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The operating theatre is a place dedicated to the cult of asepsis, which demands vigilance and discipline from the professionals who work there at all times. The scrub nurse plays an essential role in guaranteeing the quality and safety of care. In order to acquire the knowledge and skills needed to practice this specialty, a complementary post-graduate training program has been created. Over the years, this training has been regularly updated in response to technological developments and advances in surgery. Today, scrub nurse training is university-based., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Objectives: The study aimed to assess the potential for serum neurofilament light chain (NFL) levels to predict the risk of progressive multifocal leukoencephalopathy (PML) in natalizumab (NTZ)-treated patients with multiple sclerosis (MS) and to discriminate PML from MS relapses., Methods: NFL levels were measured with single molecule array (Simoa) in 4 cohorts: (1) a prospective cohort of patients with MS who developed PML under NTZ therapy (pre-PML) and non-PML NTZ-treated patients (NTZ-ctr); (2) a cohort of patients whose blood was collected during PML; (3) an independent cohort of non-PML NTZ-treated patients with serum NFL determinations at 2 years (replication cohort); and (4) a cohort of patients whose blood was collected during exacerbations., Results: Serum NFL levels were significantly increased after 2 years of NTZ treatment in pre-PML patients compared with NTZ-ctr. The prognostic performance of serum NFL levels to predict PML development at 2 years was similar in the NTZ-ctr group and replication cohort. Serum NFL levels also distinguished PML from MS relapses and were 8-fold higher during PML compared with relapses., Conclusions: These results support the use of serum NFL levels in clinical practice to identify patients with relapsing-remitting MS at higher PML risk and to differentiate PML from clinical relapses in NTZ-treated patients., Classification of Evidence: This study provides Class I evidence that serum NFL levels can identify NTZ-treated patients with MS who will develop PML with a sensitivity of 67% and specificity of 80%., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Alzheimer's disease (AD) is characterized by the accumulation of β-amyloid (Aβ) peptides and hyperphosphorylated tau protein accompanied by neuronal loss. Aβ accumulation has been associated with an impaired sphingosine 1-phosphate (S1P) metabolism. S1P is generated by sphingosine kinases (SphKs), of which there are two isoenzymes SphK1 and SphK2, and degraded by the sphingosine 1-phosphate lyase (SPL). We previously reported, that both a decrease in SphK1 expression and an increase in SPL expression, correlated with amyloid deposits in the entorhinal cortex of AD brains, suggesting a global loss of pro-survival S1P in AD neurons. SphK2 contribution has also been examined in AD yielding to conflicting results that may reflect the complexity of SphK2 regulation. The subcellular localization of SphK2, hence the compartmentalization of generated S1P, is recognized to play a crucial role in dictating either its pro-survival or pro-apoptotic functions. We therefore aimed at studying the expression of SphK2 and notably its subcellular localization in brain tissues from patients with AD., Results: We report that a decrease in SphK2 protein cytosolic expression correlated with the density of amyloid deposits in a cohort of 25 post-mortem brains. Interestingly, we observed that the equilibrium between cytoplasmic and nuclear SphK2 is disrupted and showed that SphK2 is preferentially localized in the nucleus in AD brain extracts as compared to control extracts, with a marked increase of cleaved SphK2., Conclusions: Our results suggest that a shift in the subcellular localization of the S1P generating SphK2 may compromise the well established pro-survival cytosolic S1P by favoring the production of nuclear S1P associated with adverse effects in AD pathogenesis.

Cardiomyocytes derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (hiPSCs) are increasingly used for in vitro assays and represent an interesting opportunity to increase the data throughput for drug development. In this work, we describe a 96-well recording of synchronous electrical activities from spontaneously beating hiPSC-derived cardiomyocyte monolayers. The signal was obtained with a fast-imaging plate reader using a submillisecond-responding membrane potential recording assay, FluoVolt, based on a newly derived voltage-sensitive fluorescent dye. In our conditions, the toxicity of the dye was moderate and compatible with episodic recordings for >3 h. We show that the waveforms recorded from a whole well or from a single cell-sized zone are equivalent and make available critical functional parameters that are usually accessible only with gold standard techniques like intracellular microelectrode recording. This approach allows accurate identification of the electrophysiological effects of reference drugs on the different phases of the cardiac action potential as follows: fast depolarization (lidocaine), early repolarization (nifedipine, Bay K8644, and veratridine), late repolarization (dofetilide), and diastolic slow depolarization (ivabradine). Furthermore, the data generated with the FluoVolt dye can be pertinently complemented with a calcium-sensitive dye for deeper characterization of the pharmacological responses. In a semiautomated plate reader, the two probes used simultaneously in 96-well plates provide an easy and powerful multiparametric assay to rapidly and precisely evaluate the cardiotropic profile of compounds for drug discovery or cardiac safety., (Copyright © 2016 the American Physiological Society.)

