Finerenone protects against progression of kidney and cardiovascular damage in a model of type 1 diabetes through modulation of proinflammatory and osteogenic factors.

The non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone (FIN) improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effect of FIN in a novel model of type 1 diabetic Munich Wistar Frömter (MWF) rat (D) induced by injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (D-FIN) was compared to a group of D rats receiving no treatment and a group of non-diabetic untreated MWF rats (C) (n = 7-10 animals per group). After 6 weeks, D and D-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to C (110.3 ± 4.4 mg/dl; p < 0.05). D showed a 10-fold increase of kidney damage markers Kim-1 and Ngal which was significantly suppressed in D-FIN. Blood pressure, pulse wave velocity (PWV) and arterial collagen deposition were lower in D-FIN, associated to an improvement in endothelial function due to a reduction in pro-contractile prostaglandins, as well as reactive oxygen species (ROS) and inflammatory cytokines (IL-1, IL-6, TNFα and TGFß) in perivascular and perirenal adipose tissue (PVAT and PRAT, respectively). In addition, FIN restored the imbalance observed in CKD between the procalcifying BMP-2 and the nephroprotective BMP-7 in plasma, kidney, PVAT, and PRAT. Our data show that treatment with FIN improves kidney and vascular damage in a new rat model of DKD with T1D associated with a reduction in inflammation, fibrosis and osteogenic factors independently from changes in glucose homeostasis.

Role of PVAT in coronary atherosclerosis and vein graft patency: friend or foe?

Perivascular adipose tissue (PVAT) releases numerous factors and adipokines with paracrine effects on both vascular structure and function. These effects are variable as they depend on regional differences in PVAT among blood vessels and vary with changes in adiposity. There is considerable evidence demonstrating an association between coronary PVAT and the development and progression of coronary artery disease, which is associated with inflammation, oxidative stress, angiogenesis, vascular remodelling and blood clotting. However, PVAT also has a protective role in vascular grafts, especially the no-touch saphenous vein, in patients undergoing coronary artery bypass. This beneficial influence of PVAT involves factors such as adipocyte-derived relaxing factor, nitric oxide (NO), leptin, adiponectin, prostanoids, hydrogen sulphide and neurotransmitters, as well as mechanical protection. This article aims to highlight and compare the dual role of PVAT in the development and progression of coronary atherosclerosis, as well as in increased graft patency. Different deleterious and protective mechanisms of PVAT are also discussed and the inside-outside signalling paradigm of atherosclerosis development re-evaluated. The bidirectional communication between the arterial and venous wall and their surrounding PVAT, where signals originating from the vascular wall or lumen can affect PVAT phenotype, has been shown to be very complex. Moreover, signals from PVAT also influence the structure and function of the vascular wall in a paracrine manner. LINKED ARTICLES: This article is part of a themed section on Molecular Mechanisms Regulating Perivascular Adipose Tissue - Potential Pharmacological Targets? To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.20/issuetoc.

Rotura por fatiga de la zona central del vástago Exeter(R): una complicación excepcional / Fatigue fracture of the central zone of Exeter stem: an unusual complication

Objetivos: Conocer una complicación rara pero con importante morbimortalidad como es la rotura de vástagos protésicos cementados. Material y métodos: En nuestro caso nos referimos a la rotura de un vástago pulido Exeter(R) (Stryker(R)), fabricado en acero inoxidable y ampliamente utilizado en todo el mundo. Tras implantar dicho vástago en una paciente de 74 años que sufrió una fractura subcapital, se observa a los 8 años de la cirugía una rotura del vástago en la zona central; por lo que se recambia dicho vástago por uno de anclaje diafisario con buena evolución. Resultados y conclusiones: tras analizar las posibles causas que generaron el fracaso del vástago, identificamos un defecto en la cementación como el principal causante del fallo del implante

Objetives: explain a rare but important complication for patient that is the breakage of cemented stem. Methods: in our case, we refer to a polished stem Exeter(R) (Stryker(R)), made of stainless steel and widely used around the world. We implant Exeter® stem in a 74 year old patient and 8 years after the surgery, is observed a rupture in the central area of the stem; that stem is exchanged for one of diaphyseal anchorage with good evolution. Results: after analyzing the possible causes of the failure of this stem, we identified a defect in the cement as the main cause of implant failure

Hematoma del músculo iliopsoas secundario a tratamiento anticoagulante oral / Iliopsoas muscle hematoma due to oral anticoagulant drugs

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Genetic predisposition to albuminuria is associated with increased arterial stiffness: role of elastin.

