Cellular distribution of glucose and monocarboxylate transporters in human brain white matter and multiple sclerosis lesions.

To ensure efficient energy supply to the high demanding brain, nutrients are transported into brain cells via specific glucose (GLUT) and monocarboxylate transporters (MCT). Mitochondrial dysfunction and altered glucose metabolism are thought to play an important role in the progression of neurodegenerative diseases, including multiple sclerosis (MS). Here, we investigated the cellular localization of key GLUT and MCT proteins in human brain tissue of non-neurological controls and MS patients. We show that in control brain tissue GLUT and MCT proteins were abundantly expressed in a variety of central nervous system cells, particularly in microglia and endothelial cells. In active MS lesions, GLUTs and MCTs were highly expressed in infiltrating leukocytes and reactive astrocytes. Astrocytes manifest increased MCT1 staining and maintain GLUT expression in inactive lesions, whereas demyelinated axons exhibit significantly reduced GLUT3 and MCT2 immunoreactivity in inactive lesions. Finally, we demonstrated that the co-transcription factor peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α), an important protein involved in energy metabolism, is highly expressed in reactive astrocytes in active MS lesions. Overexpression of PGC-1α in astrocyte-like cells resulted in increased production of several GLUT and MCT proteins. In conclusion, we provide for the first time a comprehensive overview of key nutrient transporters in white matter brain samples. Moreover, our data demonstrate an altered expression of these nutrient transporters in MS brain tissue, including a marked reduction of axonal GLUT3 and MCT2 expression in chronic lesions, which may impede efficient nutrient supply to the hypoxic demyelinated axons thereby contributing to the ongoing neurodegeneration in MS. GLIA 2014;62:1125-1141.

Clinical studies with a vascular vasopressin antagonist.

The effect of circulating arginine vasopressin (AVP) on blood pressure, heart rate, and skin blood flow was assessed in normotensive subjects, mild hypertensive patients, and patients with congestive heart failure, utilizing the specific antagonist of AVP at the vascular receptor level, d(CH2)5Tyr(Me)AVP (5 micrograms/kg i.v.). The renin system of the normal volunteers treated with the AVP antagonist was either intact or acutely blocked with the angiotensin converting-enzyme inhibitor captopril (25 mg p.o.). In some volunteers, the cardiovascular effect of AVP released by Finnish sauna or cigarette smoking was studied. In patients with congestive heart failure, hemodynamic measurements (pressures and cardiac output) were obtained invasively. Acute blockade of AVP vascular receptors produced no cardiovascular effect unless plasma AVP levels were markedly elevated. In our experience, abnormally high circulating AVP appears to be responsible for the decrease in skin blood flow induced by cigarette smoking and to some extent for the maintenance of vascular tone in the rare patients with particularly severe congestive heart failure.

Les cures hybrides des lésions anévrismales [Hybrid treatment of aortic aneurysms]

The hybrid treatment of aortic aneurysms is indicated in patients having the ostia of supra aortic or visceral branches taken in to the aneurysm. Indeed, these lesions are not eligible for classic endovascular treatment because the existing endoprostheses cannot provide perfusion of the side branches without inducing major endoleaks. The surgical technique consists of 2 steps: firstly, a by-pass between normal aorta and the major aortic branches involved in the aneurysm is performed to guarantee the perfusion of the organs such as brain, bowel, and after endoprosthesis deployment. Secondly, the endoprosthesis is deployed using the classical technique to isolate the aneurysm. The hybrid approach provides safe and reliable treatment of complex aortic aneurysms with mortality and morbidity rate far below the classical open surgery.

Melatonin improves glucose homeostasis and endothelial vascular function in high-fat diet-fed insulin-resistant mice.

Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

Neutrophil-derived APRIL concentrated in tumor lesions by proteoglycans correlates with human B-cell lymphoma aggressiveness.