Determining the electrical properties of the extracellular space around neurons is important for understanding the genesis of extracellular potentials, as well as for localizing neuronal activity from extracellular recordings. However, the exact nature of these extracellular properties is still uncertain. Here, we introduce a method to measure the impedance of the tissue, one that preserves the intact cell-medium interface using whole-cell patch-clamp recordings in vivo and in vitro. We find that neural tissue has marked non-ohmic and frequency-filtering properties, which are not consistent with a resistive (ohmic) medium, as often assumed. The amplitude and phase profiles of the measured impedance are consistent with the contribution of ionic diffusion. We also show that the impact of such frequency-filtering properties is possibly important on the genesis of local field potentials, as well as on the cable properties of neurons. These results show non-ohmic properties of the extracellular medium around neurons, and suggest that source estimation methods, as well as the cable properties of neurons, which all assume ohmic extracellular medium, may need to be reevaluated., (Copyright © 2016 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Use of resorbable external reinforcement of the pulmonary autograft during the Ross operation has been suggested, but the differential regional potential for dilation of the aorta, mainly regarding the neo-root and the neo-Valsalva sinuses, represents an unresolved issue. Auxetic materials could be useful in preventing dilation given their favorable mechanical properties. We designed a composite semiresorbable armoured bioprosthesis constituted by polydioxanone and expanded polytetrafluoroethylene and evaluated its effectiveness as a pulmonary autograft reinforcement device in an animal model of the Ross procedure., Methods: An experimental model of the Ross procedure was performed in 20 three-month-old growing lambs. The pulmonary autograft was alternatively nonreinforced (control group n = 10) or reinforced with composite bioprosthesis (reinforced group n = 10). Animals were followed up during growth for 6 months by angiography and echocardiography. Specific stainings for extracellular matrix and immunohistochemistry for metalloproteinase-9 were performed., Results: Reference aortic diameter increased from 14 ± 1 mm to 19 ± 2 mm over 6 months of growth. In the control group, pulmonary autograft distension (28 ± 2 mm) was immediately noted, followed by aneurysm development at 6 months (40 ± 2 mm, P < .001 vs reference). In the reinforced group, an initial dilation to 18 ± 1 mm was detected and the final diameter was 27 ± 2 mm (42% increase). Two deaths due to pulmonary autograft rupture occurred in the control group. On histology, the control group showed medial disruption with connective fibrous replacement, whereas in the reinforced group compensatory intimal hyperplasia was present in the absence of intimal tears. The bioprosthesis promoted a positive matrix rearrangement process favoring neoarterialization and elastic remodeling as demonstrated on specific staining for elastin collagen and metalloproteinase-9., Conclusions: The device adapted and functionally compensated for the characteristics of autograft growth, guaranteeing a reasonable size of the autograft at 6 months, but more important, because the device is biocompatible, it did not disrupt the biological process of growth or cause inflammatory damage to the wall., (Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Supravalvular pulmonary stenosis (SPS) remains a worrisome complication in the long term of simple transposition of the great arteries. Issues of scar formation and inability to grow are considered at the base of this phenomenon. We pioneered the use of a tissue engineering approach to guide the maturation and the growth of pulmonary autograft in the Ross procedure with encouraging results. We therefore sought to investigate the use of a similar approach in the reconstruction of neopulmonary trunk (NPT) with the aim to recreate a vascular conduit that retains the structural architecture and the same biological potential of native pulmonary artery and prevents long-term SPS., Methods: A model of NPT reconstruction in growing lambs was used. NPT was constructed with autologous pericardium and reinforced with a four-layered knitted polydioxanone mesh (PDS n=10) or left unreinforced (control n=10). Animals were left growing for 6 months and angiographic and transesophageal echocardiographic measurements were performed at day 1 and at the end of the study together with histological analysis., Results: Control group developed SPS while PDS reinforcement allowed a progressive increase in diameter with an optimal size to match the pulmonary artery of healthy growing controls. Histological analysis showed in the control group disruption of endothelial lining with fibrosis, while demonstrated in the PDS group a trilaminar vessel-like structure., Conclusions: The bioresorbable reinforcement induced the formation over time of a neopulmonary conduit able to both face the hemodynamic load of the pulmonary system and guarantee a harmonious increase in size during the somatic growth., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Importance: Early identification of Alzheimer disease (AD) is important for clinical management and affords the opportunity to assess potential disease-modifying agents in clinical trials. To our knowledge, this is the first report of a randomized trial to prospectively enrich a study population with prodromal AD (PDAD) defined by cerebrospinal fluid (CSF) biomarker criteria and mild cognitive impairment (MCI) symptoms., Objectives: To assess the safety of the γ-secretase inhibitor avagacestat in PDAD and to determine whether CSF biomarkers can identify this patient population prior to clinical diagnosis of dementia., Design, Setting, and Participants: A randomized, placebo-controlled phase 2 clinical trial with a parallel, untreated, nonrandomized observational cohort of CSF biomarker-negative participants was conducted May 26, 2009, to July 9, 2013, in a multicenter global population. Of 1358 outpatients screened, 263 met MCI and CSF biomarker criteria for randomization into the treatment phase. One hundred two observational cohort participants who met MCI criteria but were CSF biomarker-negative were observed during the same study period to evaluate biomarker assay sensitivity., Interventions: Oral avagacestat or placebo daily., Main Outcomes and Measure: Safety and tolerability of avagacestat., Results: Of the 263 participants in the treatment phase, 132 were randomized to avagacestat and 131 to placebo; an additional 102 participants were observed in an untreated observational cohort. Avagacestat was relatively well tolerated with low discontinuation rates (19.6%) at a dose of 50 mg/d, whereas the dose of 125 mg/d had higher discontinuation rates (43%), primarily attributable to gastrointestinal tract adverse events. Increases in nonmelanoma skin cancer and nonprogressive, reversible renal tubule effects were observed with avagacestat. Serious adverse event rates were higher with avagacestat (49 participants [37.1%]) vs placebo (31 [23.7%]), attributable to the higher incidence of nonmelanoma skin cancer. At 2 years, progression to dementia was more frequent in the PDAD cohort (30.7%) vs the observational cohort (6.5%). Brain atrophy rate in PDAD participants was approximately double that of the observational cohort. Concordance between abnormal amyloid burden on positron emission tomography and pathologic CSF was approximately 87% (κ = 0.68; 95% CI, 0.48-0.87). No significant treatment differences were observed in the avagacestat vs placebo arm in key clinical outcome measures., Conclusions and Relevance: Avagacestat did not demonstrate efficacy and was associated with adverse dose-limiting effects. This PDAD population receiving avagacestat or placebo had higher rates of clinical progression to dementia and greater brain atrophy compared with CSF biomarker-negative participants. The CSF biomarkers and amyloid positron emission tomography imaging were correlated, suggesting that either modality could be used to confirm the presence of cerebral amyloidopathy and identify PDAD., Trial Registration: clinicaltrials.gov Identifier: NCT00890890.