BACKGROUND AND PURPOSE: The Munich Wistar Frömter (MWF) rat strain represents an experimental model to study cardiovascular alterations under conditions of progressive albuminuria. The aim of this study was to evaluate the association between genetic predisposition to albuminuria and the development of arterial stiffness and/or vascular remodelling. EXPERIMENTAL APPROACH: Experiments were performed in mesenteric arteries from 12-week-old MWF, Wistar Kyoto (WKY) and consomic MWF-6(SHR) and MWF-8(SHR) rats in which chromosomes 6 or 8 associated with albuminuria from MWF were replaced by the respective chromosome from spontaneously hypertensive rats (SHR). KEY RESULTS: Incremental distensibility, wall stress and strain were reduced, and arterial stiffness was significantly increased in albuminuric MWF compared with WKY. Albuminuria suppression in both consomic strains was associated with lower ß-values in MWF-8(SHR) and MWF-6(SHR) compared with MWF. Moreover, elastin content was significantly lower in MWF external elastic lamina compared with WKY and both consomic strains. In addition, a reduction in arterial external and internal diameter and cross-sectional area was detected in MWF compared with WKY, thus exhibiting an inward hypotrophic remodelling. However, these alterations remained unchanged in both consomic strains. CONCLUSION AND IMPLICATIONS: These data demonstrate that albuminuria in MWF is associated with increased arterial stiffness due to a reduction of elastin content in the external elastic lamina. Moreover, inward hypotrophic remodelling in MWF is not directly associated with albuminuria. In contrast, we demonstrated that two major genetic loci affect both the development of albuminuria and arterial stiffness, thus linking albuminuria and impairment of mechanical properties of resistance arteries.

Vascular AMPK as an attractive target in the treatment of vascular complications of obesity.

The key for the survival of all organisms is the regulation and control of energy metabolism. Thus, several strategies have evolved in each tissue in order to balance nutrient supply with energy demand. Adenosine monophosphate-activated protein kinase (AMPK) is now recognized as a key participant in energy metabolism. It ensures an appropriate energetic supply by promoting energy conserving pathways in detriment of anabolic processes not essential for cell survival. Vascular AMPK plays a critical role in the regulation of blood flow and vascular tone through several mechanisms, including vasodilation by stimulating nitric oxide release in endothelial cells. Since obesity leads to endothelial damage and AMPK dysregulation, AMPK activation might be an important strategy to restore vascular function in cardiometabolic alterations. In the present review we focus on the role of vascular AMPK in both endothelial and smooth muscle cells, paying special attention to its dysregulation in obesity- and high-fat diet-related complications, as well as to the mechanisms and benefits of vascular AMPK activation.

Síndrome PFAPA: su diagnóstico en la edad adulta / PFAPA syndrome: Diagnosis in adulthood

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Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats.

Genetic obesity models exhibit endothelial dysfunction associated to adenosine monophosphate-activated protein kinase (AMPK) dysregulation. This study aims to assess if mild short-term caloric restriction (CR) restores endothelial AMPK activity leading to an improvement in endothelial function. Twelve-week old Zucker lean and obese (fa/fa) male rats had access to standard chow either ad libitum (AL, n=8) or 80% of AL (CR, n=8) for two weeks. Systolic blood pressure was significantly higher in fa/fa AL rats versus lean AL animals, but was normalized by CR. Endothelium-dependent relaxation to acetylcholine (ACh, 10(-9) to 10(-4) M) was reduced in fa/fa AL compared to control lean AL rats (p<0.001), and restored by CR. The AMPK activator AICAR (10(-5) to 8·10(-3) M) elicited a lower relaxation in fa/fa AL rings that was normalized by CR (p<0.001). Inhibition of PI3K (wortmannin, 10(-7) M), Akt (triciribine, 10(-5) M), or eNOS (L-NAME, 10(-4) M) markedly reduced AICAR-induced relaxation in lean AL, but not in fa/fa AL rats. These inhibitions were restored by CR in Zucker fa/fa rings. These data show that mild short-term CR improves endothelial function and lowers blood pressure in obesity due to the activation of the AMPK-PI3K-Akt-eNOS pathway.

Ex vivo microperfusion system of the adipose organ: a new approach to studying the mobilization of adipose cell populations.

BACKGROUND/OBJECTIVES: Adipose tissue (AT) is a dynamic organ that expands and contracts rapidly. It is composed of adipocytes and of cell populations among which immune cells and mesenchymal progenitors known as adipose stromal cells (ASCs). The AT cell turnover has been extensively studied. Surprisingly it has only been viewed as the result of both cell proliferation/death and cell infiltration. Nevertheless, both immune cells and ASCs exhibit migration abilities; therefore their egress from AT in response to physiological/pathophysiological stimuli has to be considered. To do so, the aim of the present work was to develop a model allowing the study of cell release from the adipose organ. SUBJECTS/METHODS: Mesenteric (Mes) ATs were isolated from 9-week-old C57BL/6 male mice and were catheterized via the superior mesenteric artery and were perfused with a saline solution. After an equilibration period, the mesenteric fat pad was perfused with CXCL12 (stromal-derived factor-1, SDF-1) or sphingosine 1-phosphate (S1P) to trigger cell mobilization and perfusates were collected every 30 min for subsequent flow cytometry analyses. RESULTS: We report here that CXCL12 induces the specific release of ASCs from MesAT thus demonstrating that ASCs are specifically mobilized from fat depots by a CXCL12-dependent pathway. Moreover, we showed that leukocyte mobilization can be triggered via a S1P-dependent pathway. CONCLUSIONS: We have developed a microperfusion model of an intact fat depot allowing the study of AT cell release in response to various molecules. The perfusion system described here demonstrates that ASCs and leukocytes can be pharmacologically mobilized from AT. Therefore, AT microperfusion might constitute an appropriate and reliable approach for evaluating the mobilization of different cell populations from AT in various physiological and pathophysiological contexts. Such a model might help in identifying factors and drugs controlling AT cell release, impacting the medical fields of regenerative medicine and of obesity or its associated comorbidities.

