Bone marrow cells adopt the cardiomyogenic fate in vivo

The possibility that adult bone marrow cells (BMCs) retain a remarkable degree of developmental plasticity and acquire the cardiomyocyte lineage after infarction has been challenged, and the notion of BMC transdifferentiation has been questioned. The center of the controversy is the lack of unequivocal evidence in favor of myocardial regeneration by the injection of BMCs in the infarcted heart. Because of the interest in cell-based therapy for heart failure, several approaches including gene reporter assay, genetic tagging, cell genotyping, PCR-based detection of donor genes, and direct immunofluorescence with quantum dots were used to prove or disprove BMC transdifferentiation. Our results indicate that BMCs engraft, survive, and grow within the spared myocardium after infarction by forming junctional complexes with resident myocytes. BMCs and myocytes express at their interface connexin 43 and N-cadherin, and this interaction may be critical for BMCs to adopt the cardiomyogenic fate. With time, a large number of myocytes and coronary vessels are generated. Myocytes show a diploid DNA content and carry, at most, two sex chromosomes. Old and new myocytes show synchronicity in calcium transients, providing strong evidence in favor of the functional coupling of these two cell populations. Thus, BMCs transdifferentiate and acquire the cardiomyogenic and vascular phenotypes restoring the infarcted heart. Together, our studies reveal that locally delivered BMCs generate de novo myocardium composed of integrated cardiomyocytes and coronary vessels. This process occurs independently of cell fusion and ameliorates structurally and functionally the outcome of the heart after infarction.     

A Multidisciplinary Assessment of Remote Myocardial Fibrosis After Reperfused Myocardial Infarction in Swine and Patients

In extensive nonreperfused myocardial infarction (MI), remote fibrosis has been documented. Early reperfusion by primary angioplasty represents the gold standard method to minimize the extension of the infarction. We aimed to ascertain whether fibrosis also affects remote regions in reperfused MI in swine and patients. Swine were subjected to a transient occlusion of the left anterior descending artery followed by 1-week or 1-month reperfusion. Collagen content in the remote area macroscopically, microscopically, by magnetic resonance microimaging, and at the molecular level was similar to controls. In patients with previous MI, samples from autopsies displayed a significant increase in collagen content only in the infarct region. In patients with previous MI submitted to cardiac magnetic resonance-T1 mapping, the extracellular volume fraction in remote segments was similar to that for controls. In all scenarios, the remote region did not show a significant increase of collagen content in comparison with controls.     

Surgery of Cosmetic Sequelae After Breast‐Conserving Therapy

Abstract: Although a considerable number of patients have an unfair cosmetic result after breast‐conserving therapy, which correlates with poor psychosocial functioning, surprisingly, really only very few patients undergo surgical correction. The purpose of this article was to report our experience in the surgical treatment of such patients and analyze a special subgroup which required bilateral reduction mammaplasty because of associated symptomatic macromastia and their desire to reduce their breast size. From July 2000 to November 2008, some 23 patients consulted for unsatisfactory cosmetic outcome after breast‐conserving therapy, fourteen of them accepting the surgical treatment proposed and these were operated upon. We used the following techniques: reduction mammaplasty of the contralateral breast for symmetrization (9), bilateral reduction mammaplasty (4), one mammaplasty and augmentation of contra‐lateral breast and one myocutaneous dorsi flap for surgical correction of ipsilateral breast. One patient had serious complications, having partial necrosis of the areola, fat and breast skin necrosis, and needed reoperation for surgical removal of necrotic tissue. Some factors such as obesity and heavy smoking habits could explain this. We were able to evaluate cosmetic outcome in ten patients; late cosmetic outcome was good in seven patients, fair in two and poor in one. Despite the fact that most patients treated by breast‐conserving therapy are satisfied with the fact that they have retained their breasts and minimized an unfair cosmetic outcome, cosmetic evaluation should be introduced as a matter of routine.     

Searching for new mechanisms of myocardial fibrosis with diagnostic and/or therapeutic potential

Myocardial fibrosis is the result of excessive fibrillar collagen synthesis and deposition without reciprocally balanced degradation. It causes cardiac dysfunction, arrhythmias, and ischaemia, and thereby determines the clinical course and outcome of cardiac patients even when adequately treated. Therefore, further research is needed to identify and better understand the factors that trigger and maintain the myocardial fibrotic response against different injuries in a variety of cardiac diseases. Here, we will focus on the following major areas of research: molecules that stimulate the differentiation of fibroblasts into myofibroblasts and subsequently alter collagen turnover (e.g. cardiotrophin‐1, galectin‐3, NADPH oxidases, and neutrophil gelatinase‐associated lipocalin), microRNA‐induced alterations of collagen gene expression, and matricellular protein‐ and lysyl oxidase‐mediated alterations of collagen cross‐linking and deposition.     

