9 ± 17.4 to 23.2 ± 2.6 pg/ml; P = 0.008) and did not change in response to GnRHAG + E2 (70.6 ± 12.4 to 105 ± 30.4 pg/ml; P = 0.36). The incremental area under the curve (AUCINC) responses to CRH were different between the groups for total cortisol ( P = 0.03) and cortisone ( P = 0.04) but not serum adrenocorticotropic hormone (ACTH) ( P = 0.28). When examining within-group changes, GnRHAG + PL did not alter the HPA axis response to Dex/CRH, but GnRHAG + E2 decreased the AUCINC for ACTH (AUCINC, 1,623 ± 257 to 1,211 ± 236 pg/ml·min, P = 0.004), cortisone (1,795 ± 367 to 1,090 ± 281 ng/ml·min, P = 0.009), and total cortisol (7,008 ± 1,387 to 3,893 ± 1,090 ng/ml·min, P = 0.02). Suppression of ovarian hormones by GnRHAG therapy for 20 wk did not exaggerate the HPA axis response to CRH, but physiologic E2 add-back reduced HPA axis activity compared with preintervention levels.

Asunto(s)

Hormona Liberadora de Corticotropina/farmacología , Hormona Liberadora de Gonadotropina/agonistas , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Premenopausia/fisiología , Adiposidad/efectos de los fármacos , Hormona Adrenocorticotrópica/sangre , Adulto , Composición Corporal/efectos de los fármacos , Cortisona/análisis , Cortisona/metabolismo , Dexametasona/farmacología , Método Doble Ciego , Estradiol/farmacología , Femenino , Humanos , Hidrocortisona/análisis , Hidrocortisona/metabolismo , Persona de Mediana Edad

RESUMEN

Aldose reductase (AR: human, AKR1B1; mouse, AKR1B3), the first enzyme in the polyol pathway, plays a key role in mediating myocardial ischemia/reperfusion (I/R) injury. In earlier studies, using transgenic mice broadly expressing human AKR1B1 to human-relevant levels, mice devoid of Akr1b3, and pharmacological inhibitors of AR, we demonstrated that AR is an important component of myocardial I/R injury and that inhibition of this enzyme protects the heart from I/R injury. In this study, our objective was to investigate if AR modulates the ß-catenin pathway and consequent activation of mesenchymal markers during I/R in the heart. To test this premise, we used two different experimental models: in vivo, Akr1b3 null mice and wild type C57BL/6 mice (WT) were exposed to acute occlusion of the left anterior descending coronary artery (LAD) followed by recovery for 48 hours or 28 days, and ex-vivo, WT and Akr1b3 null murine hearts were perfused using the Langendorff technique (LT) and subjected to 30 min of global (zero-flow) ischemia followed by 60 min of reperfusion. Our in vivo results reveal reduced infarct size and improved functional recovery at 48 hours in mice devoid of Akr1b3 compared to WT mice. We demonstrate that the cardioprotection observed in Akr1b3 null mice was linked to acute activation of the ß-catenin pathway and consequent activation of mesenchymal markers and genes linked to fibrotic remodeling. The increased activity of the ß-catenin pathway at 48 hours of recovery post-LAD was not observed at 28 days post-infarction, thus indicating that the observed increase in ß-catenin activity was transient in the mice hearts devoid of Akr1b3. In ex vivo studies, inhibition of ß-catenin blocked the cardioprotection observed in Akr1b3 null mice hearts. Taken together, these data indicate that AR suppresses acute activation of ß-catenin and, thereby, blocks consequent induction of mesenchymal markers during early reperfusion after myocardial ischemia. Inhibition of AR might provide a therapeutic opportunity to optimize cardiac remodeling after I/R injury.

