RESUMEN
DEP domain-containing mechanistic target of rapamycin (mTOR)-interacting protein (DEPTOR) is an important modulator of mTOR, a kinase at the center of two important protein complexes named mTORC1 and mTORC2. These highly studied complexes play essential roles in regulating growth, metabolism, and immunity in response to mitogens, nutrients, and cytokines. Defects in mTOR signaling have been associated with the development of many diseases, including cancer and diabetes, and approaches aiming at modulating mTOR activity are envisioned as an attractive strategy to improve human health. DEPTOR interaction with mTOR represses its kinase activity and rewires the mTOR signaling pathway. Over the last years, several studies have revealed key roles for DEPTOR in numerous biological and pathological processes. Here, we provide the current state of the knowledge regarding the cellular and physiological functions of DEPTOR by focusing on its impact on the mTOR pathway and its role in promoting health and disease.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Envejecimiento/metabolismo , Animales , Humanos , Inmunidad , Péptidos y Proteínas de Señalización Intracelular/química , Estructura Molecular , Neoplasias/metabolismoRESUMEN
INTRODUCTION: Owing to their privileged anatomical location, neurons of the arcuate nucleus of the hypothalamus (ARC) play critical roles in sensing and responding to metabolic signals such as leptin and glucagon-like peptide 1 (GLP-1). In addition to the well-known proopiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons, subpopulations of GABAergic neurons are emerging as key regulators of energy balance. However, the precise identity of these metabolic neurons is still elusive. Here, we identified and characterized the molecular signature of a novel population of GABAergic neurons of the ARC expressing Cellular retinoic acid binding protein 1 (Crabp1). METHODS: Using a combination of immunohistochemistry and in situ hybridization techniques, we investigated the expression of Crabp1 across the mouse brain and characterized the molecular identity of Crabp1ARC neurons. We also determined whether Crabp1ARC neurons are sensitive to fasting, leptin, and GLP1R agonism by assessing cFOS immunoreactivity as a marker of neuronal activity. RESULTS: Crabp1ARC neurons represent a novel GABAergic neuronal population robustly enriched in the ARC and are distinct from the prototypical melanocortin neurons. Crabp1ARC neurons overlap with three subpopulations of yet uncharacterized ARC neurons expressing Htr3b, Tbx19, and Tmem215. Notably, Crabp1ARC neurons express receptors for metabolic hormones and their activity is modulated by the nutritional state and GLP1R agonism. CONCLUSION: Crabp1ARC neurons represent a novel heterogeneous population of GABAergic neurons sensitive to metabolic status.
Asunto(s)
Neuronas GABAérgicas , Liraglutida , Receptores de Ácido Retinoico , Animales , Masculino , Neuronas GABAérgicas/metabolismo , Ratones , Receptores de Ácido Retinoico/metabolismo , Receptores de Ácido Retinoico/agonistas , Liraglutida/farmacología , Ratones Endogámicos C57BL , Leptina/metabolismo , Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/metabolismo , Hipoglucemiantes/farmacologíaRESUMEN
BACKGROUND: The nucleus incertus (NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle of the human brain with an 'unknown' function. More than a century later, the neuroanatomy of the NI has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus. METHODS: Histochemical staining of serial, coronal sections of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal markers, microtubule-associated protein-2 (MAP2), glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin-releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in NI neurons in diverse species. RLN3 and vesicular GABA transporter 1 (vGAT1) mRNA were detected by fluorescent in situ hybridization. Pons sections containing the NI from an AD case were immunostained for phosphorylated-tau, to explore potential relevance to neurodegenerative diseases. Lastly, sections of the human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR. RESULTS: In the dorsal, anterior-medial region of the human pons, neurons containing RLN3- and MAP2-IR, and RLN3/vGAT1 mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67- and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3- and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3 and DG areas of the hippocampus, in the absence of RLN3 mRNA. In the DG, RLN3- and SST-IR were co-localized in a small population of neurons. CONCLUSIONS: Aspects of the anatomy of the human NI are shared across species, including a population of stress-responsive, RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease.