Regular theta‐firing neurons in the nucleus incertus during sustained hippocampal activation

This paper describes the existence of theta‐coupled neuronal activity in the nucleus incertus (NI). Theta rhythm is relevant for cognitive processes such as spatial navigation and memory processing, and can be recorded in a number of structures related to the hippocampal activation including the NI. Strong evidence supports the role of this tegmental nucleus in neural circuits integrating behavioural activation with the hippocampal theta rhythm. Theta oscillations have been recorded in the local field potential of the NI, highly coupled to the hippocampal waves, although no rhythmical activity has been reported in neurons of this nucleus. The present work analyses the neuronal activity in the NI in conditions leading to sustained hippocampal theta in the urethane‐anaesthetised rat, in order to test whether such activation elicits a differential firing pattern. Wavelet analysis has been used to better define the neuronal activity already described in the nucleus, i.e., non‐rhythmical neurons firing at theta frequency (type I neurons) and fast‐firing rhythmical neurons (type II). However, the most remarkable finding was that sustained stimulation activated regular‐theta neurons (type III), which were almost silent in baseline conditions and have not previously been reported. Thus, we describe the electrophysiological properties of type III neurons, focusing on their coupling to the hippocampal theta. Their spike rate, regularity and phase locking to the oscillations increased at the beginning of the stimulation, suggesting a role in the activation or reset of the oscillation. Further research is needed to address the specific contribution of these neurons to the entire circuit.     

Characterization of multiciliated ependymal cells that emerge in the neurogenic niche of the aged zebrafish brain

In mammals, ventricular walls of the developing brain maintain a neurogenic niche, in which radial glial cells act as neural stem cells (NSCs) and generate new neurons in the embryo. In the adult brain, the neurogenic niche is maintained in the ventricular‐subventricular zone (V‐SVZ) of the lateral wall of lateral ventricles and the hippocampal dentate gyrus. In the neonatal V‐SVZ, radial glial cells transform into astrocytic postnatal NSCs and multiciliated ependymal cells. On the other hand, in zebrafish, radial glial cells continue to cover the surface of the adult telencephalic ventricle and maintain a higher neurogenic potential in the adult brain. However, the cell composition of the neurogenic niche of the aged zebrafish brain has not been investigated. Here we show that multiciliated ependymal cells emerge in the neurogenic niche of the aged zebrafish telencephalon. These multiciliated cells appear predominantly in the dorsal part of the ventral telencephalic ventricular zone, which also contains clusters of migrating new neurons. Scanning electron microscopy and live imaging analyses indicated that these multiple cilia beat coordinately and generate constant fluid flow within the ventral telencephalic ventricle. Analysis of the cell composition by transmission electron microscopy revealed that the neurogenic niche in the aged zebrafish contains different types of cells, with ultrastructures similar to those of ependymal cells, transit‐amplifying cells, and migrating new neurons in postnatal mice. These data suggest that the transformation capacity of radial glial cells is conserved but that its timing is different between fish and mice. J. Comp. Neurol. 524:2982–2992, 2016. © 2016 Wiley Periodicals, Inc.     

The surgical option in the management of acute pulmonary embolism

Abstract Objective: Massive or submassive pulmonary embolism (PE) carries a high mortality. Traditionally this condition has been treated with thrombolysis or anticoagulation and support measures. Surgical embolectomy is carried out in situations of hemodynamic instability or contraindication for thrombolysis. We present our results of surgical embolectomy in patients with massive and submassive PE. Methods: Over a three‐year period, we have carried out 20 surgical embolectomies for acute PE. The mean age was 66 years, and there were 11 males. In all cases, the diagnosis had been made by a computerized tomography (CT) pulmonary artery angiography. Nine patients (45%) arrived to the operating theater on inotropes, and two of them (10%) with ventilatory support. All patients underwent a median sternotomy, bicaval cannulation for institution of cardiopulmonary bypass (CPB), and main pulmonary arteriotomy for the removal of the thrombus. Results: The mean bypass time was 45 minutes. Two patients (12%) died after being unable to wean off CPB due to right heart failure. Among the 15 survivors, the median ventilation time in the intensive care unit was 24 hours. Twelve patients (60%) required inotropic support postoperatively for right heart failure. All but one survivor (94%) underwent an insertion of a permanent inferior vena cava filter and were anticoagulated with coumarin. The mean follow‐up is 9.8 months and is 100% complete, with a survival of 94.5%. All patients were in the World Health Organization (WHO) functional class I, with no re‐admissions for respiratory failure. Conclusion: In patients with acute massive or submassive PE, surgical embolectomy offers a valid therapeutic strategy. A right‐sided heart failure is the main complication of this condition.     

Pharmacologic treatment of fibromyalgia: Towards chemical neuromodulation

Fibromyalgia is a chronic pathology and its main symptom is pain which usually does not respond to traditional analgesia. Its clinical characteristics and the diverse neurophysiologic findings in these patients point to a central sensitization process of the nociceptive system as the central physiopathologic axis in this disease. The knowledge of the nociceptive system functioning and its behavior in this disease has led, in the past few years, to new possibilities for the therapeutic approach. In that way, drugs with a differential mechanism of action, allowing a modulation of the nociceptive system capable of producing analgesia where other medications have failed are being developed. Different drugs with the capacity increasing the activity of biologically active amines implicated in the nociceptive inhibition process and others which are destined to reduce the excitability of the system through ion channels, are being tested with some benefit in Fibromyalgia patients and may constitute a more rational neuromodulating drug profile for this disease. This article reviews the different pharmacological strategies supported by scientific evidence and points to some future research lines that fortifies the therapeutic change taking place in the treatment approach of these patients.