Muscle calcium stress cleaves junctophilin1, unleashing a gene regulatory program predicted to correct glucose dysregulation.

Calcium ion movements between cellular stores and the cytosol govern muscle contraction, the most energy-consuming function in mammals, which confers skeletal myofibers a pivotal role in glycemia regulation. Chronic myoplasmic calcium elevation ("calcium stress"), found in malignant hyperthermia-susceptible (MHS) patients and multiple myopathies, has been suggested to underlie the progression from hyperglycemia to insulin resistance. What drives such progression remains elusive. We find that muscle cells derived from MHS patients have increased content of an activated fragment of GSK3ß - a specialized kinase that inhibits glycogen synthase, impairing glucose utilization and delineating a path to hyperglycemia. We also find decreased content of junctophilin1, an essential structural protein that colocalizes in the couplon with the voltage-sensing CaV1.1, the calcium channel RyR1 and calpain1, accompanied by an increase in a 44 kDa junctophilin1 fragment (JPh44) that moves into nuclei. We trace these changes to activated proteolysis by calpain1, secondary to increased myoplasmic calcium. We demonstrate that a JPh44-like construct induces transcriptional changes predictive of increased glucose utilization in myoblasts, including less transcription and translation of GSK3ß and decreased transcription of proteins that reduce utilization of glucose. These effects reveal a stress-adaptive response, mediated by the novel regulator of transcription JPh44.

Malignant hyperthermia: what we may need to have at hand / Hipertermia maligna: lo que tendríamos que tener a la mano

Malignant hyperthermia (MH) is often neglected in anesthesia because of its rare incidence (around 1:100,000 general anesthetics). However, when it occurs, it becomes the anesthesiologist's nightmare. In the United States, Canada, and in most European countries, it is mandatory to store dantrolene wherever halogenated agents and/or succinylcholine are used by anesthesia providers (including sites that use only succinylcholine and no volatiles for electroconvulsive therapies). Unfortunately, its availability in Colombia is not mandatory or universal

La hipertermia maligna (HM) es algo a menudo se descuida durante el acto anestésico debido a su muy baja incidencia (aproximadamente 1:100.000 anestesias generales). Sin embargo, cuando se presenta, se convierte en una pesadilla para el anestesiólogo. En los Estados Unidos, Canadá y la mayoría de los países de Europa es obligatorio contar con dantroleno siempre que los anestesiólogos administran agentes halogenados y/o succinilcolina (incluidos los centros que utilizan succinilcolina sola sin agentes volátiles para terapias electroconvulsivas). En Colombia, infortunadamente, su disponibilidad no es obligatoria ni universal

Intracellular calcium leak lowers glucose storage in human muscle, promoting hyperglycemia and diabetes.

Most glucose is processed in muscle, for energy or glycogen stores. Malignant Hyperthermia Susceptibility (MHS) exemplifies muscle conditions that increase [Ca2+]cytosol. 42% of MHS patients have hyperglycemia. We show that phosphorylated glycogen phosphorylase (GPa), glycogen synthase (GSa) - respectively activated and inactivated by phosphorylation - and their Ca2+-dependent kinase (PhK), are elevated in microsomal extracts from MHS patients' muscle. Glycogen and glucose transporter GLUT4 are decreased. [Ca2+]cytosol, increased to MHS levels, promoted GP phosphorylation. Imaging at ~100 nm resolution located GPa at sarcoplasmic reticulum (SR) junctional cisternae, and apo-GP at Z disk. MHS muscle therefore has a wide-ranging alteration in glucose metabolism: high [Ca2+]cytosol activates PhK, which inhibits GS, activates GP and moves it toward the SR, favoring glycogenolysis. The alterations probably cause these patients' hyperglycemia. For basic studies, MHS emerges as a variable stressor, which forces glucose pathways from the normal to the diseased range, thereby exposing novel metabolic links.