Asunto(s)

Aldehído Reductasa/metabolismo , Biomarcadores/metabolismo , Mesodermo/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , beta Catenina/metabolismo , Aldehído Reductasa/genética , Animales , Regulación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Crecimiento Transformador beta2/metabolismo , Regulación hacia Arriba

RESUMEN

Athletes as well as elderly or hospitalized patients use dietary protein supplementation to maintain or grow skeletal muscle. It is recognized that high quality protein is needed for muscle accretion, and can be obtained from both animal and plant-based sources. There is interest to understand whether these sources differ in their ability to maintain or stimulate muscle growth and function. In this study, baseline muscle performance was assessed in 50 adult Sprague-Dawley rats after which they were assigned to one of five semi-purified "Western" diets (n = 10/group) differing only in protein source, namely 19 kcal% protein from either milk protein isolate (MPI), whey protein isolate (WPI), soy protein isolate (SPI), soy protein concentrate (SPC) or enzyme-treated soy protein (SPE). The diets were fed for 8 weeks at which point muscle performance testing was repeated and tissues were collected for analysis. There was no significant difference in food consumption or body weights over time between the diet groups nor were there differences in terminal organ and muscle weights or in serum lipids, creatinine or myostatin. Compared with MPI-fed rats, rats fed WPI and SPC displayed a greater maximum rate of contraction using the in vivo measure of muscle performance (p<0.05) with increases ranging from 13.3-27.5% and 22.8-29.5%, respectively at 60, 80, 100 and 150 Hz. When the maximum force was normalized to body weight, SPC-fed rats displayed increased force compared to MPI (p<0.05), whereas when normalized to gastrocnemius weight, WPI-fed rats displayed increased force compared to MPI (p<0.05). There was no difference between groups using in situ muscle performance. In conclusion, soy protein consumption, in high-fat diet, resulted in muscle function comparable to whey protein and improved compared to milk protein. The benefits seen with soy or whey protein were independent of changes in muscle mass or fiber cross-sectional area.

Asunto(s)

Proteínas en la Dieta/administración & dosificación , Suplementos Dietéticos , Músculo Esquelético/fisiología , Animales , Peso Corporal , Masculino , Músculo Esquelético/crecimiento & desarrollo , Ratas , Ratas Sprague-Dawley

RESUMEN

The biochemical, ionic, and signaling changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial ischemia/reperfusion (I/R) injury have not been fully elucidated. The receptor for advanced glycation end-products (RAGE) regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the binding of the RAGE cytoplasmic domain to the diaphanous-related formin, DIAPH1. The aim of this study was to investigate the role of DIAPH1 in the physiological response to experimental myocardial I/R in mice. After subjecting wild-type mice to experimental I/R, myocardial DIAPH1 expression was increased, an effect that was echoed following hypoxia/reoxygenation (H/R) in H9C2 and AC16 cells. Further, compared to wild-type mice, genetic deletion of Diaph1 reduced infarct size and improved contractile function after I/R. Silencing Diaph1 in H9C2 cells subjected to H/R downregulated actin polymerization and serum response factor-regulated gene expression. Importantly, these changes led to increased expression of sarcoplasmic reticulum Ca2+ ATPase and reduced expression of the sodium calcium exchanger. This work demonstrates that DIAPH1 is required for the myocardial response to I/R, and that targeting DIAPH1 may represent an adjunctive approach for myocardial salvage after acute infarction.

Asunto(s)

Proteínas Adaptadoras Transductoras de Señales/genética , Daño por Reperfusión Miocárdica/genética , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Animales , Línea Celular , Modelos Animales de Enfermedad , Forminas , Regulación de la Expresión Génica , Humanos , Ratones , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/patología , Miocitos Cardíacos/patología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , Transducción de Señal/genética , Intercambiador de Sodio-Calcio/genética

RESUMEN

An exercise-induced decrease in serum ionized calcium (iCa) is thought to trigger an increase in parathyroid hormone (PTH), which can stimulate bone resorption. PURPOSE: The purpose of this study was to determine whether taking a chewable calcium (Ca) supplement 30 min before exercise mitigates disruptions in Ca homeostasis and bone resorption in competitive male cyclists. METHODS: Fifty-one men (18 to 45 yr old) were randomized to take either 1000 mg Ca (CA) or placebo (PL) 30 min before a simulated 35-km cycling time trial. Serum iCa and PTH were measured before and immediately after exercise and a marker of bone resorption (C-terminal telopeptide of type I collagen) was measured before and 30 min after exercise. RESULTS: Serum iCa decreased in both groups from before to after exercise (mean ± SD, CA = 4.89 ± 0.16 to 4.76 ± 0.11 mg·dL, PL = 4.92 ± 0.15 to 4.66 ± 0.22 mg·dL, both P ≤ 0.01); the decrease was greater (P = 0.03) in the PL group. There was a nonsignificant (P = 0.07) attenuation of the increase in PTH by Ca supplementation (CA = 30.9 ± 13.0 to 79.7 ± 42.6 pg·mL, PL = 37.1 ± 14.8 to 111.5 ± 49.4 pg·mL, both P ≤ 0.01), but no effect of Ca on the change in C-terminal telopeptide of type I collagen, which increased in both groups (CA = 0.35 ± 0.17 to 0.50 ± 0.21 ng·mL, PL = 0.36 ± 0.13 to 0.54 ± 0.22 ng·mL, both P ≤ 0.01). CONCLUSION: It is possible that ingesting Ca only 30 min before exercise was not a sufficient time interval to optimize gut Ca availability during exercise. Further studies will be needed to determine whether adequate Ca supplementation before and/or during exercise can fully mitigate the exercise-induced decrease in serum iCa and increases in PTH and bone resorption.

