Funcions de les molècules associades a la mielina i la proteïna priònica cel•lular (PrPc) en neurodegeneració (Malaltia d’Alzheimer) i neuroinflamació (Esclerosi Múltiple)

Les proteïnes associades a la mielina (MAIS), Nogo-A, MAG i OMgp, són molècules que presenten una capacitat inhibitòria molt important per el recreixement axonal i la neuroreparació després de lesió. No obstant des de fa anys les seves funcions han estat ampliades i s’han involucrat en diferents processos degeneratius del sistema nerviós o en processos neuroinflamatoris del sistema nerviós central i el perifèric com ara l'Escleresi Múltiple (MS). La base neurobiològica d’indicadors moleculars que són responsables del dany axonal en MS segueixen sense estar plenament descrits. Recentment s’ha publicat que el mecanisme de senyalització Nogo-A pot regir els primers canvis de la desmielinització immunomediada del sistema nerviós central en el model animal de MS, l’encefalomielitis autoimmune experimental (EAE). De la mateixa forma la proteïna priònica cel•lular és una proteïna que s’ha associat majoritàriament a malalties espongiformes, però que recentment s’ha vinculat (no sense controvèrsia) amb la seva possible relació amb la Malaltia d'Alzheimer (AD), ja que seria capaç de reclutar els oligòmers d’Aβ (ADDLs), els quals correlacionen millor amb el grau de demència, i amb els que interacciona directament, actuant així com un possible mediador de la fosforilació de tau en la malaltia. No obstant, les funcions de les MAIS i de la PrPc en aquests models de la malaltia no estan clarament definits i, per altra banda, es desconeixen els mecanismes de senyalització implicats, no descartant de forma clara el component neural i l’immune.

Diagnostic accuracy of free and total metanephrines in plasma and fractionated metanephrines in urine of patients with pheochromocytoma.

BACKGROUND: Plasma free and urinary metanephrines are recognized biomarkers for the assessment of pheochromocytoma. Plasma total metanephrines with a long half-life may represent another useful biomarker. OBJECTIVE: The aim of this study is to evaluate the diagnostic performances of plasma total metanephrines alone or combined with free metanephrines and fractionated 24-h urinary metanephrines. METHODS: A retrospective, case-control diagnostic test study was conducted between 1999 and 2007 in two university hospitals in Switzerland and two institutions in France. The patients included 46 cases with histologically proven pheochromocytoma, and 181 controls suspected of tumor with negative investigations and 3-year follow-up. None had renal dysfunction. Sensitivity and specificity were compared after expressing each measurement result as a ratio over its upper reference limit, adding the ratios of normetanephrine and metanephrine, and defining cut-off values of 1 or 2 for this sum. RESULTS: Applying a cut-off value of 1, plasma free and total metanephrines and urinary fractionated metanephrines had similar sensitivities of 96% (95% confidence interval, 86-99%), 95% (85-99%), and 95% (84-99%) along with similar specificities of 89% (83-94%), 91% (84-95%), and 86% (80-91%). A cut-off of 2 for the sum of ratios over reference limit improves the specificity, and it can be used for a confirmation test based on another biomarker taken among the three biomarkers. CONCLUSION: All three metanephrine-based tests perform equivalently for diagnosing pheochromocytoma in the absence of renal insufficiency, and can be conveniently associated two by two for confirming/excluding tumor.

Total energy expenditure and patterns of activity in 8-10-year-old obese and nonobese children.

Total energy expenditure (TEE) and patterns of activity were measured by means of a heart rate (HR)-monitoring method in a group of 8-10-year-old children including 13 obese children (weight, 46 +/- 10 kg; fat mass: 32 +/- 9%) and 16 nonobese children (weight, 31 +/- 5 kg; fat mass, 18 +/- 5%). Time for sleeping was not statistically different in the two groups of children (596 +/- 33 vs. 582 +/- 43 min; p = NS). Obese children spent more time doing sedentary activities (400 +/- 129 vs. 295 +/- 127 min; p < 0.05) and less time in nonsedentary activities (449 +/- 126 vs. 563 +/- 135 min; p < 0.05) than nonobese children. Time spent in moderate or vigorous activity-i.e., time spent at a HR between 50% of the maximal O2 uptake (peak VO2) and 70% peak VO2 (moderate) and at a HR > or = 70% peak VO2 (vigorous)-was not statistically different in obese and nonobese children (88 +/- 69 vs. 52 +/- 35 min and 20 +/- 21 vs. 16 +/- 13 min, respectively; p = NS). TEE was significantly higher in the obese group than in the nonobese group (9.46 +/- 1.40 vs. 7.51 +/- 1.67 MJ/day; p < 0.01). The energy expenditure for physical activity (plus thermogenesis) was significantly higher in the obese children (3.98 +/- 1.30 vs. 2.94 +/- 1.39 MJ/day; p < 0.05). The proportion of TEE daily devoted to physical activity (plus thermogenesis) was not significantly different in the two groups, as shown by the ratio between TEE and the postabsorptive metabolic rate (PMR): 1.72 +/- 0.25 obese vs 1.61 +/- 0.28 non-obese. In conclusion, in free-living conditions obese children have a higher TEE than do nonobese children, despite the greater time devoted to sedentary activities. The higher energy cost to perform weight-bearing activities as well as the higher absolute PMR of obese children help explain this apparent paradox.