High-fat diets impair spatial learning in the radial-arm maze in mice.

It has been suggested that hyperglycemia and insulin resistance triggered by energy-dense diets can account for hippocampal damage and deficits of cognitive behaviour. We wonder if the impairment of learning and memory processes detected in diet-induced obese (DIO) mice is linked to diet composition itself. With this purpose we have evaluated learning performance in mice undergoing a short-term high-fat (HF) treatment, which leads to a pre-obese state characterized by increased adiposity without significant changes of glucose and insulin plasma levels. C57BL/6J mice were fed either a HF (45 kcal% from fat) or control diet (10 kcal% from fat) during 8 weeks. Learning performance was evaluated by using the four-arm baited version of the eight-arm radial maze test (RAM). Mice were trained to learn the RAM protocol and then memory was tested at different time-points. Time spent to consume food placed in baited arms and errors committed to find them were measured in all sessions. DIO mice significantly spent more time in learning the task and made a greater number of errors than controls. Moreover, retention tests revealed that both working and total memory errors were also more numerous in DIO mice. The current results show that short-term DIO impairs spatial learning and suggest that impairment of hippocampal learning elicited by HF diets might be perceptible before metabolic alterations linked to obesity develop.

Cardiac allograft vasculopathy: coronary computed tomography and virtual histology assessment.

INTRODUCTION: Cardiac allograft vasculopathy remains the leading cause of late morbidity and mortality in heart transplantation. The main diagnostic methods, coronary angiography or intracoronary ultrasound (when angiography is normal), are invasive. Other study methods, such as coronary computed tomography (CT) and virtual histological analysis, have not been widely assessed in this condition. OBJECTIVE: The objective of this study was to assess the correlation between data obtained from analysis of virtual histology compared with those obtained from the performance of coronary CT in cardiac transplant recipients. MATERIALS AND METHODS: During the same admission we performed coronary angiography and intravascular ultrasound with virtual histological analysis (automatic pull-back in anterior descending artery and one additional vessel if the former was normal) as well as coronary CT. RESULTS: The study included 10 patients. Virtual histology was done in segments with intimal thickening>0.5 mm, defining 2 groups of plaque, those with an inflammatory component (necrotic core>30% and calcium) versus those without it defined as the combination of both being <30%. A calcium component of the inflammatory plaque allowed coronary CT detection. CONCLUSIONS: The detection of inflammatory plaque in graft vessel disease can be based on an initial noninvasive method, such as coronary CT, although confirmation requires further study.

[Paraneoplastic limbic encephalitis and lung cancer]. / Encefalitis límbica paraneoplásica y cáncer de pulmón.

Paraneoplastic limbic encephalitis (PLE) is a disorder characterized by severe cognitive dysfunction and seizures. It is usually associated with small cell lung carcinoma. Diagnosis is difficult because clinical markers are often lacking, and symptoms usually precede the diagnosis of cancer. Serological detection of antineuronal antibodies can be useful. We describe a patient with symptoms of limbic encephalitis, negative for paraneoplastic antibodies, in whom lung cancer was detected.

Encefalitis límbica paraneoplásica y cáncer de pulmón / Paraneoplastic limbic encephalitis and lung cancer

La encefalitis límbica paraneoplásica (ELP) es una entidad caracterizada por severos déficits cognitivos y crisis convulsivas. Suele asociarse a carcinoma de células pequeñas de pulmón. El diagnóstico de ELP es difícil, ya que los marcadores clínicos a menudo están ausentes, y los síntomas suelen preceder al diagnóstico del cáncer. La detección de anticuerpos antineuronales puede resultar útil. Presentamos un paciente con síntomas de encefalitis límbica, con anticuerpos paraneoplásicos negativos, en el que se detectó un cancer de pulmón (AU)

Neoplasia pulmonar múltiple primaria

La neoplasia primaria múltiple de pulmón es una forma de presentación poco común entre las neoformaciones pulmonares. Acontece entre el 1,5 y el 3 per cent del total de las neoplasias de pulmón. Los criterios que la definen fueron establecidos en 1975 por Martini y Melamed, y aún son la referencia. La neoplasia primaria múltiple pulmonar puede manifestarse de forma sincrónica (aparición simultánea) o metacrónica (diferencia de aparición de más de 2 años entre ambos tumores). Se da una mayor incidencia en grandes fumadores y desde el punto de vista anatomopatológico suele tratarse de uncarcinoma epidermoide. Se considera que la supervivencia de este tipo de neoplasia pulmonar es menor que la de presentación única (AU)