Janus kinase inhibition prevents cancer- and myocardial infarction-mediated diaphragm muscle weakness in mice.

Respiratory dysfunction is prevalent in critically ill patients and can lead to adverse clinical outcomes, including respiratory failure and increased mortality. Respiratory muscles, which normally sustain respiration through inspiratory muscle contractions, become weakened during critical illness, and recent studies suggest that respiratory muscle weakness is related to systemic inflammation. Here, we investigate the pathophysiological role of the inflammatory JAK1/3 signaling pathway in diaphragm weakness in two distinct experimental models of critical illness. In the first experiment, mice received subcutaneous injections of PBS or C26 cancer cells and were fed chow formulated with or without the JAK1/3 inhibitor R548 for 26 days. Diaphragm specific force was significantly reduced in tumor-bearing mice receiving standard chow; however, treatment with the JAK1/3 inhibitor completely prevented diaphragm weakness. Diaphragm cross-sectional area was diminished by ∼25% in tumor-bearing mice but was similar to healthy mice in tumor-bearing animals treated with R548. In the second study, mice received sham surgery or coronary artery ligation, leading to myocardial infarction (MI), and were treated with R548 or vehicle 1 h postsurgery, and once daily for 3 days. Diaphragm specific force was comparable between sham surgery/vehicle, sham surgery/R548 and MI/R548 groups, but significantly decreased in the MI/vehicle group. Markers of oxidative damage and activated caspase-3, mechanisms previously identified to reduce muscle contractility, were not elevated in diaphragm extracts. These experiments implicate JAK1/3 signaling in cancer- and MI-mediated diaphragm weakness in mice, and provide a compelling case for further investigation.

The JAK-STAT pathway is critical in ventilator-induced diaphragm dysfunction.

Mechanical ventilation (MV) is one of the lynchpins of modern intensive-care medicine and is life saving in many critically ill patients. Continuous ventilator support, however, results in ventilation-induced diaphragm dysfunction (VIDD) that likely prolongs patients' need for MV and thereby leads to major associated complications and avoidable intensive care unit (ICU) deaths. Oxidative stress is a key pathogenic event in the development of VIDD, but its regulation remains largely undefined. We report here that the JAK-STAT pathway is activated in MV in the human diaphragm, as evidenced by significantly increased phosphorylation of JAK and STAT. Blockage of the JAK-STAT pathway by a JAK inhibitor in a rat MV model prevents diaphragm muscle contractile dysfunction (by ~85%, p < 0.01). We further demonstrate that activated STAT3 compromises mitochondrial function and induces oxidative stress in vivo, and, interestingly, that oxidative stress also activates JAK-STAT. Inhibition of JAK-STAT prevents oxidative stress-induced protein oxidation and polyubiquitination and recovers mitochondrial function in cultured muscle cells. Therefore, in ventilated diaphragm muscle, activation of JAK-STAT is critical in regulating oxidative stress and is thereby central to the downstream pathogenesis of clinical VIDD. These findings establish the molecular basis for the therapeutic promise of JAK-STAT inhibitors in ventilated ICU patients.

Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.

