Central leptin signaling deficiency induced by leptin receptor antagonist leads to hypothalamic proteomic remodeling.

AIMS: Leptin irresponsiveness, which is often associated with obesity, can have significant impacts on the hypothalamic proteome of individuals, including those who are lean. While mounting evidence on leptin irresponsiveness has focused on obese individuals, understanding the early molecular and proteomic changes associated with deficient hypothalamic leptin signaling in lean individuals is essential for early intervention and prevention of metabolic disorders. Leptin receptor antagonists block the binding of leptin to its receptors, potentially reducing its effects and used in cases where excessive leptin activity might be harmful. MATERIALS AND METHODS: In this work, we blocked the central actions of leptin in lean male adult Wistar rat by chronically administering intracerebroventricularly the superactive leptin receptor antagonist (SLA) (D23L/L39A/D40A/F41A) and investigated its impact on the hypothalamic proteome using label-free sequential window acquisition of all theoretical fragment ion spectra mass spectrometry (SWATH-MS) for quantitative proteomics. KEY FINDINGS: Our results show an accumulation of proteins involved in mRNA processing, mRNA stability, and translation in the hypothalamus of SLA-treated rats. Conversely, hypothalamic leptin signaling deficiency reduces the representation of proteins implicated in energy metabolism, neural circuitry, and neurotransmitter release. SIGNIFICANCE: The alterations in the adult rat hypothalamic proteome contribute to dysregulate appetite, metabolism, and energy balance, which are key factors in the development and progression of obesity and related metabolic disorders. Additionally, using bioinformatic analysis, we identified a series of transcription factors that are potentially involved in the upstream regulatory mechanisms responsible for the observed signature.

Libro "Fractura de cadera en el adulto mayor": recurso de aprendizaje para el médico general / Book "Hip fracture in the elderly": learning resource for the general practitioner

Fundamento: los medios de enseñanza constituyen uno de los ejes vertebrales de las acciones en cualquiera de los niveles de la educación. Objetivo: mostrar los fundamentos teóricos del libro: "Fractura de cadera en el adulto mayor", como recurso de aprendizaje para la superación profesional del médico de familia. Métodos: se realizó una investigación con enfoque cualitativo en la Universidad de Ciencias Médicas "Dr. Zoilo Marinello Vidaurreta" de Las Tunas en el año 2021. Se emplearon métodos del nivel teórico para la fundamentación teórica; y empírico: análisis documental para verificar los nexos y relaciones que se ofrecen en los referentes teóricos relacionados con las características que debe poseer un libro de texto como medio de enseñanza en el proceso docente educativo, su importancia, ventajas y fundamentos. Se utilizó el criterio de expertos para valorar su pertinencia, factibilidad y estructura metodológica. Resultados: se presenta un libro diseñado como recurso del aprendizaje para la superación profesional, contiene las particularidades del contenido que se desea enseñar y lo que necesitan aprender los médicos de familia sobre la atención al adulto mayor con fractura de cadera. Está estructurado en trece capítulos con predominio de interrogantes que son respondidas con precisión y claridad. Se resaltan los fundamentos teóricos que lo sustentan. Conclusiones: se mostraron los principales fundamentos teóricos del libro "Fractura de cadera en el adulto mayor", como medio de enseñanza para la superación profesional del médico de familia y se resaltaron sus principales ventajas como componente didáctico del proceso docente educativo.

Background: the teaching means constitute one of the backbones of the actions at any level of education. Objective: to show the theoretical foundations of the book: "Hip fracture in the elderly", as a learning resource for the professional improvement of the family doctor. Methods: a research with a qualitative approach was carried out at "Dr. Zoilo Marinello Vidaurreta" University of Medical Sciences from Las Tunas in 2021. Theoretical methods were used for the theoretical foundation; and documentary analysis as an empirical one to verify the links and relationships that are offered in the theoretical references related to the characteristics that a textbook must have as a teaching medium in the educational process, its importance, advantages and foundations. Expert criteria were used to assess its relevance, feasibility and methodological structure. Results: a book designed as a learning resource for professional improvement is presented; it contains the particularities of the content to be taught and what family doctors need to learn about care for the elderly with hip fracture. It is structured in thirteen chapters with a predominance of questions which are answered with precision and clarity. Its theoretical foundations are highlighted. Conclusions: the main theoretical foundations of the book "Hip fracture in the elderly" were shown as a teaching tool for the professional improvement of the family doctor and its main advantages as a didactic component of the educational teaching process were highlighted.