Animals and humans move by contracting the skeletal muscles attached to their bones. These muscles take up a type of sugar called glucose from food and use it to fuel contractions or store it for later in the form of glycogen. If muscles fail to use glucose it can lead to excessive sugar levels in the blood and a condition called diabetes. Within muscle cells are stores of calcium that signal the muscle to contract. Changes in calcium levels enhance the uptake of glucose that fuel these contractions. However, variations in calcium have also been linked to diabetes, and it remained unclear when and how these 'signals' become harmful. People with a condition called malignant hyperthermia susceptibility (MHS for short) have genetic mutations that allow calcium to leak out from these stores. This condition may result in excessive contractions causing the muscle to over-heat, become rigid and break down, which can lead to death if left untreated. A clinical study in 2019 found that out of hundreds of patients who had MHS, nearly half had high blood sugar and were likely to develop diabetes. Now, Tammineni et al. ­ including some of the researchers involved in the 2019 study ­ have set out to find why calcium leaks lead to elevated blood sugar levels. The experiments showed that enzymes that help convert glycogen to glucose are more active in patients with MHS, and found in different locations inside muscle cells. Whereas the enzymes that change glucose into glycogen are less active. This slows down the conversion of glucose into glycogen for storage and speeds up the breakdown of glycogen into glucose. Patients with MHS also had fewer molecules that transport glucose into muscle cells and stored less glycogen. These changes imply that less glucose is being removed from the blood. Next, Tammineni et al. used a microscopy technique that is able to distinguish finely separated objects with a precision not reached before in living muscle. This revealed that when the activity of the enzyme that breaks down glycogen increased, it moved next to the calcium store. This effect was also observed in the muscle cells of MHS patients that leaked calcium from their stores. Taken together, these observations may explain why patients with MHS have high levels of sugar in their blood. These findings suggest that MHS may start decades before developing diabetes and blood sugar levels in these patients should be regularly monitored. Future studies should investigate whether drugs that block calcium from leaking may help prevent high blood sugar in patients with MHS or other conditions that cause a similar calcium leak.

Noninvasive stereotactic radioablation for the treatment of atrial fibrillation: First-in-man experience.

PURPOSE: Catheter ablation is an effective therapy for atrial fibrillation (AF). However, risks remain, and improved efficacy is desired. Stereotactic body radiotherapy (SBRT) is a well-established therapy used to noninvasively treat malignancies and functional disorders with precision. We evaluated the feasibility of stereotactic radioablation for treating paroxysmal AF. METHODS: Two patients with drug-refractory paroxysmal AF underwent pulmonary vein isolation with SBRT. After placement of a percutaneous active fixation temporary pacing lead tracking fiducial, computed tomography (CT) angiography was performed to define left atrial anatomy. A tailored planning treatment volume was created to deliver contiguous linear ablations to isolate the pulmonary veins and posterior wall. Patients were treated on an outpatient basis in the radioablation suite. Clinical follow-up was performed through at least 24 months after therapy. RESULTS: Both patients successfully underwent SBRT planning and treatment without significant early or long-term side effects up to 48 months of follow-up. One patient had AF recurrence after 6 months free of arrhythmia, while the second patient remains free of AF after 24 months with fibrosis detected on MRI scan consistent with the ablation lesion set. An incidentally noted small pericardial effusion occurred in one patient. CONCLUSION: Stereotactic radioablation may be feasible for the treatment of drug-refractory AF. Further evaluation is warranted.

Validación de la Escala de Satisfacción con la Vida en trabajadores peruanos / Validation of the Satisfaction with Life Scale in Peruvian workers

Se presenta la validación de la Escala de Satisfacción con la Vida (SWLS, por sus siglas en inglés). Participaron 177 trabajadores (74% varones) de 19 a 64 años de edad (M = 36.24; DE = 9.75) provenientes de una industria pesquera de diversas ciudades del Perú. Se obtuvo la evidencia de validez relacionada con la estructura interna mediante el análisis factorial confirmatorio complementado con el análisis de la varianza extraída promedio para la convergencia interna entre los ítems. Además, se examinó la evidencia de validez por su relación con otros constructos cumpliendo la satisfacción con la vida el papel de variable dependiente frente a los efectos del síndrome de burnout. La confiabilidad de consistencia interna fue calculada con los coeficientes alfa de Cronbach, Omega y H. Los resultados demuestran una estructura unidimensional de la SWLS con errores correlacionados entre los pares 1-2 y 4-5. En el análisis de regresión, las dimensiones de eficacia profesional e agotamiento emocional del síndrome de burnout influenciaron en la satisfacción con la vida en contraste con la dimensión de indiferencia. La consistencia interna de las puntuaciones de la SWLS fue aceptable. Se discute la implicancia de los resultados a nivel práctico y teórico además de las limitaciones y recomendaciones futuras