Asunto(s)
Puente , Humanos , Puente/metabolismo , Masculino , Hipocampo/química , Hipocampo/metabolismo , Femenino , Relaxina/metabolismo , Relaxina/genética , Anciano , Neuronas/química , Memoria/fisiología , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Anciano de 80 o más Años , Inmunohistoquímica , Hibridación Fluorescente in Situ , Glutamato Descarboxilasa/metabolismo , Glutamato Descarboxilasa/genética , Receptores de Hormona Liberadora de CorticotropinaRESUMEN
Between 2013 and 2021, indicators of vascular access protection (IPAV) integrating a census of haematomas and multiple punctures were set up on the active file of chronic kidney failure patients with a vascular access dialyzed in Monaco's private haemodialysis center. They could help reduce the occurrence of complications and improve the quality of care offered to patients. This article reports on the results obtained before and after the introduction of this quality approach.
Asunto(s)
Diálisis Renal , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fallo Renal Crónico/terapia , Indicadores de Calidad de la Atención de Salud , Calidad de la Atención de Salud/normas , Diálisis Renal/normas , Dispositivos de Acceso Vascular/normasRESUMEN
The discovery of leptin in 1994 was an "eureka moment" in the field of neurometabolism that provided new opportunities to better understand the central control of energy balance and glucose metabolism. Rapidly, a prevalent model in the field emerged that pro-opiomelanocortin (POMC) neurons were key in promoting leptin's anorexigenic effects and that the arcuate nucleus of the hypothalamus (ARC) was a key region for the regulation of energy homeostasis. While this model inspired many important discoveries, a growing body of literature indicates that this model is now outdated. In this review, we re-evaluate the hypothalamic leptin-melanocortin model in light of recent advances that directly tackle previous assumptions, with a particular focus on the ARC. We discuss how segregated and heterogeneous these neurons are, and examine how the development of modern approaches allowing spatiotemporal, intersectional, and chemogenetic manipulations of melanocortin neurons has allowed a better definition of the complexity of the leptin-melanocortin system. We review the importance of leptin in regulating glucose homeostasis, but not food intake, through direct actions on ARC POMC neurons. We further highlight how non-POMC, GABAergic neurons mediate leptin's direct effects on energy balance and influence POMC neurons.
Asunto(s)
Leptina , Melanocortinas , Melanocortinas/metabolismo , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo , Metabolismo Energético/fisiologíaRESUMEN
Interactions between the brain and distinct adipose depots have a key role in maintaining energy balance, thereby promoting survival in response to metabolic challenges such as cold exposure and starvation. Recently, there has been renewed interest in the specific central neuronal circuits that regulate adipose depots. Here, we review anatomical, genetic and pharmacological studies on the neural regulation of adipose function, including lipolysis, non-shivering thermogenesis, browning and leptin secretion. In particular, we emphasize the role of leptin-sensitive neurons and the sympathetic nervous system in modulating the activity of brown, white and beige adipose tissues. We provide an overview of advances in the understanding of the heterogeneity of the brain regulation of adipose tissues and offer a perspective on the challenges and paradoxes that the community is facing regarding the actions of leptin on this system.
Asunto(s)
Tejido Adiposo/fisiología , Encéfalo/fisiología , Leptina/fisiología , Tejido Adiposo/inervación , Animales , Metabolismo Energético , Humanos , Lipólisis , Neuronas/fisiología , Sistema Nervioso Simpático/fisiología , TermogénesisRESUMEN
Energy homeostasis and metabolism in mammals are strongly influenced by seasonal changes. Variations in photoperiod patterns drive adaptations in body weight and adiposity, reflecting changes in the regulation of food intake and energy expenditure. Humans also show distinct patterns of energy balance depending on the season, being more susceptible to gaining weight during a specific time of the year. Changes in body weight are mainly reflected by the adipose tissue, which is a key metabolic tissue and is highly affected by circannual rhythms. Mostly, in summer-like (long-active) photoperiod, adipocytes adopt a rather anabolic profile, more predisposed to store energy, while food intake increases and energy expenditure is reduced. These metabolic adaptations involve molecular modifications, some of which have been studied during the last years and are summarized in this review. In addition, there is a bidirectional relation between obesity and the seasonal responses, with obesity disrupting some of the seasonal responses observed in healthy mammals, and altered seasonality being highly associated with increased risk of developing obesity. This suggests that changes in photoperiod produce important metabolic alterations in healthy organisms. Biological rhythms impact the regulation of metabolism to different extents, some of which are already known, but further research is needed to fully understand the relationship between energy balance and seasonality.