Controlled mechanical ventilation (CMV) is associated with the development of diaphragm atrophy and contractile dysfunction, and respiratory muscle weakness is thought to contribute significantly to delayed weaning of patients. Therefore, therapeutic strategies for preventing these processes may have clinical benefit. The aim of the current study was to investigate the role of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in CMV-mediated diaphragm wasting and weakness in rats. CMV-induced diaphragm atrophy and contractile dysfunction coincided with marked increases in STAT3 phosphorylation on both tyrosine 705 (Tyr705) and serine 727 (Ser727). STAT3 activation was accompanied by its translocation into mitochondria within diaphragm muscle and mitochondrial dysfunction. Inhibition of JAK signaling during CMV prevented phosphorylation of both target sites on STAT3, eliminated the accumulation of phosphorylated STAT3 within the mitochondria, and reversed the pathologic alterations in mitochondrial function, reduced oxidative stress in the diaphragm, and maintained normal diaphragm contractility. In addition, JAK inhibition during CMV blunted the activation of key proteolytic pathways in the diaphragm, as well as diaphragm atrophy. These findings implicate JAK/STAT3 signaling in the development of diaphragm muscle atrophy and dysfunction during CMV and suggest that the delayed extubation times associated with CMV can be prevented by inhibition of Janus kinase signaling.-Smith, I. J., Godinez, G. L., Singh, B. K., McCaughey, K. M., Alcantara, R. R., Gururaja, T., Ho, M. S., Nguyen, H. N., Friera, A. M., White, K. A., McLaughlin, J. R., Hansen, D., Romero, J. M., Baltgalvis, K. A., Claypool, M. D., Li, W., Lang, W., Yam, G. C., Gelman, M. S., Ding, R., Yung, S. L., Creger, D. P., Chen, Y., Singh, R., Smuder, A. J., Wiggs, M. P., Kwon, O.-S., Sollanek, K. J., Powers, S. K., Masuda, E. S., Taylor, V. C., Payan, D. G., Kinoshita, T., Kinsella, T. M. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.

Exercise performance and peripheral vascular insufficiency improve with AMPK activation in high-fat diet-fed mice.

Intermittent claudication is a form of exercise intolerance characterized by muscle pain during walking in patients with peripheral artery disease (PAD). Endothelial cell and muscle dysfunction are thought to be important contributors to the etiology of this disease, but a lack of preclinical models that incorporate these elements and measure exercise performance as a primary end point has slowed progress in finding new treatment options for these patients. We sought to develop an animal model of peripheral vascular insufficiency in which microvascular dysfunction and exercise intolerance were defining features. We further set out to determine if pharmacological activation of 5'-AMP-activated protein kinase (AMPK) might counteract any of these functional deficits. Mice aged on a high-fat diet demonstrate many functional and molecular characteristics of PAD, including the sequential development of peripheral vascular insufficiency, increased muscle fatigability, and progressive exercise intolerance. These changes occur gradually and are associated with alterations in nitric oxide bioavailability. Treatment of animals with an AMPK activator, R118, increased voluntary wheel running activity, decreased muscle fatigability, and prevented the progressive decrease in treadmill exercise capacity. These functional performance benefits were accompanied by improved mitochondrial function, the normalization of perfusion in exercising muscle, increased nitric oxide bioavailability, and decreased circulating levels of the endogenous endothelial nitric oxide synthase inhibitor asymmetric dimethylarginine. These data suggest that aged, obese mice represent a novel model for studying exercise intolerance associated with peripheral vascular insufficiency, and pharmacological activation of AMPK may be a suitable treatment for intermittent claudication associated with PAD.

[A silent killer: the primary hypertension non complicated]. / El asesino silencioso: la hipertensión arterial sistémica primaria no complicada.

The systemic high blood pressure is called the silent killer, because it is a chronic disease, most of the time asymptomatic but with risk to damage target organs if it is not diagnosis and treat with opportunity. Briefly, here is described some clinical data of the disease in the non complicated primary hypertension that could be useful at medical out care office.

Mapping Lipogenic Flux: A Gold LDI-MS Approach for Imaging Neutral Lipid Kinetics.

Spatial characterization of triglyceride metabolism is an area of significant interest which can be enabled by mass spectrometry imaging via recent advances in neutral lipid laser desorption analytical approaches. Here, we extend recent advancements in gold-assisted neutral lipid imaging and demonstrate the potential to map lipid flux in rodents. We address here critical issues surrounding the analytical configuration and interpretation of the data for a group of select triglycerides. Specifically, we examined how the signal intensity and spatial resolution would impact the apparent isotope ratio in a given analyte (which is an important consideration when performing MS based kinetics studies of this kind) with attention given to molecular ions and not fragments. We evaluated the analytics by contrasting lipid flux in well characterized mouse models, including fed vs fed states and different dietary perturbations. In total, the experimental paradigm described here should enable studies of hepatic lipogenesis; presumably, this logic can be enhanced via the inclusion of ion mobility and/or fragmentation. Although this study was carried out in robust models of liver lipogenesis, we expect that the model system could be expanded to a variety of tissues where zonated (or heterogeneous) lipid synthesis may occur, including solid tumor metabolism.