Asunto(s)

Resorción Ósea/fisiopatología , Calcio de la Dieta/administración & dosificación , Calcio/sangre , Suplementos Dietéticos , Ejercicio Físico/fisiología , Homeostasis , Adolescente , Adulto , Biomarcadores/sangre , Colágeno Tipo I/sangre , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Hormona Paratiroidea/sangre , Péptidos/sangre , Adulto Joven

RESUMEN

OBJECTIVES: CenteringPregnancy™ group prenatal care is an innovative model with promising evidence of reducing preterm birth. The outpatient costs of offering CenteringPregnancy pose barriers to model adoption. Enhanced provider reimbursement for group prenatal care may improve birth outcomes and generate newborn hospitalization cost savings for insurers. To investigate potential cost savings for investment in CenteringPregnancy, we evaluated the impact on newborn hospital admission costs of a pilot incentive project, where BlueChoice Health Plan South Carolina Medicaid managed care organization paid an obstetric practice offering CenteringPregnancy $175 for each patient who participated in at least five group prenatal care sessions. METHODS: Using a one to many case-control matching without replacement, each CenteringPregnancy participant was matched retrospectively on propensity score, age, race, and clinical risk factors with five individual care participants. We estimated the odds of newborn hospital admission type (neonatal intensive care unit [NICU] or well-baby admission) for matched CenteringPregnancy and individual care cohorts with four or more visits using multivariate logistic regression. Cost savings were calculated using mean costs per admission type at the delivery hospital. RESULTS: Of the CenteringPregnancy newborns, 3.5% had a NICU admission compared with 12.0% of individual care newborns (p < .001). Investing in CenteringPregnancy for 85 patients ($14,875) led to an estimated net savings for the managed care organization of $67,293 in NICU costs. CONCLUSIONS: CenteringPregnancy may reduce costs through fewer NICU admissions. Enhanced reimbursement from payers to obstetric practices supporting CenteringPregnancy sustainability may improve birth outcomes and reduce associated NICU costs.

Asunto(s)

Ahorro de Costo , Medicaid/economía , Obstetricia/métodos , Atención Prenatal/economía , Atención Prenatal/métodos , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Recién Nacido , Medicaid/estadística & datos numéricos , Madres , Embarazo , Resultado del Embarazo , Nacimiento Prematuro/epidemiología , Puntaje de Propensión , Estudios Retrospectivos , Factores de Riesgo , Factores Socioeconómicos , South Carolina/epidemiología , Estados Unidos

RESUMEN

Histone deacetylase 3 (HDAC3), a chromatin-modifying enzyme, requires association with the deacetylase-containing domain (DAD) of the nuclear receptor corepressors NCOR1 and SMRT for its stability and activity. Here, we show that aldose reductase (AR), the rate-limiting enzyme of the polyol pathway, competes with HDAC3 to bind the NCOR1/SMRT DAD. Increased AR expression leads to HDAC3 degradation followed by increased PPARγ signaling, resulting in lipid accumulation in the heart. AR also downregulates expression of nuclear corepressor complex cofactors including Gps2 and Tblr1, thus affecting activity of the nuclear corepressor complex itself. Though AR reduces HDAC3-corepressor complex formation, it specifically derepresses the retinoic acid receptor (RAR), but not other nuclear receptors such as the thyroid receptor (TR) and liver X receptor (LXR). In summary, this work defines a distinct role for AR in lipid and retinoid metabolism through HDAC3 regulation and consequent derepression of PPARγ and RAR.