Objectives: To circumvent the issue of pulmonary autograft (PA) dilation after the Ross procedure, surgical reinforcement strategies have been suggested in clinical or anecdotal series. However, no preclinical large-animal model of the Ross procedure is available, which is needed to enable full comprehension of the pathologic mechanisms and the effectiveness of reinforcement techniques during growth. Our aim was to develop a large-animal model of the Ross operation, to reproduce the clinical scenario in which this procedure might be applied, and allow for development and testing of various devices and techniques to improve PA performance. In addition, we aimed to test the effectiveness of a bioresorbable mesh for PA reinforcement., Methods: An experimental model of transposition of the pulmonary trunk as an autograft in the aortic position has been developed and performed under cardiopulmonary bypass in 20 growing lambs, aged 3 months. The experimental design included: a control group that underwent PA transposition; a group in which the PA was reinforced with an external, synthetic, nonresorbable, polypropylene grid; and a group that received various combinations of resorbable meshes. Animals were followed up during growth for 6 months by angiography and echocardiography and eventually killed for pathologic analysis., Results: All animals survived the procedure with no complications. The model was easy and reproducible. Resorbable meshes prevented PA dilation and preserved its progressive growth process, aiding histologic remodelling., Conclusions: We developed an easy and reproducible model of the Ross procedure, allowing for a reliable simulation of the clinical scenario. Resorbable PA reinforcement may represent an interesting option in this context., (Copyright © 2015 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Concepts from cognitive neuroscience strongly suggest that the prefrontal cortex (PFC) plays a crucial role in the cognitive functions necessary for creative thinking. Functional imaging studies have repeatedly demonstrated the involvement of PFC in creativity tasks. Patient studies have demonstrated that frontal damage due to focal lesions or neurodegenerative diseases are associated with impairments in various creativity tasks. However, against all odds, a series of clinical observations has reported the facilitation of artistic production in patients with neurodegenerative diseases affecting PFC, such as frontotemporal dementia (FTD). An exacerbation of creativity in frontal diseases would challenge neuroimaging findings in controls and patients, as well as the theoretical role of prefrontal functions in creativity processes. To explore this paradox, we reported the history of a FTD patient who exhibited the emergence of visual artistic productions during the course of the disease. The patient produced a large amount of drawings, which have been evaluated by a group of professional artists who were blind to the diagnosis. We also reviewed the published clinical cases reporting a change in the artistic abilities in patients with neurological diseases. We attempted to reconcile these clinical observations to previous experimental findings by addressing several questions raised by our review. For instance, to what extent can the cognitive, conative, and affective changes following frontal damage explain changes in artistic abilities? Does artistic exacerbation truly reflect increased creative capacities? These considerations could help to clarify the place of creativity-as it has been defined and explored by cognitive neuroscience-in artistic creation and may provide leads for future lesion studies.