Ambulatory gait analysis results after total knee arthroplasty : arguments for mobile or fixed bearing?

Background: Mobile-bearing knee replacements have some theoretical advantages over fixed-bearing devices. However, very few randomized controlled clinical trials have been published to date, and studies showed little clinical and subjective advantages for the mobile-bearing using traditional systems of scoring. The choice of the ideal outcome measure to assess total joint replacement remains a complex issue. However, gait analysis provides objective and quantifying evidences of treatment evaluation. Significant methodological advances are currently made in gait analysis laboratories and ambulatory gait devices are now available. The goal of this study was to provide gait parameters as a new objective method to assess total knee arthroplasty outcome between patients with fixed- and mobile-bearing, using an ambulatory device with minimal sensor configuration. Methods: This randomized controlled double-blind study included to date 31 patients: the gait signatures of 12 patients with mobile-bearing were compared to the gait signatures of 19 patients with fixed-bearing pre-operatively and post-operatively at 6 weeks, 3 months and 6 months. Each participant was asked to perform two walking trials of 30m long at his/her preferred speed and to complete a EQ-5D questionnaire, a WOMAC and Knee Society Score (KSS). Lower limbs rotations were measured by four miniature angular rate sensors mounted respectively, on each shank and thigh. Results: Better relative differences between pre-operative and post-operative 3 months and 6 months KSS (122% vs 34% at 3 months, 138% vs 36% at 6 months) and KSS function (154% vs 8% at 3 months, 183% vs 42% at 6 months) scores were observed for the fixed-bearing compared to the mobile-bearing. The same better improvements for fixed-bearing were also found with the range of knee angles (Affected side: 31% vs -5% at 3 months, 47% vs 5% at 6 months), (Unaffected side: 16% vs 5% at 3 months, 15% vs 6% at 6 months) and peak swing speeds of shank (Affected side: 18% vs -2% at 3 months, 30% vs 4% at 6 months), (Unaffected side: 8% vs -3% at 3 months, 7% vs 4% at 6 months). Conclusions: A new method for a portable system for gait analysis has been developed with very encouraging results regarding the objective outcome of total knee arthroplasty using mobile- and fixed-bearings.

Development and experimental validation of a finite element model of total ankle replacement.

Total ankle replacement remains a less satisfactory solution compared to other joint replacements. The goal of this study was to develop and validate a finite element model of total ankle replacement, for future testing of hypotheses related to clinical issues. To validate the finite element model, an experimental setup was specifically developed and applied on 8 cadaveric tibias. A non-cemented press fit tibial component of a mobile bearing prosthesis was inserted into the tibias. Two extreme anterior and posterior positions of the mobile bearing insert were considered, as well as a centered one. An axial force of 2kN was applied for each insert position. Strains were measured on the bone surface using digital image correlation. Tibias were CT scanned before implantation, after implantation, and after mechanical tests and removal of the prosthesis. The finite element model replicated the experimental setup. The first CT was used to build the geometry and evaluate the mechanical properties of the tibias. The second CT was used to set the implant position. The third CT was used to assess the bone-implant interface conditions. The coefficient of determination (R-squared) between the measured and predicted strains was 0.91. Predicted bone strains were maximal around the implant keel, especially at the anterior and posterior ends. The finite element model presented here is validated for future tests using more physiological loading conditions.

Diarrea crónica refractaria y malabsorción secundaria a hipogammaglobulinemia común variable, infestación crónica por giardia lambila y gastrectomía total por adenocarcinoma gástrico: un manejo nutricional complejo

Gastric cancer is a frequent cause of cancer-related mortality in the world. Surgery is the only potentially curative therapy, although the adverse effects of surgery are common and considerable. Common variable immunodeficiency is in many cases cause of gastrointestinal system problems such as chronic diarrhea caused by infestation with giardia lamblia, nodular lymphoid hiperplasia ad loss of villi leading frequently to malapsortion and malnutrition. Nutritional deficiencies due to malapsorption (postgastrectomy and secondary to loss of villi, giardiasis and common variable inmunodeficiency) are common. We present the case of a patient with gastric cancer who underwent a gastrectomy with common variable hipogammaglobulinemia and chronic infestation by giardia lamblia, with serious diarrhea resistant to treatment and malabsorption.

Dix erreurs a ne pas commettre lors de la prise en charge d'une prothèse articulaire infectée en orthopédie [Ten errors to avoid while dealing with infected total joint arthroplasties].