Asunto(s)

Aldehído Reductasa/metabolismo , PPAR gamma/metabolismo , Receptores de Ácido Retinoico/metabolismo , Animales , Células HEK293 , Histona Desacetilasas/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Co-Represor 1 de Receptor Nuclear/metabolismo , Unión Proteica

RESUMEN

White adipocytes in adults are typically derived from tissue resident mesenchymal progenitors. The recent identification of de novo production of adipocytes from bone marrow progenitor-derived cells in mice challenges this paradigm and indicates an alternative lineage specification that adipocytes exist. We hypothesized that alternative lineage specification of white adipocytes is also present in human adipose tissue. Bone marrow from transgenic mice in which luciferase expression is governed by the adipocyte-restricted adiponectin gene promoter was adoptively transferred to wild-type recipient mice. Light emission was quantitated in recipients by in vivo imaging and direct enzyme assay. Adipocytes were also obtained from human recipients of hematopoietic stem cell transplantation. DNA was isolated, and microsatellite polymorphisms were exploited to quantify donor/recipient chimerism. Luciferase emission was detected from major fat depots of transplanted mice. No light emission was observed from intestines, liver, or lungs. Up to 35% of adipocytes in humans were generated from donor marrow cells in the absence of cell fusion. Nontransplanted mice and stromal-vascular fraction samples were used as negative and positive controls for the mouse and human experiments, respectively. This study provides evidence for a nontissue resident origin of an adipocyte subpopulation in both mice and humans.

Asunto(s)

Adipocitos Blancos/fisiología , Tejido Adiposo/fisiología , Células Madre/fisiología , Animales , Células de la Médula Ósea/fisiología , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Fusión Celular/métodos , Linaje de la Célula/genética , Linaje de la Célula/fisiología , Células Madre Hematopoyéticas/fisiología , Humanos , Masculino , Ratones , Ratones Transgénicos , Regiones Promotoras Genéticas/genética

RESUMEN

BACKGROUND: Heart failure (HF) prognosis is negatively influenced by adverse environmental conditions associated with psychological distress and depression. The underlying mechanisms are not well understood because of insufficient experimental control in prior clinical and epidemiological studies. Using a validated animal model we examined whether distress-producing environmental manipulations (social isolation and crowding) increase HF progression following myocardial infarction (MI). METHODS: MI was induced using coronary artery ligation in 8-week old male Wistar rats (N=52) and results were compared to sham surgery (N=24). Housing conditions were randomly assigned at 5 days post MI or sham surgery (1/cage=isolation, 2/cage=standard reference condition, or 4/cage=crowding) and continued for 17 weeks until the end of observation. The open field test was used to test behavioral responses. Echocardiograms were obtained at weeks 8 and 16, and left ventricular (LV) weight at week 17. RESULTS: Housing conditions increased behavioral markers of distress (p=0.046) with the strongest effects for the isolated (1/cage) (p=0.022). MI did not increase distress-related behaviors compared to sham. MI-surgery resulted in characteristic HF indices (left ventricular ejection fraction (LVEF) at week 16=46 ± 12% vs. 80 ± 7% in sham, p<0.001). Housing condition was not related to LVEF or LV weight (p>0.10). CONCLUSIONS: Adverse environmental conditions, particularly isolated housing, produce increases in some of the behavioral indicators of distress. No effects of housing were found on post-MI progression of HF. The distress-HF associations observed in humans may therefore reflect common underlying factors rather than an independent causal pathway. Stronger environmental challenges may be needed in future animal research examining distress as related HF progression.

Asunto(s)

Aglomeración , Insuficiencia Cardíaca/fisiopatología , Infarto del Miocardio/fisiopatología , Aislamiento Social , Estrés Psicológico/fisiopatología , Animales , Aglomeración/psicología , Modelos Animales de Enfermedad , Ecocardiografía , Insuficiencia Cardíaca/complicaciones , Insuficiencia Cardíaca/psicología , Vivienda para Animales , Masculino , Infarto del Miocardio/complicaciones , Infarto del Miocardio/psicología , Distribución Aleatoria , Ratas Wistar , Aislamiento Social/psicología , Estrés Psicológico/complicaciones , Función Ventricular Izquierda/fisiología