Introduction: Heterogeneous clinical presentation and gender differences were reported in Charcot-Marie-Tooth disease type 1A (CMT1A)., Methods: This report examined demographic and clinical data collected during a randomised controlled trial, to describe the clinical spectrum of a large and well-defined cohort of CMT1A patients., Results: Among the 189 symptomatic patients screened, three patients (1.6%) reported first symptoms in the upper limbs, which may be misleading when establishing the clinical diagnosis. The quality of life (QoL) of patients was significantly deteriorated compared to the standard population, and slightly better compared to multiple sclerosis patients. According to the literature, patients reported several disorders which may be associated with CMT1A, including auditory dysfunction (7.9%), Carpal Tunnel Syndrome (CTS) (7.9%) or sleep apnoea (4.2%). Compared to available data, we reported more patients with CTS and fewer patients with sleep apnoea. Women were more affected by CTS than men (11% and 2.8%, respectively). Women also reported an earlier onset of symptoms than men (8.6±9.5 years and 13.1±14 years, respectively), higher deterioration of their QoL and higher disability of their upper limb, assessed by Overall Neuropathy Limitation Scale (p=0.023)., Conclusions: This information will be useful for better understanding of this disease and for designing future clinical studies., (© 2013. Published by Elsevier B.V. All rights reserved.)

In studying phagocytosis of zymosan particles by human blood monocytes in phase-contrast videomicroscopy, we found that monocytes loaded with zymosan particles became chemotactic for polymorphonuclear leukocytes (PMN) which closed on them and purloined their particle content. This despoliation usually occurred in monocytes that had begun to swell-prefiguring their death. The violent seizure of their contents by the aggressing PMN often tore the monocytes apart. However, some apparently healthy monocyte survived the removal of zymosan content by PMN or, more commonly, its removal by another monocyte. PMN-a much hardier cell in slide preparations-that were similarly loaded with zymosan particles, also attracted PMN. The latter could remove zymosan from the target cell without killing it. Thus, leukocytes were sacrificing significant portions of themselves without losing residual membrane integrity and motile function. Their behavior with respect to other particles (e.g., bacteria) will be of interest. We suggest that the membrane fusagen resides in the inner membrane leaflets when they are brought together in an extreme hourglass configuration. This event may be similar to the fragmentation of erythrocytes into intact pieces, the formation of cytokineplasts, the rear extrusion of content by migrating cells on surfaces, and the phagocytic process itself.