Grape seed extract supplementation modulates hepatic lipid metabolism in rats. Implication of PPARß/δ.

In mammals, the liver is involved in nutrient metabolism and in the regulation of lipid and glucose homeostasis. Multiple studies have described improvements in liver disorders after regular consumption of grape seed extract (GSE). GSE prevents or ameliorates hepatic metabolic dysfunction through AMPK activation, which reduces hepatic lipogenesis while enhancing hepatic lipid oxidation. However, the involvement of ChREBPß and PPARß/δ in these effects has not been fully elucidated. We aim to demonstrate that chronic consumption of GSE at low doses (25 mg kg-1 body weight per day) produces beneficial effects on hepatic glucose and lipid metabolism in young lean Wistar rats and that part of these effects involve ChREBPß inactivation and PPARß/δ activation. In our study, increased concentrations of structurally related (-)-(epi)catechin metabolites and 5-carbon ring fission metabolites were found in the serum of GSE-supplemented rats parallel with the reduction in triglycerides and leptin levels, hepatic cholesterol content and visceral adiposity. GSE supplementation inactivates ChREBP and GSK-3ß, which has been linked to improvements in hepatic lipid and glucose metabolism. Furthermore, the consumption of GSE promotes the expression of Pparß/δ, as well as Pgc-1α and Acox-1, which control hepatic lipid oxidation. Interestingly, pharmacological inhibition of PPARß/δ slowed the induction of Pgc-1α and Acox-1, as well as the activation of AMPK triggered by GSE consumption. Our data suggest that PPARß/δ activation is involved in the metabolic reprogramming effects of chronic GSE consumption in young rats, by modulating, at least, part of the transcriptional programs that maintain hepatic and systemic fuel homeostasis.

2021 DORIS definition of remission in SLE: final recommendations from an international task force.

OBJECTIVE: To achieve consensus on a definition of remission in SLE (DORIS). BACKGROUND: Remission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation. METHODS: Several systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on. RESULTS: Based on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator's Global Assessment <0.5 (0-3), prednisolone 5 mg/day or less, and stable antimalarials, immunosuppressives, and biologics. CONCLUSION: The 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies.

Leptin, Acting at Central Level, Increases FGF21 Expression in White Adipose Tissue via PPARß/δ.

The altered function of adipose tissue can result in obesity, insulin resistance, and its metabolic complications. Leptin, acting on the central nervous system, modifies the composition and function of adipose tissue. To date, the molecular changes that occur in epididymal white adipose tissue (eWAT) during chronic leptin treatment are not fully understood. Herein we aimed to address whether PPARß/δ could mediate the metabolic actions induced by leptin in eWAT. To this end, male 3-month-old Wistar rats, infused intracerebroventricularly (icv) with leptin (0.2 µg/day) for 7 days, were daily co-treated intraperitoneally (ip) without or with the specific PPARß/δ receptor antagonist GSK0660 (1 mg/kg/day). In parallel, we also administered GSK0660 to control rats fed ad libitum without leptin infusion. Leptin, acting at central level, prevented the starvation-induced increase in circulating levels of FGF21, while induced markedly the endogenous expression of FGF21 and browning markers of eWAT. Interestingly, GSK0660 abolished the anorectic effects induced by icv leptin leading to increased visceral fat mass and reduced browning capacity. In addition, the pharmacological inhibition of PPARß/δ alters the immunomodulatory actions of central leptin on eWAT. In summary, our results demonstrate that PPARß/δ is involved in the up-regulation of FGF21 expression induced by leptin in visceral adipose tissue.