RESUMEN

Suppressing sex hormones in women for 1 wk reduces resting energy expenditure (REE). The effects of more chronic suppression on REE and other components of total energy expenditure (TEE), and whether the reduction in REE is specifically due to loss of estradiol (E2), are not known. We compared the effects of 5 mo of sex hormone suppression (gonadotropin releasing hormone agonist therapy, GnRHAG) with placebo (PL) or E2 add-back therapy on REE and the components of TEE. Premenopausal women received GnRHAG (leuprolide acetate 3.75 mg/mo) and were randomized to receive transdermal therapy that was either E2 (0.075 mg/d; n = 24; means ± SD, aged = 37 ± 8 yr, BMI = 27.3 ± 6.2 kg/m(2)) or placebo (n = 21; aged = 34 ± 9 yr, BMI = 26.8 ± 6.2 kg/m(2)). REE was measured by using a metabolic cart, and TEE, sleep EE (SEE), exercise EE (ExEE, 2 × 30 min bench stepping), non-Ex EE (NExEE), and the thermic effect of feeding (TEF) were measured by using whole room indirect calorimetry. REE decreased in GnRHAG+PL [mean (95% CI), -54 (-98, -15) kcal/d], but not GnRHAG+E2 [+6 (-33, +45) kcal/d] (difference in between-group changes, P < 0.05). TEE decreased in GnRHAG+PL [-128 (-214, -41) kcal/d] and GnRHAG+E2 [-96 (-159, -32) kcal/d], with no significant difference in between-group changes (P = 0.55). SEE decreased similarly in both GnRHAG+PL [-0.07 (-0.12, -0.03) kcal/min] and GnRHAG+E2 [-0.07 (-0.12, -0.02) kcal/min]. ExEE decreased in GnRHAG+PL [-0.46 (-0.79, -0.13) kcal/min], but not GnRHAG+E2 [-0.30 (-0.65, +0.06) kcal/min]. There were no changes in TEF or NExEE in either group. In summary, chronic pharmacologic suppression of sex hormones reduced REE and this was prevented by E2 therapy.

Asunto(s)

Metabolismo Energético/efectos de los fármacos , Estradiol/farmacología , Hormona Liberadora de Gonadotropina/agonistas , Leuprolida/efectos adversos , Entrenamiento de Fuerza , Adulto , Composición Corporal , Densidad Ósea , Método Doble Ciego , Ejercicio Físico , Femenino , Humanos , Persona de Mediana Edad , Premenopausia , Adulto Joven

RESUMEN

OBJECTIVE: Suppression of ovarian hormones in premenopausal women on gonadotropin-releasing hormone agonist (GnRH(AG)) therapy can cause fat mass (FM) gain and fat-free mass (FFM) loss. Whether this is specifically caused by a decline in serum estradiol (E2) is unknown. This study aims to evaluate the effects of GnRH(AG) with placebo (PL) or E2 add-back therapy on FM, FFM, and bone mineral density (BMD). Our exploratory aim was to evaluate the effects of resistance exercise training on body composition during the drug intervention. METHODS: Seventy healthy premenopausal women underwent 5 months of GnRH(AG) therapy and were randomized to receive transdermal E2 (GnRH(AG) + E2, n = 35) or PL (GnRH(AG) + PL, n = 35) add-back therapy. As part of our exploratory aim to evaluate whether exercise can minimize the effects of hormone suppression, some women within each drug arm were randomized to undergo a resistance exercise program (GnRH(AG) + E2 + Ex, n = 12; GnRH(AG) + PL + Ex, n = 12). RESULTS: The groups did not differ in mean (SD) age (36 [8] and 35 [9] y) or mean (SD) body mass index (both 28 [6] kg/m). FFM declined in response to GnRH(AG) + PL (mean, -0.6 kg; 95% CI, -1.0 to -0.3) but not in response to GnRH(AG) + E2 (mean, 0.3 kg; 95% CI, -0.2 to 0.8) or GnRH(AG) + PL + Ex (mean, 0.1 kg; 95% CI, -0.6 to 0.7). Although FM did not change in either group, visceral fat area increased in response to GnRH(AG) + PL but not in response to GnRH(AG) + E2. GnRH(AG) + PL induced a decrease in BMD at the lumbar spine and proximal femur that was prevented by E2. Preliminary data suggest that exercise may have favorable effects on FM, FFM, and hip BMD. CONCLUSIONS: Suppression of ovarian E2 results in loss of bone and FFM and expansion of abdominal adipose depots. Failure of hormone suppression to increase total FM conflicts with previous studies of the effects of GnRH(AG). Further research is necessary to understand the role of estrogen in energy balance regulation and fat distribution.

