Heterogeneous cardiac sympathetic innervation gradients promote arrhythmogenesis in murine dilated cardiomyopathy.

Ventricular arrhythmias (VAs) in heart failure are enhanced by sympathoexcitation. However, radiotracer studies of catecholamine uptake in failing human hearts demonstrate a proclivity for VAs in patients with reduced cardiac sympathetic innervation. We hypothesized that this counterintuitive finding is explained by heterogeneous loss of sympathetic nerves in the failing heart. In a murine model of dilated cardiomyopathy (DCM), delayed PET imaging of sympathetic nerve density using the catecholamine analog [11C]meta-Hydroxyephedrine demonstrated global hypoinnervation in ventricular myocardium. Although reduced, sympathetic innervation in 2 distinct DCM models invariably exhibited transmural (epicardial to endocardial) gradients, with the endocardium being devoid of sympathetic nerve fibers versus controls. Further, the severity of transmural innervation gradients was correlated with VAs. Transmural innervation gradients were also identified in human left ventricular free wall samples from DCM versus controls. We investigated mechanisms underlying this relationship by in silico studies in 1D, 2D, and 3D models of failing and normal human hearts, finding that arrhythmogenesis increased as heterogeneity in sympathetic innervation worsened. Specifically, both DCM-induced myocyte electrical remodeling and spatially inhomogeneous innervation gradients synergistically worsened arrhythmogenesis. Thus, heterogeneous innervation gradients in DCM promoted arrhythmogenesis. Restoration of homogeneous sympathetic innervation in the failing heart may reduce VAs.

Tiered sympathetic control of cardiac function revealed by viral tracing and single cell transcriptome profiling.

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart, we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing. We investigated electrophysiologic, morphologic, and physiologic roles for subsets of cardiac-specific neurons and found that three of five adrenergic SGN subtypes innervate the heart. These three subtypes stratify into two subpopulations; high (NA1a) and low (NA1b and NA1c) neuropeptide-Y (NPY) -expressing cells, exhibit distinct morphological, neurochemical, and electrophysiologic characteristics. In physiologic studies in transgenic mouse models modulating NPY signaling, we identified differential control of cardiac responses by these two subpopulations to high and low stress states. These findings provide novel insights into the unique properties of neurons responsible for cardiac sympathetic regulation, with implications for novel strategies to target specific neuronal subtypes for sympathetic blockade in cardiac disease.

Tiered Sympathetic Control of Cardiac Function Revealed by Viral Tracing and Single Cell Transcriptome Profiling.

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing. We investigated electrophysiologic, morphologic, and physiologic roles for subsets of cardiac-specific neurons and found that three of five adrenergic SGN subtypes innervate the heart. These three subtypes stratify into two subpopulations; high (NA1a) and low (NA1b and NA1c) Npy-expressing cells, exhibit distinct morphological, neurochemical, and electrophysiologic characteristics. In physiologic studies in transgenic mouse models modulating NPY signaling, we identified differential control of cardiac responses by these two subpopulations to high and low stress states. These findings provide novel insights into the unique properties of neurons responsible for cardiac sympathetic regulation, with implications for novel strategies to target specific neuronal subtypes for sympathetic blockade in cardiac disease.

Single-cell transcriptomic profiling of satellite glial cells in stellate ganglia reveals developmental and functional axial dynamics.