A PRoliferation-Inducing TNF Ligand (APRIL) costimulates B-cell activation. When overexpressed in mice, APRIL induces B-cell neoplasia, reminiscent of human B-cell chronic lymphoid leukemia (B-CLL). We analyzed APRIL expression in situ in human non-Hodgkin lymphomas. APRIL up-regulation was only observed in high-grade B-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma (BL). Up-regulation was seen in 46% and 20% of DLBCL and BL, respectively. In DLBCL, neutrophils, constitutively producing APRIL and infiltrating the tumor tissue, were the main cellular source of APRIL. Rare DLBCL cases showed a predominance of histiocytes or mesenchymal cells as APRIL source. APRIL secreted by neutrophils accumulated on tumor cells via proteoglycan binding. In addition to proteoglycans, DLBCL tumor cells expressed the APRIL signaling receptor, TACI and/or BCMA, indicating that these tumor cells are fully equipped to respond to APRIL. A retrospective clinical analysis revealed a significant correlation between high expression of APRIL in tumor lesions and decreased overall patient survival rate. Hence, APRIL produced by inflammatory cells infiltrating lymphoma lesions may increase tumor aggressiveness and affect disease outcome.

Are there vascular density gradients along myocardial laser channels?

BACKGROUND: Clinical studies suggest that transmyocardial laser revascularization may improve regional blood flow of the subendocardial layer. The vascular growth pattern of laser channels was analyzed. METHODS: Twenty pigs were randomized to undergo ligation of left marginal arteries (n = 5), to undergo transmyocardial laser revascularization of the left lateral wall (n = 5), to undergo both procedures (n = 5) or to a control group (n = 5). All the animals were sacrificed after 1 month. Computed morphometric analysis of vascular density of the involved area was expressed as number of vascular structures per square millimeter (+/-1 standard deviation). RESULTS: The vascular density of the scar tissue of the laser channel was significantly increased in comparison with myocardial infarction alone: 49.6+/-12.8/mm2 versus 25.5+/-8.6/mm2 (p < 0.0001). The vascular densities of subendocardial and subepicardial channel areas were similar: 52.9+/-16.8/mm2 versus 46.3+/-13.6/mm2 (p = 0.41). The area immediately adjacent to the channels showed a vascular density similar to that of normal tissue: 6.02+/-1.7/mm2 versus 5.2+/-1.9/mm2 (p = 0.08). In the infarction + transmyocardial laser revascularization group, the channels were indistinguishable from infarction scar. CONCLUSIONS: Scars of transmyocardial laser revascularization channels exhibit an increased vascular density in comparison with scar tissue of myocardial infarction, which does not extend into their immediate vicinity. There was no vascular density gradient along the longitudinal axis of the channels.

Will endoscopists soon replace pathologists in the diagnosis of (pre-)neoplastic and inflammatory mucosal lesions?

This short review addresses the question whether pathologists will continue to play a central role in the diagnosis of mucosal lesions of the gastrointestinal tract or whether their role will soon be assumed by clinical colleagues equipped with modern high-resolution endoscopes. In order to support the raison d'etre of the pathologist - at least for the time being and the near future - the author lists three arguments, related to (i) the differences in the orientation of the plane of view (histology: perpendicular to the mucosal surface vs. endoscopy: parallel to the mucosal surface), (ii) the advantages of staining and immunostaining tissue sections, and (iii) the possibility to perform deeper sections and to consul with colleagues in the case of difficult diagnoses.

Abnormal balance between proliferation and apoptotic cell death in fibroblasts derived from keloid lesions.