Asunto(s)

Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Estrógenos Conjugados (USP)/administración & dosificación , Ejercicio Físico , Hormona Liberadora de Gonadotropina/agonistas , Adulto , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Femenino , Humanos , Ovario/efectos de los fármacos , Resultado del Tratamiento

RESUMEN

Prostaglandins (PG) increase in bone in response to mechanical loading and stimulate bone formation. Inhibition of cyclooxygenase (COX), the enzyme responsible for PG synthesis, by non-steroidal anti-inflammatory drugs (NSAIDs) impairs the bone formation response to loading in animals when administered before, but not after, loading. The aim was to determine whether the timing of ibuprofen use (400 mg before versus after exercise sessions) is a significant determinant of the adaptive response of BMD to exercise training in older adults. We hypothesized that taking ibuprofen before exercise would attenuate the improvements in total hip and lumbar spine BMD in response to 36 weeks of training when compared with placebo or with ibuprofen use after exercise. Untrained women and men (N=189) aged 60 to 75 years were randomly assigned to 1 of 3 treatment arms: placebo before and after exercise (PP); ibuprofen before and placebo after exercise (IP); and placebo before and ibuprofen after exercise (PI). The difference between groups in the change in BMD was not significant when IP was compared with either PP (hip, -0.5% (-1.4, 0.4); spine, 0.1% (-0.9, 1.2)) or PI (hip, 0.3% (-0.6, 1.2); spine, 0.5% (-0.5, 1.5)). Ibuprofen use appeared to have more adverse effects on BMD in women than men. The study demonstrated that ibuprofen use did not significantly alter the BMD adaptations to exercise in older adults, but this finding should be interpreted cautiously. It had been expected that the inhibition of bone formation by ibuprofen would be as robust in men than women, but this did not appear to be the case and may have limited the power to detect the effects of ibuprofen. Further research is needed to understand whether NSAID use counteracts, in part, the beneficial effects of exercise on bone.

RESUMEN

INTRODUCTION: Disruptions in calcium (Ca) homeostasis during exercise may influence skeletal adaptations to exercise training. In young men, vigorous cycling causes increases in parathyroid hormone (PTH) and bone resorption (C-terminal telopeptides of type I collagen [CTX]); responses are attenuated by Ca supplementation. The study aimed to determine whether vigorous walking causes similar increases in PTH and CTX in older women and how the timing of Ca supplementation before and during exercise influences these responses. METHODS: In experiment 1, 10 women (61 ± 4 yr) consumed 125 mL of either a Ca-fortified (1 g·L) or control beverage every 15 min during exercise starting 60 min before and continuing during 60 min of exercise. In experiment 2, 23 women (61 ± 4 yr) consumed 200 mL of a Ca-fortified (1 g·L) or control beverage every 15 min starting 15 min before and continuing during 60 min of exercise. The exercise was treadmill walking at 75%-80% V˙O2peak. RESULTS: In experiment 1, serum ionized Ca decreased in the control condition (P < 0.001), but not with Ca supplementation. PTH increased after exercise on both days (Ca, P = 0.05; control, P = 0.009) but was attenuated by Ca supplementation (8.3 vs 26.1 pg·mL; P = 0.03). CTX increased only on the control day (P = 0.02). In experiment 2, serum ionized Ca decreased on Ca and control days (Ca and control, P < 0.001), but less so on the Ca day (P = 0.04). PTH (Ca and control, P < 0.001) and CTX (Ca, P = 0.02; control P = 0.007) increased on the Ca and control day, and there were no differences in the changes. CONCLUSION: The timing of Ca supplementation may be a key mediator of Ca homeostasis during acute exercise. Further research is necessary to determine how this influences skeletal adaptations to training.

