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.

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.

Los santos patronos de la medicina, la cirugía y la odontología / Patron saints of medicine, surgery and odontology

Resumen En la medicina occidental existen varios santos y santas que fungen como patronos, defensores, cuyo conocimiento es de interés, desde el punto de vista médico-cultural y no solo religioso. Expongo algunos ejemplos representativos de estos santos de la medicina.

Abstract In western medicine there are several saints who act as patrons, defenders, whose knowledge is of interest, from the cultural medical point of view, and not only religious. I present some representative examples of these saints of medicine.

Las enfermedades mortales de los presidentes de México / The deadly diseases of the presidents of Mexico

Resumen: La política, la historia y la medicina no son disciplinas necesariamente inconexas, como lo demuestran algunas publicaciones. En el caso de los presidentes que ha tenido la República Mexicana, es infrecuente que los médicos mexicanos (y aún los biógrafos de los personajes) sepan la causa de la muerte, así como los detalles de sus enfermedades previas y, en su caso, los detalles de sus autopsias, por lo que resulta de interés médico cultural el tratamiento del tema.

Abstract: Politics, history and medicine are not necessarily disconnected disciplines, as some publications show. In the case of the presidents the Mexican Republic has had, it is uncommon for Mexican doctors (and even the biographers of the characters) to know the cause of death, as well as the details of their previous illnesses and, where appropriate, the details of their autopsies. For what is of cultural medical interest, the treatment of the subject.

Los dioses mitológicos de la medicina / The mythological gods of medicine

Resumen EL hombre, al menos desde que hay registros de la historia de la humanidad, ha asignado rasgos de divinidad a fenómenos naturales, pero también a fenómenos humanos, acorde con la cosmovisión de cada tiempo y lugar. Además de formar parte de la historia, en algunos casos han sido determinantes para la construcción de una historia e identidad nacional, regional o gremial, tal fenómeno persiste hasta nuestros días. A continuación se presenta una compilación de datos de las diferentes mitologías en la medicina mundial.

Abstract Humans, at least since there are records of the history of humanity, have assigned features of divinity to natural phenomena but also to human phenomena, according to the worldview of each time and place. In addition to being part of history, in some cases they have been decisive for the construction of a national, regional or union history and identity, such a phenomenon persists to this day. Below is a compilation of data from the different mythologies in world medicine.

Panaceas, medicinas alternativas y similares: el auge y triunfo de la pseudociencia médica / Panaceas, alternative and similar medicines: the boom and triumph of medical pseudoscience

Resumen México en particular parece ser, desde hace más de un siglo, uno de los paraísos mundiales de los charlatanes. Precisamente fue en nuestro país en donde se acuñó el término "merolico", derivado del apellido del "médico" judío polaco Rafael Juan de Meraulyock. Desde entonces hasta nuestro días, hemos visto un desfile de panaceas, medicinas alternativas y similares, que en no pocas ocasiones compiten con nuestro quehacer cotidiano en la búsqueda de la salud de los pacientes mexicanos. A continuación hacemos una revisión de las principales terapias mencionadas.

Abstract Mexico in particular seems to be, for more than a century, one of the world's paradises of charlatans. It was precisely in our country where the term "merolico" was coined, derived from the surname of the Polish Jewish "doctor" Rafael Juan de Meraulyock. From then until our days, we have seen a parade of panaceas, alternative medicines and similar, that in many occasions compete with our daily work in the search for the health of Mexican patients. Below we review the main therapies mentioned.

Enfermedad de Chagas (tripanosomiasis americana) / Chagas disease (American trypanosomiasis)

Resumen La enfermedad de Chagas (tripanosomiasis americana) es una zoonosis descrita en Brasil, en 1909, por Carlos Chagas. Afecta a cerca de 20 millones de personas distribuidas en todos los países de América y, debido a las migraciones, actualmente se considera que la enfermedad está globalizada, por lo que se ha diagnosticado, incluso, en Australia, Japón, Canadá y Francia. El agente causal es Trypanosoma cruzi y las vías de trasmisión son: vectorial (por medio de un triatomino), congénita, oral, transfusional, por accidentes de laboratorio, por trasplantes y por lactancia. El cuadro clínico tiene tres fases: aguda, latente y crónica. La fase aguda suele no ser grave, la fase de latencia puede durar incluso 50 años y la fase crónica se caracteriza por alteraciones irreversibles, sobre todo, cardiacas y digestivas. Aún no existe un tratamiento médico satisfactorio, por lo que representa un problema de salud pública que los médicos deben tener en cuenta.