Asunto(s)
Adiposidad , Fotoperiodo , Animales , Humanos , Obesidad/metabolismo , Peso Corporal/fisiología , Mamíferos/fisiología , Metabolismo Energético/fisiología , Estaciones del AñoRESUMEN
OBJECTIVE: To report a surgical technique and outcomes of transiliosacral toggle suture repair to treat feline bilateral sacroiliac luxation/fracture (SILF). STUDY DESIGN: Retrospective study. ANIMALS: Fifteen client-owned cats. METHODS: The medical records of cats with bilateral SILF treated using a transiliosacral toggle suture repair were reviewed. Short- and medium-term outcomes were assessed through standard postoperative clinical evaluation and radiographs, including measurements of angle of deviation (AoD), percentage of reduction (PoR), and pelvic canal width ratio (PCWR). Long-term functional follow up was obtained from a questionnaire derived from the Feline Musculoskeletal Pain Index (FMPI). RESULTS: Fifteen cats were enrolled retrospectively, among which 13 survived to discharge. One minor wound complication, treated by secondary intention healing, was encountered. No major complication was reported. Immediately postoperatively, the mean absolute PoR values were 88.1 ± 11.2% and 91 ± 11.6% on the right and left side, respectively. The mean absolute AoD was 3.1 ± 2.8°, and the mean PCWR was 1.24 ± 0.08. The medium-term radiographic follow up at a median of 205 (71-682) days postsurgery revealed the good stability of the repair. Excellent functional outcomes were identified upon the analysis of 12 long-term questionnaires at a median of 365 (119-798) days postsurgery. CONCLUSION: Anatomic reduction was satisfactory and comparable with previously described techniques with good implant placement documented. Functional outcomes based on FMPI-derived questionnaires were good to excellent in our population. CLINICAL SIGNIFICANCE: Transiliosacral toggle suture stabilization of bilateral SILF was associated with good outcomes in cats. Further studies are required to compare biomechanical properties and outcomes between this technique and previously described transiliosacral stabilization.
Asunto(s)
Enfermedades de los Gatos , Fracturas Óseas , Luxaciones Articulares , Humanos , Gatos/cirugía , Animales , Estudios Retrospectivos , Tornillos Óseos/veterinaria , Articulación Sacroiliaca , Luxaciones Articulares/veterinaria , Fracturas Óseas/veterinaria , Suturas , Resultado del Tratamiento , Enfermedades de los Gatos/cirugíaRESUMEN
OBJECTIVES: For medical devices, a usability assessment is mandatory for market access; the objective is to detect potentially harmful use errors that stem from the device's design. The manufacturer assesses the final version of the device and determines the risk-benefit ratio for remaining errors. Nevertheless, the decision rule currently used to determine the sample size for this testing has statistical limitations and the lack of a clear decision-making perspective. METHODS: As an alternative, we developed a value-of-information analysis from the medical device manufacturer's perspective. The consequences of use errors not detected during usability testing and the errors' probability of occurrence were embedded in a loss function. The value of further testing was assessed as a reduction in the expected loss for the manufacturer. The optimal sample size was determined using the expected net benefit of sampling (ENBS) (the difference between the value provided by new participants and the cost of their inclusion). RESULTS: The value-of-information approach was applied to a real usability test of a needle-free adrenaline autoinjector. The initial estimate (performed on the first n = 20 participants) gave an optimal sample size of 100 participants and an ENBS of 255 453. This estimation was updated iteratively as new participants were included. After the inclusion of 90 participants, the ENBS was null for any sample size; hence, the cost of adding more participants outweighed the expected value of information, and therefore, the study could be stopped. CONCLUSIONS: On the basis of these results, our method seems to be highly suitable for sample size estimation in the usability testing of medical devices before market access.