The nutrient sensing pathways FoxO1/3 and mTOR in the heart are coordinately regulated by central leptin through PPARß/δ. Implications in cardiac remodeling.

BACKGROUND: Cardiovascular disease in obese individuals with type 2 diabetes is often associated with hyperleptinemia and leptin resistance, while other studies support that leptin has cardioprotective effects. Besides, the role of leptin in regulating cardiac atrophy or hypertrophy remains to be clearly defined. In fact, in rats with normal leptin sensitivity, the molecular underpinnings of the effects of central leptin regulating cardiac structural pathways remain poorly understood. OBJECTIVE: Hence, we assessed the effects of intracerebroventricular (icv) leptin infusion on cardiac remodeling analyzing FOXO1/3 and mTORC1 pathways, focusing special attention to PPARß/δ as mediator of central leptin's effects on cardiac metabolism. METHODS: Male 3-months-old Wistar rats, infused with icv leptin (0.2 µg/day) for 7 days, were daily co-treated intraperitoneally with the specific PPARß/δ antagonist GSK0660, at 1 mg/kg per day along leptin treatment. RESULTS: Central leptin regulated dynamically, in an opposite manner, the network between FOXOs and mTORC1 and induced an atrophy-related gene program in cardiac tissue. Leptin activated the anti-hypertrophic kinase GSK3ß and increased the protein levels of muscle-specific ubiquitin ligases, muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/Atrogin-1 involved in limiting cardiac hypertrophy. FOXO1 activity and the expression of their target genes, Sod2 and Lpl, were also increased in the heart upon central leptin infusion. Besides, Beclin-1 and LC3B-II, gene products of the autophagic pathway response, were upregulated, while the content and expression levels of phenotypic markers of cardiac hypertrophy as ANP and ß-myosin heavy chain, gene product of Myh7 were significantly decreased. On the other hand, mTORC1 activity and OXPHOS protein levels were decreased suggesting a key role of central leptin preventing cardiac oxidative stress. In fact, the content of carbonylated proteins, TBARS and ROS/RSN were not increased in cardiac tissue in response to central leptin infusion. Finally, the pharmacological inhibition of PPARß/δ, via in vivo administration of the selective antagonist GSK0660, blunted the induction of FOXO1/3, Atrogin-1, MuRF1 and GSK3ß in the heart mediated by icv leptin infusion. CONCLUSIONS: Our results demonstrate that, in lean rats with normal leptin sensitivity, central leptin regulates nutrient sensing pathways in heart contributing to balance cardiac remodeling through the anti- and pro-hypertrophic programs, and in this process is involved PPARß/δ.

Pesquisa activa comunitaria ante la COVID-19. Experiencias en el municipio de Cumanayagua, 2020 / Active community inquiry facing COVID-19: Experiences in the Cumanayagua municipality, 2020

RESUMEN Fundamento: la pesquisa activa es una herramienta que facilita la detección de enfermedades relevantes en el perfil epidemiológico. Objetivo: describir las experiencias en la implementación de un sistema de pesquisa activa comunitaria municipal para la COVID-19. Métodos: estudio prospectivo, descriptivo, de corte transversal realizado en el municipio de Cumanayagua, provincia Cienfuegos, Cuba, entre los días 19 de marzo y 17 de abril del 2020. El universo estuvo compuesto por todos los pobladores (48 412) y pesquizadores (627) en dicho período. Se hizo revisión de registros médicos, estadísticas municipales y se utilizó la observación participativa. Resultados: se describe la estructura de la pesquisa activa, su base desde el consultorio del médico-enfermero de familia y su forma, mediante entrevista a los pobladores en sus viviendas. Un total de 627 pesquisidores, principalmente profesionales de la salud (43,38 %) y estudiantes de medicina (33,33 %), evaluaron diariamente hasta el 88,88 % de todos los pobladores y el 95,28 % de todas las viviendas dispensarizadas en el territorio. El sistema de pesquisa permitió detectar el 97, 08 % de las infecciones respiratorias agudas diagnosticadas en el municipio. Conclusiones: el trabajo de pesquisa activa masiva comunitaria, realizado por el equipo básico de salud, estudiantes de las ciencias médicas y profesionales de varios sectores ha permitido: acceder a todas las comunidades, pesquisar diariamente a la mayoría de los pobladores y tener una precisión de la incidencia de infección respiratoria del municipio. El sistema implementado se articuló adecuadamente al programa del médico-enfermero de la familia en el nivel primario de atención.