Friedreich's ataxia (FRDA) is a neurodegenerative disease caused by low levels of the mitochondrial protein frataxin. The main phenotypic features of frataxin-deficient human and yeast cells include iron accumulation in mitochondria, iron-sulfur cluster defects and high sensitivity to oxidative stress. Frataxin deficiency is also associated with severe impairment of glutathione homeostasis and changes in glutathione-dependent antioxidant defenses. The potential biological consequences of oxidative stress and changes in glutathione levels associated with frataxin deficiency include the oxidation of susceptible protein thiols and reversible binding of glutathione to the SH of proteins by S-glutathionylation. In this study, we isolated mitochondria from frataxin-deficient ∆yfh1 yeast cells and lymphoblasts of FRDA patients, and show evidence for a severe mitochondrial glutathione-dependent oxidative stress, with a low GSH/GSSG ratio, and thiol modifications of key mitochondrial enzymes. Both yeast and human frataxin-deficient cells had abnormally high levels of mitochondrial proteins binding an anti-glutathione antibody. Moreover, proteomics and immunodetection experiments provided evidence of thiol oxidation in α-ketoglutarate dehydrogenase (KGDH) or subunits of respiratory chain complexes III and IV. We also found dramatic changes in GSH/GSSG ratio and thiol modifications on aconitase and KGDH in the lymphoblasts of FRDA patients. Our data for yeast cells also confirm the existence of a signaling and/or regulatory process involving both iron and glutathione., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Since the approval of riluzole for the treatment of amyotrophic lateral sclerosis (ALS) 17 years ago, more than 30 large clinical trials have been conducted, but none has proved successful. The failure to translate positive preclinical results into the clinical setting raises questions about the validity of the rodent model that is used to study ALS, and about the quality of both preclinical and clinical studies. However, the greatest challenge is the disease itself as, with rare exceptions, the causes are unknown. In this Perspectives article, we highlight key issues related to the pathophysiology, preclinical studies and clinical trials that should be addressed in the future. These areas include the relationships between different disease mechanisms, the challenges presented by the heterogeneity of the disease, and the need for early intervention, optimal dose selection and effective biomarkers.

Mitochondria are a major source of intracellular reactive oxygen species, the production of which increases with cancer. The deleterious effects of reactive oxygen species may be responsible for the impairment of mitochondrial function observed during various pathophysiological states associated with oxidative stress and cancer. These organelles are also targets of oxidative damage (oxidation of mitochondrial DNA, lipids, protein). An important factor for protein maintenance in the presence of oxidative stress is enzymatic reversal of oxidative modifications and/or protein degradation. Failure of these processes is likely a critical component of the cancer process. Mitochondrial proteases degrade misfolded and non-assemble polypeptides, thus performing quality control surveillance in the organelle. Mitochondrial proteases may be directly involved in cancer development as recently shown for HtrA2/Omi or may regulate crucial mitochondrial molecule such as cytochrome c oxidase 4 a subunit of the cytochrome c oxidase complex degraded by the Lon protease. Thus, the role of mitochondrial proteases is further addressed in the context of oxidative stress and cancer., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A 64-year old patient underwent aortic valve replacement with a bileaflet Medtronic Advantage prosthesis. Six years later, she presented with a recurrence of symptoms, at which time Doppler echocardiography revealed an obstruction of the aortic mechanical prosthesis (mean transvalvular gradient 35 mmHg). Both, transesophageal echocardiography and fluoroscopy failed to identify the mechanism of valve obstruction. Multislice computed tomography (CT) scanning provided indirect signs as well as direct evidence of pannus formation, which was confirmed at surgery. The value of CT scanning to assess the mechanism of aortic mechanical prosthesis obstruction is emphasized.