Abstract Chagas disease (American trypanosomiasis) is a zoonosis described in Brazil, in 1909, by Carlos Chagas. It affects about 20 million people distributed in all the countries of America, and due to migration, it is currently considered that the disease is globalized, so it has been diagnosed even in Australia, Japan, Canada and France. The causative agent is Trypanosoma cruzi, and the transmission routes are: vectorial (by means of a triatomine), congenital, oral, transfusional, by laboratory accidents, by transplants, and by lactation. The clinical picture has three phases: acute, latent and chronic. The acute phase is usually not serious, the latency phase can last up to 50 years, and the chronic phase is characterized by irreversible alterations, especially at the cardiac and digestive levels. There is still no satisfactory medical treatment. For what it represents a public health problem that doctors must take into account.

Origen del término Medicina Interna / Origin of the term Internal Medicine

Estimado Dr. Matijasevic: Primeramente, le agradezco me haya citado (1) en la bibliografía de uno de sus artículos (2). En dicho artículo, bien hace usted la diferenciación entre la celebración del Primer Congreso de Medicina Interna de que se tiene noticia, en Alemania (1882), y el empleo del término Medicina Interna como tal; al respecto, dice usted: "… el primer uso documentado de la expresión medicina interna… data del año 1839 con ocasión del primer Congresso degli Scienziati Italiani…celebrado en Pisa…". Francisco Medrano González (3) dice que el término Medicina Interna apareció desde 1807, en un libro de M. Cartier (1768-1839), titulado De la Médicine Interne appliqué aux aladies chirurgicales (4). Atentamente, Dr. Guillermo Murillo-Godínez.

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.

AMPK activation through mitochondrial regulation results in increased substrate oxidation and improved metabolic parameters in models of diabetes.

Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor of cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation of AMPK results in the mobilization of nutrient uptake and catabolism for mitochondrial ATP generation to restore energy homeostasis. How these nutrient pathways are affected in the presence of a potent modulator of mitochondrial function and the role of AMPK activation in these effects remain unclear. We have identified a molecule, named R419, that activates AMPK in vitro via complex I inhibition at much lower concentrations than metformin (IC50 100 nM vs 27 mM, respectively). R419 potently increased myocyte glucose uptake that was dependent on AMPK activation, while its ability to suppress hepatic glucose production in vitro was not. In addition, R419 treatment of mouse primary hepatocytes increased fatty acid oxidation and inhibited lipogenesis in an AMPK-dependent fashion. We have performed an extensive metabolic characterization of its effects in the db/db mouse diabetes model. In vivo metabolite profiling of R419-treated db/db mice showed a clear upregulation of fatty acid oxidation and catabolism of branched chain amino acids. Additionally, analyses performed using both (13)C-palmitate and (13)C-glucose tracers revealed that R419 induces complete oxidation of both glucose and palmitate to CO2 in skeletal muscle, liver, and adipose tissue, confirming that the compound increases mitochondrial function in vivo. Taken together, our results show that R419 is a potent inhibitor of complex I and modulates mitochondrial function in vitro and in diabetic animals in vivo. R419 may serve as a valuable molecular tool for investigating the impact of modulating mitochondrial function on nutrient metabolism in multiple tissues and on glucose and lipid homeostasis in diabetic animal models.

Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases.

Limited neural input results in muscle weakness in neuromuscular disease because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission. We developed a small-molecule fast-skeletal-troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neural input is otherwise diminished secondary to neuromuscular disease. Binding selectively to the fast-skeletal-troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards, as does the force-frequency relationship of a nerve-muscle pair, so that CK-2017357 increases the production of muscle force in situ at sub-maximal nerve stimulation rates. Notably, we show that sensitization of the fast-skeletal-troponin complex to calcium improves muscle force and grip strength immediately after administration of single doses of CK-2017357 in a model of the neuromuscular disease myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.

Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.

Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.