A new culture model was developed to study the role of proliferation and apoptosis in the etiology of keloids. Fibroblasts were isolated from the superficial, central, and basal regions of six different keloid lesions by using Dulbecco's Modified Eagle Medium containing 10% fetal calf serum as a culture medium. The growth behavior of each fibroblast fraction was examined in short-term and long-term cultures, and the percentage of apoptotic cells was assessed by in situ end labeling of fragmented DNA. The fibroblasts obtained from the superficial and basal regions of keloid tissue showed population doubling times and saturation densities that were similar to those of age-matched normal fibroblasts. In contrast, the fibroblasts from the center of the keloid lesions showed significantly reduced doubling times (25.9 +/- 6.3 hours versus 43.5 +/- 6.3 hours for normal fibroblasts) and reached higher cell densities. In long-term culture, central keloid fibroblasts formed a stratified three-dimensional structure, contracted the self-produced extracellular matrix, and gave rise to nodular cell aggregates, mimicking the formation of keloid tissue. Apoptotic cells were detected in both normal and keloid-derived fibroblasts, but their numbers were twofold higher in normal cells compared with all keloid fibroblasts. To examine whether apoptosis mediates the therapeutic effect of ionizing radiation on keloids, the cells were exposed to gamma rays at a dose of 8 Gy. Under these conditions, a twofold increase in the population of apoptotic cells was detected. These results indicate that the balance between proliferation and apoptosis is impaired in keloid fibroblasts, which could be responsible for the formation of keloid tumors. The results also suggest that keloids contain at least two different fibroblast fractions that vary in growth behavior and extracellular matrix metabolism.

Incidents and complications of totally implanted vascular access devices in children: a prospective study.

BACKGROUND: Totally implanted vascular access devices are frequently used in children for repeated blood samples or intravenous treatments. This prospective study aims at identifying the risk factors associated with infections, obstructions and surgical complications of these devices in pediatric patients. METHODS: From January 2006 to January 2008, all children older than one year of age with a diagnosis of solid or blood cell malignancy were included in the study. Insertion was performed by the surgeon according to a standardized protocol after landmark-guided puncture of the subclavian or internal jugular vein by a senior anesthesiologist. Dressing and post-operative care were standardized. Every manipulation was prospectively recorded by specialized dedicated nurses, and all patients were screened for complications one month post-surgery. RESULTS: 45 consecutive patients 1 to 16 years old were enrolled in the study. Mean age at the time of procedure was 8.5 years (range 1.3-15.6; SD +/- 4.88). There were 12 peroperative adverse events in 45 procedures (27%), detailed as follows: 3 pneumothoraces (7%), 3 hematomas (7%), 6 arterial punctures (13%). Among these events, intervention was necessary for two pneumothorax and one arterial puncture. There was no air embolism. At one month, we recorded 5 post-operative complications (11%): 2 thrombotic obstructions, one unsightly scar, and one scapular pain of unknown etiology. One patient needed repositioning of the catheter. There was no catheter-related infection. CONCLUSION: Prospective recording of TIVA insertion in children reveals a significant number of early incidents and complications, mainly associated with the percutaneous puncture technique. We found no infection in this series. Results of a longer follow-up in the same population are pending.

Neural control of vascular reactions: impact of emotion and attention.

This study investigated the neural regions involved in blood pressure reactions to negative stimuli and their possible modulation by attention. Twenty-four healthy human subjects (11 females; age = 24.75 ± 2.49 years) participated in an affective perceptual load task that manipulated attention to negative/neutral distractor pictures. fMRI data were collected simultaneously with continuous recording of peripheral arterial blood pressure. A parametric modulation analysis examined the impact of attention and emotion on the relation between neural activation and blood pressure reactivity during the task. When attention was available for processing the distractor pictures, negative pictures resulted in behavioral interference, neural activation in brain regions previously related to emotion, a transient decrease of blood pressure, and a positive correlation between blood pressure response and activation in a network including prefrontal and parietal regions, the amygdala, caudate, and mid-brain. These effects were modulated by attention; behavioral and neural responses to highly negative distractor pictures (compared with neutral pictures) were smaller or diminished, as was the negative blood pressure response when the central task involved high perceptual load. Furthermore, comparing high and low load revealed enhanced activation in frontoparietal regions implicated in attention control. Our results fit theories emphasizing the role of attention in the control of behavioral and neural reactions to irrelevant emotional distracting information. Our findings furthermore extend the function of attention to the control of autonomous reactions associated with negative emotions by showing altered blood pressure reactions to emotional stimuli, the latter being of potential clinical relevance.

Calcifications vasculaires et déficit en vitamine K: un facteur de risque modifiable dans l'insuffisance rénale chronique [Vascular calcifications and vitamin K deficiency: a modifiable risk factor in chronic kidney disease].