Objective: This study aims to evaluate the clinical implications of radial artery graft stenosis and the performance of percutaneous intervention (PCI) of radial artery (RA) grafts., Methods: Out of 291 patients, 18 (6.2%) underwent PCI of an RA graft. The indications for PCI were acute myocardial infraction (n=1), angina (n=10) and scintigraphic abnormality (n=5). Two patients were asymptomatic and underwent PCI prior to major extracardiac surgery. The location of the RA stenosis was proximal (n=2) or distal anastomosis (n=5) and body of the conduit (n=11). From 1992 to 2001, balloon dilatation alone was performed on nine RA grafts at 1.7 years after surgery. Since 1999, stenting of nine RA grafts was achieved at 9.2 years after surgery. Three bare-metal and six drug-eluting stents were implanted. Stent mean diameter and length were 2.75 mm and 16 mm, respectively. Simultaneous PCI of other coronaries was achieved in five cases., Results: At 5.8 years, clinical follow-up showed heart failure (n=2) and recurrent angina (n=3), all after balloon dilatation. Control angiogram was performed in 14 cases at 4.5 years by conventional angiography (n=8) and 64-slice CT scan (n=6). One RA graft was occluded due to competitive flow from the native coronary vessel. Two RA restenoses following balloon dilatation were treated by stenting with long-term success (n=1) and secondary occlusion (n=1). Intra-stent RA stenosis was noted in one asymptomatic patient. All patients survived at long term except for one non-cardiac death at 5.9 years., Conclusion: Focal stenosis of radial artery graft is a rare angiographic finding and its meaning is unequivocal. PCI with balloon alone should be restricted to the early postoperative period during which spasm is difficult to exclude. Stenting offers excellent and durable results and shall be preferred in most cases., (Copyright (c) 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.)

Stimulation (DBS) of the globus pallidus (GP) is effective to treat generalized dystonia. Little is known about the evolution of dystonia in case of arrest after a long period of stimulation. This study describes the course of dystonia during a 48 hours period without stimulation followed by a 24 hours period after turning ON the stimulator. 14 patients with generalized dystonia treated with bilateral GP DBS for 3 years or more were recruited. Blinded video-based analysis was performed using Burke-Fahn-Marsden scale at (1) baseline (ON stimulation), (2) up to 48 hours after the stimulator was turned OFF, and (3) 24 hours after the stimulator was turned ON. 13 patients completed the 48 hours OFF-stimulation period. The dystonia movement score progressively worsened from 24.3 +/- 13.9 at baseline to 48.9 +/- 19.8 after 48 hours (P < 0.00001). The disability score also worsened from 4.4 +/- 1.2 at baseline to 5.7 +/- 1.5 after 48 hours without stimulation (P < 0.001). When the neurostimulator was turned ON, the dystonia scores returned to baseline level after 10 hours. The interruption of GP DBS in dystonia results in a progressive worsening which is rapidly reversible once the neurostimulator is turned ON., ((c) 2009 Movement Disorder Society.)

Our objective was to assess the efficacy and safety of 40 mg/day glatiramer acetate (GA) in patients with ALS. We conducted a double-blind, randomized, placebo-controlled, multicentre trial. Three hundred and sixty-six patients with definite, probable or probable laboratory supported ALS and a slow vital capacity > or = 70% were randomly assigned to treatment with placebo or 40 mg GA daily. The primary intention-to-treat analysis was the comparison between the two treated groups of the rates of deterioration on the ALSFRSR scale. The secondary outcome measure was time to death, tracheostomy or permanent assisted ventilation. Safety and tolerability of GA were evaluated. After 52 weeks of follow-up, the slope of the ALSFRSR score was comparable in the both groups (placebo, -1.00+/-0.06/month; GA, -1.05+/-0.06/month; p=0.48). The secondary endpoint was non-significant with 159 patients (87.4%) alive in the placebo group and 162 patients (88.1%) in the GA group (log rank, p=0.75). The most common events were the injection site reactions (76.1% in the GA group, 14.8% in the placebo group), comparable to the known profile of 20 mg GA. In conclusion, GA at a dose of 40 mg/day did not show any beneficial effect in ALS patients, and safety and tolerability of GA were good in this population.