Asunto(s)
Tamaño de la Muestra , Evaluación de la Tecnología Biomédica/economía , Análisis Costo-Beneficio , Equipos y Suministros , Humanos , Proyectos de Investigación , Evaluación de la Tecnología Biomédica/métodosRESUMEN
Cannabinoid 1 receptor (CB1R) inverse agonists reduce body weight and improve several parameters of glucose homeostasis. However, these drugs have also been associated with deleterious side effects. CB1R expression is widespread in the brain and in peripheral tissues, but whether specific sites of expression can mediate the beneficial metabolic effects of CB1R drugs, while avoiding the untoward side effects, remains unclear. Evidence suggests inverse agonists may act on key sites within the central nervous system to improve metabolism. The ventromedial hypothalamus (VMH) is a critical node regulating energy balance and glucose homeostasis. To determine the contributions of CB1Rs expressed in VMH neurons in regulating metabolic homeostasis, we generated mice lacking CB1Rs in the VMH. We found that the deletion of CB1Rs in the VMH did not affect body weight in chow- and high-fat diet-fed male and female mice. We also found that deletion of CB1Rs in the VMH did not alter weight loss responses induced by the CB1R inverse agonist SR141716. However, we did find that CB1Rs of the VMH regulate parameters of glucose homeostasis independent of body weight in diet-induced obese male mice.NEW & NOTEWORTHY Cannabinoid 1 receptors (CB1Rs) regulate metabolic homeostasis, and CB1R inverse agonists reduce body weight and improve parameters of glucose metabolism. However, the cell populations expressing CB1Rs that regulate metabolic homeostasis remain unclear. CB1Rs are highly expressed in the ventromedial hypothalamic nucleus (VMH), which is a crucial node that regulates metabolism. With CRISPR/Cas9, we generated mice lacking CB1Rs specifically in VMH neurons and found that CB1Rs in VMH neurons are essential for the regulation of glucose metabolism independent of body weight regulation.
Asunto(s)
Peso Corporal/fisiología , Glucosa/metabolismo , Homeostasis/fisiología , Neuronas/metabolismo , Receptor Cannabinoide CB1/fisiología , Núcleo Hipotalámico Ventromedial/metabolismo , Animales , Composición Corporal/fisiología , Proteína 9 Asociada a CRISPR , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Dieta Alta en Grasa , Metabolismo Energético/fisiología , Femenino , Edición Génica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Obesidad/etiología , Obesidad/metabolismo , Receptor Cannabinoide CB1/deficiencia , Receptor Cannabinoide CB1/genéticaRESUMEN
BACKGROUND: Usability testing of medical devices are mandatory for market access. The testings' goal is to identify usability problems that could cause harm to the user or limit the device's effectiveness. In practice, human factor engineers study participants under actual conditions of use and list the problems encountered. This results in a binary discovery matrix in which each row corresponds to a participant, and each column corresponds to a usability problem. One of the main challenges in usability testing is estimating the total number of problems, in order to assess the completeness of the discovery process. Today's margin-based methods fit the column sums to a binomial model of problem detection. However, the discovery matrix actually observed is truncated because of undiscovered problems, which corresponds to fitting the marginal sums without the zeros. Margin-based methods fail to overcome the bias related to truncation of the matrix. The objective of the present study was to develop and test a matrix-based method for estimating the total number of usability problems. METHODS: The matrix-based model was based on the full discovery matrix (including unobserved columns) and not solely on a summary of the data (e.g. the margins). This model also circumvents a drawback of margin-based methods by simultaneously estimating the model's parameters and the total number of problems. Furthermore, the matrix-based method takes account of a heterogeneous probability of detection, which reflects a real-life setting. As suggested in the usability literature, we assumed that the probability of detection had a logit-normal distribution. RESULTS: We assessed the matrix-based method's performance in a range of settings reflecting real-life usability testing and with heterogeneous probabilities of problem detection. In our simulations, the matrix-based method improved the estimation of the number of problems (in terms of bias, consistency, and coverage probability) in a wide range of settings. We also applied our method to five real datasets from usability testing. CONCLUSIONS: Estimation models (and particularly matrix-based models) are of value in estimating and monitoring the detection process during usability testing. Matrix-based models have a solid mathematical grounding and, with a view to facilitating the decision-making process for both regulators and device manufacturers, should be incorporated into current standards.