This paper presents the validation of the Satisfaction with Life Scale (SWLS). Participants were 177 workers (74% males) between 19 and 64 years of age (M = 36.24, SD = 9.75) from fishing companies located in different cities of Peru. Evidence of validity related to the internal structure was obtained through the confirmatory factor analysis complemented with the analysis of the average variance that determines the internal convergence between the items. In addition, evidence of validity was examined to assess its relationship with other constructs: the satisfaction with life fulfilled the role of dependent variable versus the effects of the burnout syndrome. The reliability of the internal consistency was calculated with Cronbach's alpha coefficient, McDonald's omega coefficient, and Mueller & Hancock´s H coefficient. The results demonstrate a one-dimensional structure of the SWLS with errors correlated between pairs 1-2 and 4-5. In the regression analysis, the dimensions professional efficacy and emotional exhaustion of burnout syndrome influenced the satisfaction with life dimension in contrast to the indifference dimension. The internal consistency of the SWLS scores was acceptable. The implication of the results at practical and theoretical level is discussed, as well as the limitations and future recommendations.

Causes of sore throat after intubation: a prospective observational study of multiple anesthesia variables.

BACKGROUND: Sore throat is common after intubation for surgery. This observational study investigated cuff pressure and a large range of clinical covariates to explore the etiology of sore throat. METHODS: Approximately 24 hours after surgery six questions relating to pain, upper airway symptoms and sore throat were delivered to patients who had undergone intubation. Sore throat was correlated with demographics, anesthesia variables and cuff pressure (measured for a subset of patients). RESULTS: Sore throat was reported by 270/518 (52%) patients with VAS Score 45.9±25.1 (range 0-100). Sore throat patients were significantly younger, had a lower ASA status, were more frequently female, had shorter surgeries and lower nitrous oxide exposure, had a higher proportion of smaller tracheal tubes (7.5 mm internal diameter vs. 8 mm), had a higher incidence of nasogastric drainage, higher propofol doses and a higher usage of ketorolac. Decreasing age (odds ratio 0.976, 95% confidence intervals 0.961-0.992, P=0.003) and the presence of a nasogastric tube when the questionnaire was delivered (OR 1.83, 95% CI: 1.06-3.14, P=0.03) remained significant predictors of sore throat on multivariate analysis. Mean cuff pressure (measured for 160 patients) was 56.8±41.9 mmHg. Cuff pressure was similar amongst patients with and without sore throat (57±46 vs. 53±38 mmHg, P=0.58). There was no correlation between cuff pressure and severity of sore throat (r=0.004, P=0.37). CONCLUSIONS: Only age and the presence of a nasogastric tube after surgery were significant predictors for sore throat. This result contradicts most other studies of cuff pressure where fewer covariates were measured.

Purification and characterization of tenerplasminin-1, a serine peptidase inhibitor with antiplasmin activity from the coral snake (Micrurus tener tener) venom.

A plasmin inhibitor, named tenerplasminin-1 (TP1), was isolated from Micrurus tener tener (Mtt) venom. It showed a molecular mass of 6542Da, similarly to Kunitz-type serine peptidase inhibitors. The amidolytic activity of plasmin (0.5nM) on synthetic substrate S-2251 was inhibited by 91% following the incubation with TP1 (1nM). Aprotinin (2nM) used as the positive control of inhibition, reduced the plasmin amidolytic activity by 71%. Plasmin fibrinolytic activity (0.05nM) was inhibited by 67% following incubation with TP1 (0.1nM). The degradation of fibrinogen chains induced by plasmin, trypsin or elastase was inhibited by TP1 at a 1:2, 1:4 and 1:20 enzyme:inhibitor ratio, respectively. On the other hand, the proteolytic activity of crude Mtt venom on fibrinogen chains, previously attributed to metallopeptidases, was not abolished by TP1. The tPA-clot lysis assay showed that TP1 (0.2nM) acts like aprotinin (0.4nM) inducing a delay in lysis time and lysis rate which may be associated with the inhibition of plasmin generated from the endogenous plasminogen activation. TP1 is the first serine protease plasmin-like inhibitor isolated from Mtt snake venom which has been characterized in relation to its mechanism of action, formation of a plasmin:TP1 complex and therapeutic potential as anti-fibrinolytic agent, a biological characteristic of great interest in the field of biomedical research. They could be used to regulate the fibrinolytic system in pathologies such as metastatic cancer, parasitic infections, hemophilia and other hemorrhagic syndromes, in which an intense fibrinolytic activity is observed.