ABSTRACT Foundation: active research is a tool that facilitates the detection of relevant diseases in the epidemiological profile. Objective: to describe the experiences in the implementation of a municipal community active research system for COVID-19. Methods: prospective, descriptive, cross-sectional study carried out in the municipality of Cumanayagua, Cienfuegos province, Cuba, between March 19 and April 17, 2020. The universe was all the inhabitants (48,412) and researchers (627) in that period. Medical records, municipal statistics were reviewed and participatory observation was used. Results: active research structure, its basis from the family doctor-nurse's office and its form are described by interviewing the residents in their homes. A total of 627 researchers, mainly health professionals (43.38%) and medical students (33.33%), evaluated daily up to 88.88% of all residents and 95.28% of all homes dispensed in the territory. The research system allowed detecting 97, 08% of the acute respiratory infections diagnosed in the municipality. Conclusions: massive community active research carried out by the basic health team, medical sciences students and professionals from various sectors, has allowed: access to all the communities, daily research of the majority of the inhabitants and respiratory infection accuracy incidence in the municipality. The implemented system was properly articulated to the family physician-nurse program at the primary care level.

Effects of Moderate Chronic Food Restriction on the Development of Postprandial Dyslipidemia with Ageing.

Ageing is a major risk factor for the development of metabolic disorders linked to dyslipidemia, usually accompanied by increased adiposity. The goal of this work was to investigate whether avoiding an excessive increase in adiposity with ageing, via moderate chronic food restriction (FR), ameliorates postprandial dyslipidemia in a rat model of metabolic syndrome associated with ageing. Accordingly, we performed an oral lipid loading test (OLLT) in mature middle-aged (7 months) and middle-old-aged (24 months) Wistar rats fed ad libitum (AL) or under moderate FR for 3 months. Briefly, overnight fasted rats were orally administered a bolus of extra-virgin olive oil (1 mL/Kg of body weight) and blood samples were taken from the tail vein before fat load (t = 0) and 30, 60, 90, 120, 180, and 240 min after fat administration. Changes in serum lipids, glucose, insulin, and glucagon levels were measured at different time-points. Expression of liver and adipose tissue metabolic genes were also determined before (t = 0) and after the fat load (t = 240 min). Postprandial dyslipidemia progressively increased with ageing and this could be associated with hepatic ChREBP activity. Interestingly, moderate chronic FR reduced adiposity and avoided excessive postprandial hypertriglyceridemia in 7- and 24-month-old Wistar rats, strengthening the association between postprandial triglyceride levels and adiposity. The 24-month-old rats needed more insulin to maintain postprandial normoglycemia; nevertheless, hyperglycemia occurred at 240 min after fat administration. FR did not alter the fasted serum glucose levels but it markedly decreased glucagon excursion during the OLLT and the postprandial rise of glycemia in the 24-month-old rats, and FGF21 in the 7-month-old Wistar rats. Hence, our results pointed to an important role of FR in postprandial energy metabolism and insulin resistance in ageing. Lastly, our data support the idea that the vWAT might function as an ectopic site for fat deposition in 7-month-old and in 24-month-old Wistar rats that could increase their browning capacity in response to an acute fat load.

Central leptin regulates heart lipid content by selectively increasing PPAR ß/δ expression.