Asunto(s)
Proyectos de Investigación , Sesgo , Humanos , ProbabilidadRESUMEN
Foot and mouth disease (FMD) is an important livestock disease impacting mainly intensive production systems. In southern Africa, the FMD virus is maintained in wildlife and its control is therefore complicated. However, FMD control is an important task to allow countries access to lucrative foreign meat market and veterinary services implement drastic control measures on livestock populations living in the periphery of protected areas, negatively impacting local small-scale livestock producers. This study investigated FMD primary outbreak data in Zimbabwe from 1931 to 2016 to describe the spatio-temporal distribution of FMD outbreaks and their potential drivers. The results suggest that: (i) FMD outbreaks were not randomly distributed in space across Zimbabwe but are clustered in the Southeast Lowveld (SEL); (ii) the proximity of protected areas with African buffalos was potentially responsible for primary FMD outbreaks in cattle; (iii) rainfall per se was not associated with FMD outbreaks, but seasons impacted the temporal occurrence of FMD outbreaks across regions; (iv) the frequency of FMD outbreaks increased during periods of major socio-economic and political crisis. The differences between the spatial clusters and other areas in Zimbabwe presenting similar buffalo/cattle interfaces but with fewer FMD outbreaks can be interpreted in light of the recent better understanding of wildlife/livestock interactions in these areas. The types of wildlife/livestock interfaces are hypothesized to be the key drivers of contacts between wildlife and livestock, triggering a risk of FMD inter-species spillover. The management of wildlife/livestock interfaces is therefore crucial for the control of FMD in southern Africa.
Asunto(s)
Enfermedades de los Bovinos/epidemiología , Brotes de Enfermedades/veterinaria , Fiebre Aftosa/epidemiología , Animales , Bovinos , Enfermedades de los Bovinos/virología , Fiebre Aftosa/virología , Virus de la Fiebre Aftosa/fisiología , Incidencia , Medición de Riesgo , Análisis Espacio-Temporal , Zimbabwe/epidemiologíaRESUMEN
Brown adipose tissue (BAT) thermogenesis is a key controller of energy metabolism. In response to cold or other adrenergic stimuli, brown adipocytes increase their substrate uptake and oxidative activity while uncoupling ATP synthesis from the mitochondrial respiratory chain activity. Brown adipocytes are found in classic depots such as in the interscapular BAT (iBAT). They can also develop in white adipose tissue (WAT), such as in the inguinal WAT (iWAT), where their presence has been associated with metabolic improvements. We previously reported that the induction of oxidative metabolism in iWAT is low compared with that of iBAT, even after sustained adrenergic stimulation. One explanation to this apparent lack of thermogenic ability of iWAT is the presence of an active iBAT, which may prevent the full activation of iWAT. In this study, we evaluated whether iBAT denervation-induced browning of white fat enhanced the thermogenic activity of iWAT following cold acclimation, under beta-3 adrenergic stimulation (CL 316,243). Following a bilateral denervation of iBAT, we assessed energy balance, evaluated the oxidative activity of iBAT and iWAT using 11C-acetate, and quantified the dynamic glucose uptake of those tissues using 2-deoxy-2-[18F]- fluoro-d-glucose. Our results indicate that despite portraying marked browning and mildly enhanced glucose uptake, iWAT of cold-adapted mice does not exhibit significant oxidative activity following beta-3 adrenergic stimulation in the absence of a functional iBAT. The present results suggest that iWAT is not readily recruitable as a thermogenic organ even when functional iBAT is lacking.