Stellate ganglion neurons, important mediators of cardiopulmonary neurotransmission, are surrounded by satellite glial cells (SGCs), which are essential for the function, maintenance, and development of neurons. However, it remains unknown whether SGCs in adult sympathetic ganglia exhibit any functional diversity, and what role this plays in modulating neurotransmission. We performed single-cell RNA sequencing of mouse stellate ganglia (n = 8 animals), focusing on SGCs (n = 11,595 cells). SGCs were identified by high expression of glial-specific transcripts, S100b and Fabp7. Microglia and Schwann cells were identified by expression of C1qa/C1qb/C1qc and Ncmap/Drp2, respectively, and excluded from further analysis. Dimensionality reduction and clustering of SGCs revealed six distinct transcriptomic subtypes, one of which was characterized the expression of pro-inflammatory markers and excluded from further analyses. The transcriptomic profiles and corresponding biochemical pathways of the remaining subtypes were analyzed and compared with published astrocytic transcriptomes. This revealed gradual shifts of developmental and functional pathways across the subtypes, originating from an immature and pluripotent subpopulation into two mature populations of SGCs, characterized by upregulated functional pathways such as cholesterol metabolism. As SGCs aged, these functional pathways were downregulated while genes and pathways associated with cellular stress responses were upregulated. These findings were confirmed and furthered by an unbiased pseudo-time analysis, which revealed two distinct trajectories involving the five subtypes that were studied. These findings demonstrate that SGCs in mouse stellate ganglia exhibit transcriptomic heterogeneity along maturation or differentiation axes. These subpopulations and their unique biochemical properties suggest dynamic physiological adaptations that modulate neuronal function.

Visiones de los actores claves sobre el proceso de acreditación de los Centros de Salud Familiar de la comuna de Concepción 2016 / Views of relevant stakeholders on the accreditation process of the family health centers in concepción 2016

INTRODUCCIÓN. La Ley N° 19.966, publicada en septiembre de 2004, establece la garantía de calidad en las prestaciones de salud. Para ello se implementa un sistema de acreditación de las instituciones que proveen prestaciones en salud, las realicen en forma segura y cumplan con las expectativas de los/las usuarias. El presente estudio analiza las percepciones de actores claves en cargos directivos de coordinación del proceso de acreditación a nivel local para centros de salud familiar de la comuna de Concepción al año 2016. MATERIALES Y MÉTODOS. Estudio descriptivo exploratorio de carácter cualitativo que utilizó entrevistas semiestructuradas de actores claves del proceso de acreditación en los centros de salud familiar de la comuna de Concepción, región del Biobío, Chile, durante el año 2016. RESULTADOS. Las y los actores valoran positivamente la incorporación de la calidad en el sistema pública público de salud como principio organizacional, demuestran conocimientos sobre aspectos conceptuales de calidad y la normativa pública que regula el proceso. Se identifican aspectos a mejorar el liderazgo del proceso de acreditación, sobrecarga de funciones en los encargados de calidad, resistencia al cambio en los funcionarios de los centros de salud, deficiencias de infraestructura y trazabilidad de la biopsia, así como abordar la continuidad del servicio de atención de salud en periodos de paralización por razones gremiales. DISCUSIÓN. Para los actores relevantes del proceso de acreditación de centros de salud familiar en Concepción dicho proceso es un importante factor para que las prestaciones se realicen con calidad y así mejorar la seguridad en los usuarios y sus expectativas.

INTRODUCTION. Law N° 19.966, passed in September 2004, establishes quality assurance in health services. Accordingly, an accreditation system for health service providers to offer services safely and meet the expectations of the users was implemented. Our study reports the views of relevant stakeholders involved in the accreditation process of Family Health Centers in Concepción in 2016.MATERIALS AND METHODS. Qualitative exploratory descriptive study that used semi-structured interviews as research technique. Interviewees were relevant stakeholders involved in the accreditation process of Family Health Centers in Concepción in 2016.RESULTS. The interviewees positively value the adoption of a quality-of-care culture within the public health care institutions as an organizational principle. Interviewees have knowledge about the conceptual aspects of quality of health care and the accreditation regulation framework. Leadership of the accreditation process, overload of responsibilities of quality managers, resis-tance to change by health center officials, infrastructure deficiencies and biopsy traceability, are identified as areas for improvement as well as addressing the challenge of continuity of service in periods of union strikes. DISCUSSION. For relevant stakeholders involved in the accreditation process of Family Health Centers in Concepción the accreditation process is an important factor to strengthen quality and safety of care as well as patients' expectations.

Providing Ancillary Care in Clinical Research: A Case of Diffuse Large B-Cell Lymphoma during a Malaria Vaccine Trial in Equatorial Guinea.