The mechanisms of vascular calcifications in chronic renal failure are complex. Apart for clotting factors, vitamin K-dependent proteins include matrix Gla protein. Glutamic acid residues in matrix Gla protein are carboxylated by vitamin K-dependent gamma-carboxylase, which enables it to inhibit calcification. The purpose of this review is to discuss available evidence implicating vitamin K as a modifiable risk factor in the pathogenesis of vascular calcification in renal diseases.

Acidente Vascular Cerebral (AVC): os desafios de enfermagem no atendimento de urgência

A incidência do Acidente Vascular Cerebral (AVC) em Cabo Verde acompanha a tendência mundial, sendo uma das primeiras causas de morte; nos anos 2013 e 2014, é a primeira causa de morte entre as doenças do aparelho circulatório, isto justificado pelo aumento da esperança média de vida. Também tendo como influência a adoção de novos estilos e padrões de vida não saudáveis, e com o aumento dos fatores de risco que o avançar da idade acarreta. Sendo que a enfermagem como a base de qualquer organização de saúde, necessita fundamentar a sua prática em bases científicas, levando em consideração o individuo como um ser holístico. Desta forma, considerou-se pertinente desenvolver um estudo no âmbito do atendimento de urgência a um utente com Acidente Vascular Cerebral, tendo como objetivo principal identificar as dificuldades que os enfermeiros enfrentam no atendimento de urgência a um utente com AVC. No entanto para dar resposta ao estudo foram considerados outros pontos não menos importantes, tais como: aspetos utilizado no atendimento do AVC, as dificuldades e as estratégias na prestação do cuidado e as técnicas para superar os mesmos. Optou-se por um estudo do tipo fenomenológico, com base na metodologia qualitativo. Sendo que a população do estudo é constituído por 6 enfermeiros, que trabalham no serviço da urgência do Hospital Doutor Baptista de Sousa (HBS). Para que fosse possível recolher os dados, foi estabelecido como instrumento de recolha de dados um guião de entrevista semiestruturada. O tratamento dos dados foi efetuado através da análise de conteúdo. Os resultados dos dados recolhidos, foram apresentados através de quadros e daí retiradas as conclusões consideradas importantes para dar respostas aos objetivos estabelecidos. Uma das principais conclusões do estudo, realça o fato do serviço da urgência apresentar algumas dificuldades no tratamento dos utentes com AVC, devido a falta de alguns recursos materiais considerados indispensáveis, para o diagnóstico diferencial do AVC e assim a tomada de decisões para um tratamento adequado do mesmo. Sendo que, a enfermagem tem um papel pivô no atendimento dos pacientes com Acidente Vascular Cerebral, são esses profissionais que estabelecem o contato entre esses utentes e o resto da equipa multidisciplinar.

Risc cardiovascular en pacients que consulten a urgències d´un hospital general amb un esdeveniment vascular agut

La malaltia cardiovascular és una de les principals causes de morbimortalitat. Els factors de risc cardiovasculars són diversos. Hi ha moltes guies de prevenció clínica i escales de risc. Malgrat l’existència de guies de pràctica clínica i millor identificació dels factors de risc, persisteix l’impacte negatiu cardiovascular. L’estudi enregistra aquests esdeveniments cardiovasculars en pacients que ingressen a urgències, durant tres anys, els factors de risc, els tractaments a l’ingrés i a l’alta i l’evolució i mortalitat durant l’ingrés. Compararà la població que ens ocupa amb d’altres i els tractaments. Detectarà el seguiment de les guies i circuits de millora.

Syndromes néoplasiques héréditaires avec atteinte cutanée [Cutaneous lesions in genetic tumor syndromes]

Genetic tumor syndromes reflect an inherited predisposition to develop benign and malignant tumors. Increased frequency of neoplasms within the family or occurring at an early age are clinical clues for a possible underlying genetic susceptibility. Awareness of their associated cutaneous manifestations can facilitate early detection of risk for tumors. The goal of this article is to review clinical and molecular features of some genetic tumor syndrome which present with skin involvement at birth or during childhood.