Asunto(s)
Aclimatación/fisiología , Tejido Adiposo Pardo/inervación , Tejido Adiposo Blanco/metabolismo , Termogénesis/fisiología , Aclimatación/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Animales , Frío , Desnervación , Dioxoles/farmacología , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Masculino , Ratones , Oxidación-Reducción , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Termogénesis/efectos de los fármacosRESUMEN
To get insights into the temporal pattern of commensal Escherichia coli populations, we sampled the feces of four healthy cows from the same herd in the Hwange District of Zimbabwe daily over 25 days. The cows had not received antibiotic treatment during the previous 3 months. We performed viable E. coli counts and characterized the 326 isolates originating from the 98 stool samples at a clonal level, screened them for stx and eae genes, and tested them for their antibiotic susceptibilities. We observed that E. coli counts and dominant clones were different among cows, and very few clones were shared. No clone was shared by three or four cows. Clone richness and evenness were not different between cows. Within each host, the variability in the E. coli count was evidenced between days, and no clone was found to be dominant during the entire sampling period, suggesting the existence of clonal interference. Dominant clones tended to persist longer than subdominant ones and were mainly from phylogenetic groups A and B1. Five E. coli clones were found to contain both the stx1 and stx2 genes, representing 6.3% of the studied isolates. All cows harbored at least one Shiga toxin-producing E. coli (STEC) strain. Resistance to tetracycline, penicillins, trimethoprim, and sulfonamides was rare and observed in three clones that were shed at low levels in two cows. This study highlights the fact that the commensal E. coli population, including the STEC population, is host specific, is highly dynamic over a short time frame, and rarely carries antibiotic resistance determinants in the absence of antibiotic treatment.IMPORTANCE The literature about the dynamics of commensal Escherichia coli populations is very scarce. Over 25 days, we followed the total E. coli counts daily and characterized the sampled clones in the feces of four cows from the same herd living in the Hwange District of Zimbabwe. This study deals with the day-to-day dynamics of both quantitative and qualitative aspects of E. coli commensal populations, with a focus on both Shiga toxin-producing E. coli and antibiotic-resistant E. coli strains. We show that the structure of these commensal populations was highly specific to the host, even though the cows ate and roamed together, and was highly dynamic between days. Such data are of importance to understand the ecological forces that drive the dynamics of the emergence of E. coli clones of particular interest within the gastrointestinal tract and their transmission between hosts.
Asunto(s)
Bovinos/microbiología , Escherichia coli/fisiología , Animales , Bovinos/fisiología , Escherichia coli/clasificación , Escherichia coli/genética , Escherichia coli/aislamiento & purificación , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Heces/microbiología , Filogenia , Toxina Shiga/genética , Toxina Shiga/metabolismo , Simbiosis , ZimbabweRESUMEN
BACKGROUND: Although the current guidelines recommend anticoagulation up until 6 weeks after delivery in women at high risk of venous thromboembolism (VTE), the risk of VTE may extend beyond 6 weeks. Our objective was to estimate the risk of a pulmonary embolism in successive 2-week intervals during the postpartum period. METHODS: In a population-based, case-crossover study, we analyzed the French national inpatient database from 2007 to 2013 (n = 5,517,680 singleton deliveries). Using ICD-10 codes, we identified women who were diagnosed with a postpartum pulmonary embolism between July 1st, 2008, and December 31st, 2013. Deliveries were identified during a case "period" immediately before the pulmonary embolism, and five different control periods one year before the pulmonary embolism. Using conditional logistic regression, Odds ratios (ORs) and 95% confidential intervals (CIs) were estimated for ten successive 2-week intervals that preceded the diagnosis of pulmonary embolism. RESULTS: We identified 167,103 cases with a pulmonary embolism during the inclusion period. After delivery, the risk of pulmonary embolism declined progressively over time, with an OR [95%CI] of 17.2 [14.0-21.3] in postpartum weeks 1 to 2 and 1.9 [1.4-2.7] in postpartum weeks 11 to 12. The OR [95%CI] in postpartum weeks 13 to 14 was 1.4 [0.9-2.0], and the OR did not fall significantly after postpartum week 14. CONCLUSIONS: Our findings indicate that women are at risk of a pulmonary embolism up to 12 weeks after delivery. The shape of the risk curve suggests that the risk decreases exponentially over time. Future research is needed to establish whether the duration of postpartum anticoagulation should be extended beyond 6 weeks.