Asunto(s)

Calcio de la Dieta/farmacología , Hormona Paratiroidea/sangre , Posmenopausia/sangre , Caminata/fisiología , Anciano , Resorción Ósea , Calcio de la Dieta/administración & dosificación , Colágeno Tipo I/sangre , Estudios Cruzados , Suplementos Dietéticos , Método Doble Ciego , Femenino , Homeostasis , Humanos , Persona de Mediana Edad , Péptidos/sangre

RESUMEN

Oxidative stress is a central mechanism by which the receptor for advanced glycation endproducts (RAGE) mediates its pathological effects. Multiple experimental inquiries in RAGE-expressing cultured cells have demonstrated that ligand-RAGE interaction mediates generation of reactive oxygen species (ROS) and consequent downstream signal transduction and regulation of gene expression. The primary mechanism by which RAGE generates oxidative stress is via activation of NADPH oxidase; amplification mechanisms in the mitochondria may further drive ROS production. Recent studies indicating that the cytoplasmic domain of RAGE binds to the formin mDia1 provide further support for the critical roles of this pathway in oxidative stress; mDia1 was required for activation of rac1 and NADPH oxidase in primary murine aortic smooth muscle cells treated with RAGE ligand S100B. In vivo, in multiple distinct disease models in animals, RAGE action generates oxidative stress and modulates cellular/tissue fate in range of disorders, such as in myocardial ischemia, atherosclerosis, and aneurysm formation. Blockade or genetic deletion of RAGE was shown to be protective in these settings. Indeed, beyond cardiovascular disease, evidence is accruing in human subjects linking levels of RAGE ligands and soluble RAGE to oxidative stress in disorders such as doxorubicin toxicity, acetaminophen toxicity, neurodegeneration, hyperlipidemia, diabetes, preeclampsia, rheumatoid arthritis and pulmonary fibrosis. Blockade of RAGE signal transduction may be a key strategy for the prevention of the deleterious consequences of oxidative stress, particularly in chronic disease.

Asunto(s)

Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Productos Finales de Glicación Avanzada/metabolismo , Estrés Oxidativo/fisiología , Transducción de Señal/fisiología , Animales , Humanos

RESUMEN

We investigated the pre-clinical utility of carbon monoxide form of PEGylated hemoglobin (PEG-Hb also named SANGUINATE(™)) in myocardial infarction (MI) and in particular the response of diabetic tissues to superimposed ischemia/reperfusion injury. SANGUINATE(™) was evaluated in diabetic and normal mice subjected to 30 min of coronary artery ligation followed by either 48 h or 28 days of reperfusion. Our results demonstrate that SANGUINATE(™) was effective in reducing infarct size when administered either prior to left anterior descending coronary artery (LAD) occlusion or during reperfusion. This finding is an important step in exploring the efficacy of a pharmacoinvasive strategy using SANGUINATE(™) in patients with acute coronary syndromes.

Asunto(s)

Monóxido de Carbono/química , Monóxido de Carbono/farmacología , Complicaciones de la Diabetes/prevención & control , Corazón/efectos de los fármacos , Hemoglobinas/química , Hemoglobinas/farmacología , Daño por Reperfusión Miocárdica/prevención & control , Polietilenglicoles/química , Polietilenglicoles/farmacología , Animales , Biomarcadores/metabolismo , Sustitutos Sanguíneos/química , Sustitutos Sanguíneos/farmacología , Complicaciones de la Diabetes/metabolismo , Metabolismo Energético/efectos de los fármacos , Ratones , Infarto del Miocardio/complicaciones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/metabolismo , Estrés Oxidativo/efectos de los fármacos , Factores de Tiempo

RESUMEN

Mitochondrial dysfunction in heart failure includes greater susceptibility to mitochondrial permeability transition (MPT), which may worsen cardiac function and decrease survival. Treatment with a mixture of the n3 polyunsaturated fatty acids (n3 PUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is beneficial in heart failure patients and increases resistance to MPT in animal models. We assessed whether DHA and EPA have similar effects when given individually, and whether they prolong survival in heart failure. Male δ-sarcoglycan null cardiomyopathic hamsters were untreated or given either DHA, EPA, or a 1:1 mixture of DHA + EPA at 2.1% of energy intake. Treatment did not prolong survival: mean survival was 298 ± 15 days in untreated hamsters and 335 ± 17, 328 ± 14, and 311 ± 15 days with DHA, EPA, and DHA + EPA, respectively (n = 27-32/group). A subgroup of cardiomyopathic hamsters treated for 26 wk had impaired left ventricular function and increased cardiomyocyte apoptosis compared with normal hamsters, which was unaffected by n3 PUFA treatment. Evaluation of oxidative phosphorylation in isolated subsarcolemmal and interfibrillar mitochondria with substrates for complex I or II showed no effect of n3 PUFA treatment. On the other hand, interfibrillar mitochondria from cardiomyopathic hamsters were significantly more sensitive to Ca(2+)-induced MPT, which was completely normalized by treatment with DHA and partially corrected by EPA. In conclusion, treatment with DHA or EPA normalizes Ca(2+)-induced MPT in cardiomyopathic hamsters but does not prolong survival or improve cardiac function. This suggest that greater susceptibility to MPT is not a contributor to cardiac pathology and poor survival in heart failure.