Providing medical care for participants in clinical trials in resource-limited settings can be challenging and costly. Evaluation and treatment of a young man who developed cervical lymphadenopathy during a malaria vaccine trial in Equatorial Guinea required concerted efforts of a multinational, multidisciplinary team. Once a diagnosis of diffuse large B-cell lymphoma was made, the patient was taken to India to receive immunochemotherapy. This case demonstrates how high-quality medical care was provided for a serious illness that occurred during a trial that was conducted in a setting in which positron emission tomography for diagnostic staging, an oncologist for supervision of treatment, and an optimal therapeutic intervention were not available. Clinical researchers should anticipate the occurrence of medical conditions among study subjects, clearly delineate the extent to which health care will be provided, and set aside funds commensurate with those commitments.

Genes and lipids that impact uptake and assimilation of exogenous coenzyme Q in Saccharomyces cerevisiae.

Coenzyme Q (CoQ) is an essential player in the respiratory electron transport chain and is the only lipid-soluble antioxidant synthesized endogenously in mammalian and yeast cells. In humans, genetic mutations, pathologies, certain medical treatments, and aging, result in CoQ deficiencies, which are linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The only strategy available for these patients is CoQ supplementation. CoQ supplements benefit a small subset of patients, but the poor solubility of CoQ greatly limits treatment efficacy. Consequently, the efficient delivery of CoQ to the mitochondria and restoration of respiratory function remains a major challenge. A better understanding of CoQ uptake and mitochondrial delivery is crucial to make this molecule a more efficient and effective therapeutic tool. In this study, we investigated the mechanism of CoQ uptake and distribution using the yeast Saccharomyces cerevisiae as a model organism. The addition of exogenous CoQ was tested for the ability to restore growth on non-fermentable medium in several strains that lack CoQ synthesis (coq mutants). Surprisingly, we discovered that the presence of CoQ biosynthetic intermediates impairs assimilation of CoQ into a functional respiratory chain in yeast cells. Moreover, a screen of 40 gene deletions considered to be candidates to prevent exogenous CoQ from rescuing growth of the CoQ-less coq2Δ mutant, identified six novel genes (CDC10, RTS1, RVS161, RVS167, VPS1, and NAT3) as necessary for efficient trafficking of CoQ to mitochondria. The proteins encoded by these genes represent essential steps in the pathways responsible for transport of exogenously supplied CoQ to its functional sites in the cell, and definitively associate CoQ distribution with endocytosis and intracellular vesicular trafficking pathways conserved from yeast to human cells.

1,25-Vitamin D3 promotes cardiac differentiation through modulation of the WNT signaling pathway.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. Low levels of vitamin D are associated with high risk of myocardial infarction, even after controlling for factors associated with coronary artery disease. A growing body of evidence indicates that vitamin D plays an important role in CVD-related signaling pathways. However, little is known about the molecular mechanism by which vitamin D modulates heart development. The WNT signaling pathway plays a pivotal role in tissue development by controlling stem cell renewal, lineage selection and, even more importantly, heart development. In this study, we examined the role of 1,25-D3 (the active form of vitamin D) on cardiomyocyte proliferation, apoptosis, cell phenotype, cell cycle progression and differentiation into cardiomyotubes. We determined that the addition of 1,25-D3 to cardiomyocytes cells: i) inhibits cell proliferation without promoting apoptosis; ii) decreases expression of genes related to the regulation of the cell cycle; iii) promotes formation of cardiomyotubes; iv) induces the expression of casein kinase-1-α1, a negative regulator of the canonical WNT signaling pathway; and v) increases the expression of the noncanonical WNT11, which it has been demonstrated to induce cardiac differentiation during embryonic development and in adult cells. In conclusion, we postulate that vitamin D promotes cardiac differentiation through a negative modulation of the canonical WNT signaling pathway and by upregulating the expression of WNT11. These results indicate that vitamin D repletion to prevent and/or improve cardiovascular disorders that are linked with abnormal cardiac differentiation, such as post infarction cardiac remodeling, deserve further study.