Asunto(s)
Complicaciones Cardiovasculares del Embarazo/epidemiología , Trastornos Puerperales/epidemiología , Embolia Pulmonar/epidemiología , Adulto , Estudios de Casos y Controles , Femenino , Francia/epidemiología , Humanos , Oportunidad Relativa , Vigilancia de la Población , Embarazo , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Physical activity (PA) is a health determinant among middle-aged and older adults. In contrast, poor health is expected to have a negative impact on PA. This study sought to assess to what extent specific International Classification of Functioning, Disability and Health (ICF) health components were associated with PA among older adults. METHODS: We used a sample of 864 persons aged ≥50 years, positively screened for disability or cognition in a cross-sectional community survey in Spain. Weekly energy expenditure during PA was measured with the Yale Physical Activity Survey (YPAS) scale. The associations between body function impairment, health conditions or World Health Organization Disability Assessment Schedule (WHODAS 2.0) disability scores and energy expenditure were quantified using negative-binomial regression, and expressed in terms of adjusted mean ratios (aMRs). RESULTS: Mean energy expenditure was 4542 Kcal/week. A lower weekly energy expenditure was associated with: severe/extreme impairment of mental functions, aMR 0.38, 95% confidence interval, CI (0.21-0.68), and neuromusculoskeletal and movement functions, aMR 0.50 (0.35-0.72); WHODAS 2.0 disability, aMR 0.55 (0.34-0.91); dementia, aMR 0.45 (0.31-0.66); and heart failure, aMR 0.54 (0.34-0.87). In contrast, people with arthritis/osteoarthritis had a higher energy expenditure, aMR 1.27 (1.07-1.51). CONCLUSION: Our results suggest that there is a strong relationship between selected body function impairments, mainly mental, and PA. Although more research is needed to fully understand causal relationships, strategies to improve PA among the elderly may require targeting mental, neuromusculoskeletal and movement functions, disability determinants (including barriers), and specific approaches for persons with dementia or heart failure.
Asunto(s)
Trastornos del Conocimiento/metabolismo , Personas con Discapacidad , Metabolismo Energético/fisiología , Ejercicio Físico/fisiología , Anciano , Anciano de 80 o más Años , Trastornos del Conocimiento/fisiopatología , Estudios Transversales , Evaluación de la Discapacidad , Personas con Discapacidad/estadística & datos numéricos , Femenino , Humanos , Masculino , Persona de Mediana Edad , España/epidemiologíaRESUMEN
Hepatic metabolism requires mitochondria to adapt their bioenergetic and biosynthetic output to accompany the ever-changing anabolic/catabolic state of the liver cell, but the wiring of this process is still largely unknown. Using a postprandial mouse liver model and quantitative cryo-EM analysis, we show that when the hepatic mammalian target of rapamycin complex 1 (mTORC1) signaling pathway disengages, the mitochondria network fragments, cristae density drops by 30%, and mitochondrial respiratory capacity decreases by 20%. Instead, mitochondria-ER contacts (MERCs), which mediate calcium and phospholipid fluxes between these organelles, double in length. These events are associated with the transient expression of two previously unidentified C-terminal fragments (CTFs) of Optic atrophy 1 (Opa1), a mitochondrial GTPase that regulates cristae biogenesis and mitochondria dynamics. Expression of Opa1 CTFs in the intermembrane space has no effect on mitochondria morphology, supporting a model in which they are intermediates of an Opa1 degradation program. Using an in vitro assay, we show that these CTFs indeed originate from the cleavage of Opa1 at two evolutionarily conserved consensus sites that map within critical folds of the GTPase. This processing of Opa1, termed C-cleavage, is mediated by the activity of a cysteine protease whose activity is independent from that of Oma1 and presenilin-associated rhomboid-like (PARL), two known Opa1 regulators. However, C-cleavage requires Mitofusin-2 (Mfn2), a key factor in mitochondria-ER tethering, thereby linking cristae remodeling to MERC assembly. Thus, in vivo, mitochondria adapt to metabolic shifts through the parallel remodeling of the cristae and of the MERCs via a mechanism that degrades Opa1 in an Mfn2-dependent pathway.