Unlabelled: In familial amyloid polyneuropathy (FAP), destruction of nerve fibres is related to accumulation of mutated transthyretin (mTTR) derived amyloid deposits (AD) in the endoneurium. Liver transplantation (LT), which removes the main source of mTTR, does not prevent deterioration of the clinical condition in all recipients., Material and Methods: We evaluated the distribution of AD in the central and peripheral nervous system in order to better understand the pathophysiology of FAP and the potential role of lesions of nerve blood vessels and of mTTR released by choroid plexuses (CP). Forty nerve biopsy specimens and 3 autopsy cases, including 7 patients who underwent liver transplantation, all from patients with symptomatic FAP and DNA mutation of the TTR gene, were included., Results: Patients were ranged into three categories: MORPHOLOGICAL CHANGES: Amyloid predominated around endoneurial capillaries in 37 patients, with occlusion/destruction of endoneurial capillaries in 15 nerves at late stages of the disease. Post-mortem examination showed amyloid in choroid plexuses and perivascular spaces in the brain and around blood vessels penetrating the endoneurium, following arachnoid and connective tissue septae. Destruction of endoneurial blood vessels is a late event in the natural course of FAP. Morphological findings were similar in patients who underwent liver transplantation and in those who did not. The distribution of amyloid in areas communicating with the subarachnoid space suggests that mutated TTR released in the CSF may move to the endoneurial fluid and accumulate in peripheral nerves, accounting for lack of efficacy of liver transplantation in some individuals.

Background: Treatment with a regimen of bevacizumab-irinotecan has been shown to be effective in recurrent grade 3 and 4 gliomas, but the effect of this regimen against recurrent oligodendroglial tumors has not been specifically studied., Methods: The bevacizumab-irinotecan regimen was retrospectively evaluated in a consecutive series of 25 patients with recurrent oligodendroglial tumors. All patients had not responded to previous treatment with radiation therapy and at least one line of temozolomide chemotherapy. Bevacizumab (10 mg/kg) and irinotecan (125 or 340 mg/m(2) according to the antiepileptic regimen) were administered every 14 days. Response was measured clinically and on monthly MRI., Results: The objective response rate was 72% (20% complete response, 52% partial response). After a median follow up of 202 days, the median progression-free survival was 140 days (95% confidence interval [CI] 116-infinity), and overall survival had not been reached. The 6-month progression-free survival was 42% (95% CI 26%-67%). Among the 17 patients in whom the status of the main molecular alterations of gliomas could be evaluated (search for deletions of chromosomes 1p, 19q, 9p, and 10q and amplification of epidermal growth factor receptor, mouse double-minute gene, and cyclin-dependent kinase 4 gene), no relation could be found between the response rate and the type of genetic change (including 1p-19q codeletion). The profile of tolerance was fair, with treatment discontinuation in 20% of patients. Intratumoral hemorrhages occurred in 6 patients (24%), but the treatment had to be discontinued because of symptomatic bleeding in only 1 patient (4%)., Conclusions: This regimen is effective in recurrent oligodendrogliomas, and the overall tolerance is acceptable.

Naturally occurring clefts in the posterior leaflet of the mitral valve and/or the mitral commissures themselves may become the foci of residual mitral regurgitation when distorted by an adjacent rigid suture line. Herein are reported the details of three cases in which cleft/commissure closure resolved such leaks. The anatomical substrate which predisposed to this problem is also discussed.

Penetrating ulcer of the ascending aorta is a very rare pathological entity with known potential for progression towards intramural hematoma or dissection. Intraoperative diagnosis of an asymptomatic ulcer of the ascending aorta was carried in a 60-year-old male with rheumatic valve disease. The tubular portion of the aorta was slightly dilated (45 mm) and the aortic valve was tricuspid. A supracoronary replacement of the ascending aorta was performed with a Dacron tube. Pathological analysis of the operative sample showed a considerable thinning of the aortic wall with a complete lack of elastic fibers at the level of the penetrating ulcer surrounded by a slightly dystrophic ascending aorta free from calcification and atheroma.

Objectives: The aim of the Pre-Al study is to evaluate and compare the predictive value of different tools for an early identification of Alzheimer's disease., Design and Participants: Patients coming for consultation to memory clinics without dementia were included if they had an objective memory or attention trouble assessed by a MMSE score > 25 (with at least one missing item at the words recall) and / or an Isaac set test score < 28. All were examined by a neuropsychological battery (Free and Cued Selective Reminding Test, digit ordering test, WAIS-R digit symbol, Trail making test, Benton visual retention test, verbal fluency, confrontation naming and Baddeley's double task test). A subpopulation received an MRI and SPECT assessment., Results and Discussion: 251 patients were included (mean age: 72.0 years; mean education duration: 10.9 years). Validation of the predictive tests will be based on the comparison of these tests in patients developing dementia and others, after a follow-up of at least 3 years. This paper presents methodology of the study and the population description.