Morfometría de los nervios isquiático, tibial y fibular común en el hombre / Morphometry of the sciatic, tibial and common fibular nerves in man

El nervio isquiático, el más extenso del cuerpo humano, emerge de la pelvis por el foramen isquiático mayor, dividiéndose proximal a la articulación de la rodilla en los nervios tibial y fibular común. Con frecuencia, estos nervios son afectados por accidentes, por tanto, la microcirugía reparadora requiere de detallada información anatómica para efectuar con éxito sus procedimientos. El nervio isquiático puede ser lesionado por heridas penetrantes, en las luxaciones posteriores de la articulación coxal y por inyecciones intramusculares mal aplicadas en la región glútea, siendo rara la lesión del nervio tibial por estar situado profundamente protegido. En cambio, la lesión del nervio fibular común, es frecuente debido a su posición superficial, quedando muy expuesto cuando abandona la fosa poplítea y rodea el cuello de la fíbula. Realizamos el estudio debido a la escasa información morfométrica y estereológica de estos nervios. Se disecaron en 5 cadáveres de individuos adultos, de sexo masculino los nervios isquiático, tibial y fibular común. Se obtuvieron secciones transversales de cada uno de los nervios a nivel de la división del nervio isquiático y del origen de los nervios tibial y fibular común. Realizamos cortes de 5 µm de grosor, los que fueron teñidos con H.E. Obtuvimos información cuantitativa sobre medidas morfométricas, determinamos el número de fibras nerviosas de cada fascículo así como el número de fascículos existente en cada nervio. Además, determinamos, por planimetría a través del conteo de puntos, el área de los fascículos que constituían cada nervio. El número de fascículos en el nervio isquiático varió de 63 a 70, con un promedio de 66,8 (D. E. 2,59). En el nervio tibial, el número de fascículos varió de 35 a 43, con un promedio de 30 (D. E. 3,00) y en el nervio fibular común el número de fascículos varió de 17 a 25, con un promedio de 21 (D. E. 2,92). El número promedio de fibras en el nervio ciático fue de 64.535 (D. E. 3.193). En los ...

The sciatic nerve, the longest of the human body, emerging from the pelvis through the greater sciatic foramen, dividing proximal to the knee joint in the tibial and common fibular nerves. Frequently these nerves are affected by accidents, therefore, the repairing microsurgery requires detailed anatomical information in order to successfully complete these procedures. The sciatic nerve can be damaged by penetrating injuries in the posterior luxations of the hip joint, and by intramuscular injections, given incorrectly the gluteal region. Injury to the tibial nerve is rare as it is deeply located and protected. On the other hand, injury to the common fibular nerve is frequent due to its superficial position, leaving it exposed when it leaves the popliteal fossa and surrounds the fibular neck. The study was conducted due to scarce morphometric and stereologic information on these nerves. The sciatic tibial and common fibular nerves in five cadavers of individual male adults were dissected. Transverse section of each of the nerves were obtained at the level of the division of the sciatic nerve and of the origin of the tibial and common fibular nerves. Sections of 5 µm were cut which were stained with H.E. We obtained quantitative information regarding morphomtric measurements, determined the number of nerve fibres of each fascicle, as well as the number of existing fascicles in each nerve. We also determined by planimetry, through counting of points, the area of the fascicles that constituted each nerve. The number of fascicles in the sciatic nerve varied from 63 to 70 with an average of 66.8 (S.D. 2.59). In the tibial nerve the number of fascicles varied from 17 to 25 with an average of 21 (S.D. 2.92). The mean number of fibres in the sciatic nerve as of 64,535 (S.D. 3,193). In the tibial nerve it was 40,317 (S.D. 4,067) and in the common fibular nerve it was: 22,191 (S.D. 1,038). The median area of the sciatic, tibial and common fibular nerves was: 11,42 mm².

[Indications and long term results of elective surgery for sigmoid diverticular disease]. / Indicaciones resultados alejados del tratamiento quirúrgico electivo de la enfermedad diverticular del colon sigmoides.