Asunto(s)

Cardiomiopatía Dilatada/tratamiento farmacológico , Cardiotónicos/farmacología , Ácidos Docosahexaenoicos/farmacología , Ácido Eicosapentaenoico/farmacología , Insuficiencia Cardíaca/tratamiento farmacológico , Mitocondrias Cardíacas/efectos de los fármacos , Proteínas de Transporte de Membrana Mitocondrial/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Animales , Animales Modificados Genéticamente , Apoptosis/efectos de los fármacos , Calcio/metabolismo , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Cardiomiopatía Dilatada/fisiopatología , Cricetinae , Modelos Animales de Enfermedad , Quimioterapia Combinada , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Masculino , Mitocondrias Cardíacas/metabolismo , Mitocondrias Cardíacas/patología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Poro de Transición de la Permeabilidad Mitocondrial , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Fosforilación Oxidativa/efectos de los fármacos , Fosfolípidos/metabolismo , Sarcoglicanos/deficiencia , Sarcoglicanos/genética , Volumen Sistólico/efectos de los fármacos , Factores de Tiempo , Función Ventricular Izquierda/efectos de los fármacos

RESUMEN

Aldose reductase (AR), an enzyme mediating the first step in the polyol pathway of glucose metabolism, is associated with complications of diabetes mellitus and increased cardiac ischemic injury. We investigated whether deleterious effects of AR are due to its actions specifically in cardiomyocytes. We created mice with cardiac specific expression of human AR (hAR) using the α-myosin heavy chain (MHC) promoter and studied these animals during aging and with reduced fatty acid (FA) oxidation. hAR transgenic expression did not alter cardiac function or glucose and FA oxidation gene expression in young mice. However, cardiac overexpression of hAR caused cardiac dysfunction in older mice. We then assessed whether hAR altered heart function during ischemia reperfusion. hAR transgenic mice had greater infarct area and reduced functional recovery than non-transgenic littermates. When the hAR transgene was crossed onto the PPAR alpha knockout background, another example of greater heart glucose oxidation, hAR expressing mice had increased heart fructose content, cardiac fibrosis, ROS, and apoptosis. In conclusion, overexpression of hAR in cardiomyocytes leads to cardiac dysfunction with aging and in the setting of reduced FA and increased glucose metabolism. These results suggest that pharmacological inhibition of AR will be beneficial during ischemia and in some forms of heart failure.

Asunto(s)

Aldehído Reductasa/fisiología , Insuficiencia Cardíaca/enzimología , Isquemia Miocárdica/enzimología , Miocitos Cardíacos/enzimología , Aldehído Reductasa/biosíntesis , Aldehído Reductasa/genética , Animales , Apoptosis , Ceramidas/metabolismo , Ácidos Grasos/metabolismo , Fibrosis/enzimología , Fructosa/metabolismo , Glucosa/metabolismo , Insuficiencia Cardíaca/diagnóstico por imagen , Insuficiencia Cardíaca/fisiopatología , Humanos , Metabolismo de los Lípidos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Ratones Transgénicos , Isquemia Miocárdica/diagnóstico por imagen , Isquemia Miocárdica/fisiopatología , Miocardio/enzimología , Miocardio/metabolismo , Miocardio/patología , Cadenas Pesadas de Miosina/genética , Oxidación-Reducción , PPAR alfa/genética , Regiones Promotoras Genéticas , Especies Reactivas de Oxígeno/metabolismo , Recuperación de la Función , Daño por Reperfusión/enzimología , Daño por Reperfusión/fisiopatología , Ultrasonografía