The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein, we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2 µg/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective upregulation of gene and protein expression of peroxisome proliferator-activated receptor ß/δ (PPARß/δ, encoded by Pparb/d) and their target genes, adipose triglyceride lipase (encoded by Pnpla2, herefater referred to as Atgl), hormone sensitive lipase (encoded by Lipe, herefater referred to as Hsl), pyruvate dehydrogenase kinase 4 (Pdk4) and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization. Besides, central leptin decreased the expression of stearoyl-CoA deaturase 1 (Scd1) and diacylglycerol acyltransferase 1 (Dgat1) involved in TAG synthesis and increased the CPT-1 independent palmitate oxidation, as an index of peroxisomal ß-oxidation. Finally, the pharmacological inhibition of PPARß/δ decreased the effects on gene expression and cardiac TAG content induced by leptin. These results indicate that leptin, acting at central level, regulates selectively the cardiac expression of PPARß/δ, contributing in this way to regulate the cardiac TAG accumulation in rats, independently of its effects on body weight.

Infecciones por candia en terapia intensiva / Candida infections in Intensive Care

Se presentan ocho pacientes con cultivos significativos para Cándida obtenidos entre marzo de 1986 y 1989. El 100 por ciento de ellos presentó ATB previos, catéter venoso central (CIV) y desnutrición (DN) de moderada a severa. El 37 por ciento (318) cursaba posoperatorio de cirugía abdominal (POA) y el 62,5 por ciento (518) fue tratado previamente con nutrición parenteral (NPT). Tres de los ocho pacientes cursaron una candidiasis diseminada (CD), dos de ellos que habían recibido tratamiento corticoideo previo a dosis inmunodepresoras desarrollaron endoftalmitis. Los pacientes con correlación, hemocultivos y punta de catéter (PC) positivos desarrollaron cuadros de fungemia que requirieron expansión, a la vez que un paciente padeció una candidemia transitoria (CT). Un paciente presentó endocarditis por Cándida (EC) y dos pacientes cumplieron criterios para candidiasis intraabdominal (CIA). Un solo paciente tuvo diagnóstico de candidiasis urinaria (CU). Los resultados de cultivo fueron: HC 62,5 por ciento - PC 62,5 por ciento - URO 25 por ciento - ABS IntraBD 25 por ciento. Todos los pacientes se trataron con anfotericina B/intravenosa, hallándose una sobrevida del 37 por ciento. Los fallecidos en relación a la micosis fueron el 40 por ciento y el otro 60 por ciento falleció por falta multiorgánica asociada a sepsis bacteriana (FMO). Los efectos adversos en el tratamiento no difirieron de los ya conocidos. Se revisa y discute la literatura hasta la fecha

Infecciones por candia en terapia intensiva / Candida infections in Intensive Care

Se presentan ocho pacientes con cultivos significativos para Cándida obtenidos entre marzo de 1986 y 1989. El 100 por ciento de ellos presentó ATB previos, catéter venoso central (CIV) y desnutrición (DN) de moderada a severa. El 37 por ciento (318) cursaba posoperatorio de cirugía abdominal (POA) y el 62,5 por ciento (518) fue tratado previamente con nutrición parenteral (NPT). Tres de los ocho pacientes cursaron una candidiasis diseminada (CD), dos de ellos que habían recibido tratamiento corticoideo previo a dosis inmunodepresoras desarrollaron endoftalmitis. Los pacientes con correlación, hemocultivos y punta de catéter (PC) positivos desarrollaron cuadros de fungemia que requirieron expansión, a la vez que un paciente padeció una candidemia transitoria (CT). Un paciente presentó endocarditis por Cándida (EC) y dos pacientes cumplieron criterios para candidiasis intraabdominal (CIA). Un solo paciente tuvo diagnóstico de candidiasis urinaria (CU). Los resultados de cultivo fueron: HC 62,5 por ciento - PC 62,5 por ciento - URO 25 por ciento - ABS IntraBD 25 por ciento. Todos los pacientes se trataron con anfotericina B/intravenosa, hallándose una sobrevida del 37 por ciento. Los fallecidos en relación a la micosis fueron el 40 por ciento y el otro 60 por ciento falleció por falta multiorgánica asociada a sepsis bacteriana (FMO). Los efectos adversos en el tratamiento no difirieron de los ya conocidos. Se revisa y discute la literatura hasta la fecha (AU)