Fibrinogen is associated with silent myocardial ischaemia in type 2 diabetes mellitus.

OBJECTIVE: Because traditional risk factors only partially explain coronary events, it is necessary to search for new ones like fibrinogen which has been related with coronary disease in healthy middle-aged adults. We attempted to determine the impact of fibrinogen on silent myocardial ischaemia (SMI) in diabetic patients. METHODS AND RESULTS: In a cross-sectional study, 134 type 2 diabetes patients with no history of cardiovascular disease were assessed for SMI. A personal history and physical evaluation of each patient was conducted as well as evaluation of cholesterol, glucose, fibrinogen, blood cell counts, glycated haemoglobin, urine albumin quantification, and urinalysis. A modified Bruce test was performed on all study participants to evaluate the presence of SMI. RESULTS: Eleven patients had SMI (8.2%) that was associated with systolic, diastolic and mean blood pressure, hypertension, and fibrinogen. The correlation coefficient was obtained for quintiles of fibrinogen with the percentage of patients with SMI in that quintile (r = 0.97; 95% = 0.66-0.99). Fibrinogen levels were associated with SMI. A receiver-operator curve analysis showed that the cutoff value for fibrinogen to predict SMI was 400 mg/dL (82% sensitivity, 81% specificity). A cutoff value of 306 mg/dL of fibrinogen would rule in the diagnosis of SMI (100% sensitivity, 17% specificity), while fibrinogen cutoff of 682 mg/dL would rule out SMI (100% specificity, 9% sensitivity). CONCLUSIONS: Fibrinogen strongly predicts SMI in diabetic patients and may identify individuals with high cardiovascular risk. Fibrinogen should be evaluated in diabetic patients for a more accurate cardiovascular evaluation.

Impact of Classical Risk Factors for Arterial or Venous Thrombosis in Patients With Antiphospholipid Syndrome.

There are classical risk factors associated with arterial thrombosis (AT) or venous thromboembolic disease (VTD). However, less is known about these risk factors and AT or VTD episodes in patients with antiphospholipid syndrome (APS). Our aim was to elucidate whether APS-related thrombotic episodes are associated with the same risk factors as the non-APS population. We gathered demographics, medical history, complications, and causes of death associated with the risk factors for AT or VTD in patients with APS. We analyzed 677 thrombotic events in 386 patients. Type 2 diabetes mellitus and grade 3 obesity were associated with VTD instead of AT. There were no significant differences between the groups for almost all laboratory tests analyzed, although lupus anticoagulant was significantly higher in the VTD group. We suggest that thrombosis in APS is due to the APS itself and that the risks factors for AT or VTD do not have a main role. Our findings may have an ethnical background. Therefore, it may be difficult to elaborate predictive thrombotic clinical scores applicable to patients with different ethnical background.

[Comment on article "Acute appendicitis. Surgical and non surgical treatment"]. / Comentario al artículo "Apendicitis aguda. Manejo quirúrgico y no quirúrgico".

No abstract.

Sin abstract.

Los padres de la Medicina Interna / The parents of Internal Medicine

Resumen: En medicina, cada especialidad ha considerado padre a determinado personaje por el hecho de sus obras en relación con ella. De tal manera que, partiendo de Hipócrates de Cos (c. 460-370 a.n.e.) como el padre de la medicina en general,1 podemos encontrar a quienes se consideran los padres de la medicina interna; la descripción de sus vidas y obras nos pueden ilustrar el porqué de su consideración.

Abstract: In medicine, each specialty has considered father a certain person because of the fact of his works in relation to it. Thus, starting from Hippocrates de Cos (c. 460-370 bC.) as the father of medicine in general, we can find those who are considered the parents of internal medicine. The description of their lives and works can illustrate the reason for their consideration.