BACKGROUND: There are no clear guidelines for the indication of elective surgery in sigmoid diverticular disease. AIM: To analyze the indications and long term results of elective surgery in sigmoid diverticular disease. MATERIAL AND METHODS: Retrospective review of 100 patients (age range 25-86 years, 51 male) with sigmoid diverticular disease, operated in a lapse of 22 years. Sixty seven patients answered a survey about their disease at the end of follow up. RESULTS: Among patients aged more than 70 years, there was a higher proportion of women. The main indication for surgery was recurrent diverticulitis in 54 patients, followed by diverticular fistula in 19. A sigmoidectomy was performed in 91 patients. Stapled anastomosis was performed in half of these patients. No patient died or required reoperation in the immediate postoperative period. During a follow up ranging from 8 to 280 months, 28 patients died for causes not associated with diverticular disease and five were lost. Those patients that answered the survey were free of symptoms related to diverticular disease and did not require new operations. CONCLUSIONS: In patients with sigmoid diverticular disease and recurrent diverticulitis or with fistulae, the long term results of surgery are satisfactory.

Predictive factors of stenosis after stapled colorectal anastomosis: prospective analysis of 179 consecutive patients.

The incidence, risk factors, and clinical relevance of stenosis of stapled colorectal anastomosis (CRA) were studied prospectively. Anastomotic stricture was defined as the inability of traversing the anastomosis with the rigid proctoscope. The population studied consisted of 179 patients (94 males) with an average age of 59.3 years (range: 20 to 91 years). The main indication for surgery was colorectal cancer in 59% of the cases, followed by diverticular disease in 23%. The first endoscopic control was performed before 4 months in 25% of the patients, between 5 and 10 months in 50%, and during the following 10 months in 25%. Stenosis was verified with the rigid instrument in 21.1% of the cases and with the flexible colonoscope in 4.4%. The barium enema performed in 12 cases confirmed a punctiform stenosis in 5 patients, 4 of whom had been asymptomatic. An endoscopic dilatation was performed on 5 of the 8 symptomatic patients, with one relapse that required an additional dilatation. In the univariate analysis only the lesser 4-month interval was statistically significant (p = 0.033; odds ratio (OR) = 2.3; confidence interval (CI) 95% = 1.06 to 4.97). Male patients (p = 0.057; OR = 2.08; IC 95% = 0.97-4.44) show a tendency to CRA stricture that does not reach statistically significant levels. In the multivariate analysis, only sex (p = 0.04; OR = 4.11; IC 95% = 1.03 to 5.41) and the time interval (p = 0.012; OR = 2.87; IC 95% = 1.25 to 6.57) appear as independent variables in stenosis risk of a stapled CRA. The incidence of this complication depends on the criteria used for defining it. It is clinically relevant in no more than 5% of the patients. Five out of eight patients in category II were treated successfully with an endoscopic dilatation, while the other three improved spontaneously. Early stenosis, although frequent, is generally asymptomatic and disappears spontaneously. Considering the lack of correlation between the degree of stricture and its symptomatology, it is convenient to combine both the anatomic and the clinical criteria in the selection of candidates for an eventual therapeutic procedure.

[Carcinoembryonic antigen (CEA) as an independent prognostic factor in colorectal carcinoma]. / Antígeno carcinoembrionario preoperatorio como factor pronóstico independiente en cáncer de colon y recto.

BACKGROUND: CEA is widely used in the follow up of patients with colorectal carcinoma. AIM: To study the value of preoperative CEA as an independent prognostic factor in colorectal carcinoma. PATIENTS AND METHODS: Analysis of 373 operated patients (204 females, age range 21-92 years) with colorectal carcinoma and a mean follow up of 53 months. The cutoff value for CEA was 5 ng/ml. Ninety four percent of patients had an excisable tumor, 79% had involvement of perirectal/pericolonic adipose tissue and 46% had lymph node involvement. Staging was done using Dukes-Turnbull and TNM classifications. RESULTS: CEA was normal in 61% of cases, over 5 ng/ml in 39% and over 15 ng/ml in 22%. There was a strong correlation between mean preoperative CEA and tumor stage, depth and lymph node involvement. During the follow up, 140 patients died, 57 with normal and 83 with elevated CEA. Cancer mortality in patients subjected to a curative excision of the tumor (Dukes A-C2/TNM I-III) was 9% for colonic tumors and 36% for rectal tumors (p < 0.001). There were no survival differences in patients with Dukes B/TNM II tumors according to preoperative CEA. Among Dukes C/TNM III tumors, survival difference was only significant for rectal tumors. A Cox model disclosed tumor stage, location and preoperative CEA as independent prognostic factors for survival. CONCLUSIONS: CEA is an independent prognostic factor for survival in colorectal carcinoma and high levels suggest an advanced disease.