Asunto(s)
Señalización del Calcio/fisiología , Retículo Endoplásmico/metabolismo , GTP Fosfohidrolasas/metabolismo , Mitocondrias Hepáticas/metabolismo , Periodo Posprandial/fisiología , Animales , Retículo Endoplásmico/genética , GTP Fosfohidrolasas/genética , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Metaloproteasas/genética , Metaloproteasas/metabolismo , Ratones , Mitocondrias Hepáticas/genética , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Complejos Multiproteicos/genética , Complejos Multiproteicos/metabolismo , Proteolisis , Serina-Treonina Quinasas TOR/genética , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Classical brown adipocytes such as those found in interscapular brown adipose tissue (iBAT) represent energy-burning cells, which have been postulated to play a pivotal role in energy metabolism. Brown adipocytes can also be found in white adipose tissue (WAT) depots [e.g., inguinal WAT (iWAT)] following adrenergic stimulation, and they have been referred to as "beige" adipocytes. Whether the presence of these adipocytes, which gives iWAT a beige appearance, can confer a white depot with some thermogenic activity remains to be seen. In consequence, we designed the present study to investigate the metabolic activity of iBAT, iWAT, and epididymal white depots in mice. Mice were either 1) kept at thermoneutrality (30°C), 2) kept at 30°C and treated daily for 14 days with an adrenergic agonist [CL-316,243 (CL)], or 3) housed at 10°C for 14 days. Metabolic activity was assessed using positron emission tomography imaging with fluoro-[(18)F]deoxyglucose (glucose uptake), fluoro-[(18)F]thiaheptadecanoic acid (fatty acid uptake), and [(11)C]acetate (oxidative activity). In each group, substrate uptakes and oxidative activity were measured in anesthetized mice in response to acute CL. Our results revealed iBAT as a major site of metabolic activity, which exhibited enhanced glucose and nonesterified fatty acid uptakes and oxidative activity in response to chronic cold and CL. On the other hand, beige adipose tissue failed to exhibit appreciable increase in oxidative activity in response to chronic cold and CL. Altogether, our results suggest that the contribution of beige fat to acute-CL-induced metabolic activity is low compared with that of iBAT, even after sustained adrenergic stimulation.
Asunto(s)
Tejido Adiposo Beige/efectos de los fármacos , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Blanco/efectos de los fármacos , Agonistas de Receptores Adrenérgicos beta 3/farmacología , Frío , Dioxoles/farmacología , Acetatos , Tejido Adiposo Beige/diagnóstico por imagen , Tejido Adiposo Beige/metabolismo , Tejido Adiposo Pardo/diagnóstico por imagen , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/diagnóstico por imagen , Tejido Adiposo Blanco/metabolismo , Animales , Radioisótopos de Carbono , Ácidos Grasos , Fluorodesoxiglucosa F18 , Masculino , Ratones , Tomografía de Emisión de Positrones , RadiofármacosRESUMEN
We report on the long-distance movements of subadult female buffalo within a Transfrontier Conservation Area in Africa. Our observations confirm that bovine tuberculosis and other diseases can spread between buffalo populations across national parks, community land, and countries, thus posing a risk to animal and human health in surrounding wildlife areas.
Asunto(s)
Migración Animal , Búfalos , Zoonosis/epidemiología , Zoonosis/etiología , África Austral , Animales , Bovinos , Femenino , Geografía , Humanos , Masculino , RiesgoRESUMEN
The synthesis of lipids in response to food intake represents a key advantage that allows organisms to survive when energy availability is limited. In mammals, circulating levels of insulin and nutrients, which fluctuate between fasting and feeding, dictate whether lipids are synthesized or catabolized by tissues. The mechanistic target of rapamycin (mTOR), a kinase that is activated by anabolic signals, plays fundamental roles in regulating lipid biosynthesis and metabolism in response to nutrition. The mTOR kinase nucleates two large protein complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). Following their activation, these complexes facilitate the accumulation of triglycerides by promoting adipogenesis and lipogenesis and by shutting down catabolic processes such as lipolysis and ß-oxidation. Here, we review and discuss the roles of mTOR complexes in various aspects of lipid metabolism in mammals. We also use this opportunity to discuss the implication of these relations to the maintenance of systemic lipid homeostasis.