Infections after total joint arthroplasty are rare but come with severe consequences. Timely, adequate and standardized treatment beginning at the onset of symptoms will have a major impact on the handling of this dreaded complication. In absences of clear guidelines, errors are often committed, with occasionally severe consequences for the patient. In this article, the 10 most frequent errors starting with diagnostics till antibiotic and surgical treatment will be discussed.

Decrease in beta-Cell Proliferation Precedes Apoptosis during Diabetes Development in Bio-Breeding/Worcester Rat: Beneficial Role of Exendin-4

In autoimmune type 1 diabetes mellitus, proinflammatory cytokine-mediated apoptosis of beta-cells has been considered to be the first event directly responsible for beta-cell mass reduction. In the Bio-Breeding (BB) rat, an in vivo model used in the study of autoimmune diabetes, beta-cell apoptosis is observed from 9 wk of age and takes place after an insulitis period that begins at an earlier age. Previous studies by our group have shown an antiproliferative effect of proinflammatory cytokines on cultured beta-cells in Wistar rats, an effect that was partially reversed by Exendin-4, an analogue of glucagon-like peptide-1. In the current study, the changes in beta-cell apoptosis and proliferation during insulitis stage were also determined in pancreatic tissue sections in normal and thymectomized BB rats, as well as in Wistar rats of 5, 7, 9, and 11 wk of age. Although stable beta-cell proliferation in Wistar and thymectomized BB rats was observed along the course of the study, a decrease in beta-cell proliferation and beta-cell mass from the age of 5 wk, and prior to the commencement of apoptosis, was noted in BB rats. Exendin-4, in combination with anti-interferon-gamma antibody, induced a near-total recovery of beta-cell proliferation during the initial stages of insulitis. This highlights the importance of early intervention and, as well, the possibilities of new therapeutic approaches in preventing autoimmune diabetes by acting, initially, in the insulitis stage and, subsequently, on beta-cell regeneration and on beta-cell apoptosis.

Total antioxidant capacity of plasma in asymptomatic carrier state of Neisseria meningitidis

Reduction of the antioxidant capacity of plasma has been linked with the impairment of an effective immune response and so we hypothesized that the carriage rate of Neisseria meningitidis in asymptomatic subjects might correlate with the levels of antioxidants in plasma. To this end we took pharyngeal swabs from 339 children in Marquesado Basic Health Zone, Granada, Spain and in addition determined the total antioxidant capacity (TAC) in plasma samples from these subjects. The overall prevalence of N. meningitidis carriage was 5.9% (mean age 7.1 years) with rates of 10.3% in children aged 3 < or =years, 3.9% between 4 and 7 years and 2.4% in older subjects. Plasma TAC for the < or =3-year-olds was 0.13 for carriers and 1.10 for non-carrier controls (P=0.04), 0.13 for carriers aged 4-7 years (controls 0.63) and 0.28 for carriers aged >7 years (controls 0.52). We analysed the association between TAC in plasma (<0.37 - 2 S.D.) and the carrier state of N. meningitidis. In the carrier state, the odds ratio for this association (TAC in plasma <0.25) was 8.44 (95% CI 1.5-48.9). These findings may suggest a reduced immune response in the host favourable to nasopharyngeal persistence of meningococci.

Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak.

Androgen-sensitive prostate cancer cells turn androgen resistant through complex mechanisms that involve dysregulation of apoptosis. We investigated the role of antiapoptotic Bcl-xL in the progression of prostate cancer as well as the interactions of Bcl-xL with proapoptotic Bax and Bak in androgen-dependent and -independent prostate cancer cells. Immunohistochemical analysis was used to study the expression of Bcl-xL in a series of 139 prostate carcinomas and its association with Gleason grade and time to hormone resistance. Expression of Bcl-xL was more abundant in prostate carcinomas of higher Gleason grades and significantly associated with the onset of hormone-refractory disease. In vivo interactions of Bcl-xL with Bax or Bak in untreated and camptothecin-treated LNCaP and PC3 cells were investigated by means of coimmunoprecipitation. In the absence of any stimuli, Bcl-xL interacts with Bax and Bak in androgen-independent PC3 cells but only with Bak in androgen-dependent LNCaP cells. Interactions of Bcl-xL with Bax and Bak were also evidenced in lysates from high-grade prostate cancer tissues. In LNCaP cells treated with camptothecin, an inhibitor of topoisomerase I, the interaction between Bcl-xL and Bak was absent after 36 h, Bcl-xL decreased gradually and Bak increased coincidentally with the progress of apoptosis. These results support a model in which Bcl-xL would exert an inhibitory effect over Bak via heterodimerization. We propose that these interactions may provide mechanisms for suppressing the activity of proapoptotic Bax and Bak in prostate cancer cells and that Bcl-xL expression contributes to androgen resistance and progression of prostate cancer.