[Lower gastrointestinal bleedings: results of a study and surgical treatment in 20 patients]. / Hemorragia digestiva baja masiva: resultados del estudio y el tratamiento quirúrgico en 20 pacientes consecutivos.

BACKGROUND: Ten to 22% of lower gastrointestinal bleedings require emergency surgery. The overall mortality of the procedure is 22%. AIM: To report our experience in the management of patients with massive lower gastrointestinal bleeding. PATIENTS AND METHODS: Retrospective analysis of 20 patients (10 male) aged 19 to 79 years old, with lower gastrointestinal bleeding. RESULTS: Nine patients were operated on after the bleeding stopped and 11 were operated while still bleeding. In ten, the cause of bleeding was diverticular disease or angiodysplasia. In four, the bleeding originated in the small bowel and in 7 it was of vascular origin. Two patients with a torrential bleeding, were operated on without prior study. Colonoscopy, done in 18 patients, identified the bleeding site in 66% of cases. Scintigraphy was performed in 7 patients and it was positive in five without operative mortality. Selective angiography was done in four patients and was positive in three. A partial intestinal resection was performed in 15 patients and a total colectomy in five without operative mortality. Six patients had major postoperative complications and mean hospital stay was 18 days. Patients have been followed for 9 to 144 months and six have died. Eleven patients were reassessed and all have complete fecal continence. CONCLUSIONS: In this series, the main causes of massive lower gastrointestinal bleeding were diverticulosis and angiodysplasia. In a high percentage of patients, the bleeding originated in the small bowel.

Cirugía resectiva electiva de la enfermedad diverticular del colon / Elective resective surgery of the colon diverticular disease

Se estudia en forma retrospectiva 38 pacientes resecados electivamente por enfermedad diverticular del colon (EDC). Las indicaciones de cirugía fueron el antecedente de perforación en 18 casos (47 porciento), diverticulitis recurrente en 9 (26 porciento), fístula colovesical o entérica en 7 (18 porciento) y otras causas en 4. Se realizaron 55 operaciones, 35 sigmoidectomías (más 4 cistorrafias y 2 resecciones de intestino delgado), 2 hemocolectomías izquierdas y 2 derechas. Además 16 cierres de colostomías transversas. No hubo mortalidad operatoria y la morbilidad operatoria relacionada con la cirugía consistió en 2 fístulas estercoráceas del cierre de colostomía transversa, que cicatrizaron espontáneamente. La histopatología mostró un 82 porciento de inflamación en las piezas resecadas. El seguimiento a largo plazo se logró en el 95 porciento sin recurrencias sintomáticas por EDC. Se concluye que la sigmoidectomía es la intervención de elección en la EDC. Que la indicación más importante para la resección es la complicación y que la anatomía patológica no siempre es concordante

Eficacia del diazepam en la prevención de algunos efectos indeseables de la succinilcolina / Efficacy of diazepan for the preventions of some indesivable effects of succinilcoline

Con el propósito de comparar el efecto del Diazepam con el de Pancuronio y D-Tubocurarina en la prevención de los efectos indeseables de la Succinilcolina, se estudiaron 33 pacientes anestésicos tratados con estas drogas en quienes se determinaron: la intensidad de las fasciculaciones musculares, la calidad y duración del bloqueo neuromuscular, el dolor muscular postoperatorio, y los niveles séricos de Potasio y Creatinfosfoquinasa antes y después de la administración de Succinilcolina. A diferencia de lo sostenido por algunos autores, se encontró que el Diazepam no resultó eficaz en prevenir estos efectos y por lo tanto, no presenta ninguna ventaja comparado con el Pancuronio y la D-Tubocurarina