A program of nutritional education in schools reduced the prevalence of iron deficiency in students.

The objective was to determine the prevalence of iron, folates and retinol deficiencies in school children and to evaluate the changes after an intervention of nutritional education. The project was developed in 17 schools. The sample included 1,301 children (678 males and 623 females). A subsample of 480 individuals, was randomly selected for drawing blood for biochemical determinations before and after the intervention of nutritional education, which included in each school: written pre and post-intervention tests, 6 workshops, 2 participative talks, 5 game activities, 1 cooking course and 1 recipe contest. Anthropometrical and biochemical determinations included weight, height, body-mass index, nutritional status, hematocrit, serum ferritin, retinol and folate concentrations. There was high prevalence of iron (25%), folates (75%) and vitamin A (43%) deficiencies in school children, with a low consumption of fruit and vegetables, high consumption of soft drinks and snacks and almost no physical activity. The nutritional education intervention produced a significant reduction in iron deficiency prevalence (25 to 14%), and showed no effect on vitamin A and folates deficiencies. There was a slight improvement in nutritional status. This study shows, through biochemical determinations, that nutritional education initiatives and programs have an impact improving nutritional health in school children.

Malignant hyperthermia susceptibility diagnosed with a family-specific ryanodine receptor gene type 1 mutation.

Malignant hyperthermia (MH) is an autosomal dominant disorder of skeletal muscle calcium regulation, and the rate of calcium-induced calcium release (CICR), determined by using skinned fibers of skeletal muscle, has been employed as a diagnostic test for MH susceptibility in Japan. The ryanodine receptor (RYR1), encoding the major calcium-release channel in skeletal muscle sarcoplasmic reticulum, has been shown to be mutated in a number of MH pedigrees. We experienced the detection of accelerated CICR and/or an RYR1 mutation in a patient with an MH episode and his family. Accelerated CICR and an RYR1 mutation (c.14512C>G, p.L4838V) were found in the patient and his father. The MH-causative mutation (c.14512C>G, p.L4838V) was also found in his brother and his son (resulting in the diagnosis of MH without the CICR test), but the mutation was not found in his mother or two daughters. With the detection of the family-specific mutation in other family members, the diagnosis of MH was made without the invasive CICR test.

[Incidence of congenital heart disease in navarra (1989-1998)]. / Incidencia de las cardiopatías congénitas en Navarra (1989-1998).

INTRODUCTION AND OBJECTIVES: Congenital cardiopathies are the most common forms of congenital malformation. They occur in between 5.2 and 12.5 in every thousand live births. The aim of this study was to describe the incidence and nature of congenital heart disease in the Spanish region of Navarra during a specified time period (1989-1998). PATIENTS AND METHOD: The study involved all children with congenital heart disease among the 47 783 born in the region in the specified time period. RESULTS: The incidence was 8.96 per thousand live births, with 90% having one of the 10 most common types of cardiac malformation. The accumulative percentage diagnosed was 25.3% in the first 24 hours of life, 45% in the first week, 65% in the first month, and 83.1% during the first year. Some 30.8% of cases of congenital heart disease required invasive treatment: 25.4% underwent surgery and 6.4%, cardiac catheterization. CONCLUSIONS: The incidence of congenital heart disease in Navarra falls within the range reported for developed countries. The level of care provided in this region is good, as demonstrated by existing diagnostic capabilities and treatment provision.

Reporte y seguimiento de un programa comunitario médico-social: Proyecto Maniapure año 2000 / Report and follow up of a medical-social community program: Maniapure Proyect year 2000

Dentro del proyecto Maniapure en área de la salud se ha consolidado. Se han incorporado líderes de la comunidad que toman las riendas de su propio desarrollo. Hay que seguir aportando proyectos y recursos para el desarrollo en higiene ambiental, además apoyar los proyectos del área de educación-cultura y de formación para el trabajo, determinando de esta manera un incremento de la calidad de vida de estos dignos y notables pobladores.