Iatrogenic injury to the circumflex coronary artery following mitral annuloplasty is a potentially fatal complication. It can be clinically silent or else be responsible for a cardiogenic shock. The diagnosis should be suspected on EKG changes with segmental dysfunction of the lateral wall on the intraoperative echography. The author reports one case whose recognition relied on emergency angiography; the patient was successfully treated by angioplasty and stenting. The management of this complication remains controversial and the various treatment modalities are discussed.

The purpose of this article is to examine the similarities and differences between patients with Major Depressive Disorder (MDD) versus Generalized Anxiety Disorder (GAD) versus MDD with anxiety symptoms. Data were analysed from all randomized double-blind clinical studies with escitalopram that measured symptoms using either Hamilton Anxiety Scale (HAMA) or Montgomery-Asberg Depression Rating Scale (MADRS). The contribution of each item of a scale to the total score was calculated before and after treatment, in remitters. Most single items of the HAMA contribute nearly equally in patients with GAD. In patients with MDD, four symptoms (i.e. anxious mood, tension, insomnia and concentration) contribute to most to the HAMA total score. In patients with GAD, three symptoms (tension, sleep and concentration) contribute two-thirds of the MADRS total score. In contrast, most MADRS items contribute equally to the total score in patients with MDD. After treatment to remission, the profile of residual symptoms MDD or GAD was similar to the symptom profile before treatment. Anxiety symptoms are very common in patients with MDD or GAD, and the symptomatic pattern is similar. In both disorders, the symptomatic pattern of residual symptoms is similar to the pattern of symptoms before treatment.

Objective: To assess the efficacy and safety of pentoxifylline, a US Food and Drug Administration-approved drug, in patients with ALS treated with riluzole., Methods: The authors conducted a double-blind, randomized, placebo-controlled, multicenter trial. Four hundred patients with probable or definite ALS and vital capacity less than 100% were randomly assigned to treatment with placebo or 1.2 g pentoxifylline daily. The primary outcome was death. Secondary outcomes were rates of deterioration of ALS Functional Rating Scale-Respiratory and muscle strength. The primary intention-to-treat analysis was the survival comparison of drug vs placebo, assessed before (log-rank test) and after adjustment (Cox model) for predefined prognostic factors., Results: At the end of the study, after 547 days of follow-up, 103 patients (51.7%) in the pentoxifylline group and 120 (59.7%) in the placebo group were alive (unadjusted risk 1.28, p = 0.107; adjusted risk 1.43, p = 0.02). In contrast, analysis of secondary outcome functional variables did not show the same negative effect of the drug. The most common adverse reactions were nausea, dysphagia, and flushing, all reversible after stopping the drug., Conclusions: Pentoxifylline is not beneficial in ALS and should be avoided in patients treated with riluzole. The discrepancy between survival and measures of functional changes urges caution in equating these end points in phase III trials, and suggests that both survival and function should be used in phase III trials.

Objective: The aim of this study was to assess the mechanisms of prolapse in ischemic mitral valve regurgitation (MR) and the techniques of valve repair., Methods: Out of 121 patients operated upon for ischemic MR, a prolapse was present in 44 patients (36.4%). The operation was performed emergently in four cases (9.1%) and electively in 40 patients (90.9%). Fifteen patients (34.1%) were operated upon within 60 days following acute myocardial infarction., Results: The diagnosis of prolapse had been overlooked by echography in five cases (11.4%). A commissural area was involved as the site of prolapse in 31 cases (70.4%). The mechanism of prolapse was a papillary muscle (PM) lesion in 38 cases (86.4%) (anterior PM: n=8, posterior PM n=36) or a chordal lesion in six cases (13.6%). PM injury was elongation (n=16), or rupture (total n=1, partial n=21, incomplete n=4). The operative technique was mitral valve repair with Carpentier's techniques in 42 cases (95.5%) or replacement in two cases (4.5%). Hospital mortality was 11.4% (n=4). The mean follow-up was to 44.7+/-29.6 months. Overall survival and freedom from reoperation were 68.3+/-9.0 and 89.9+/-5.7% at 5 years, respectively. Freedom from MR equal or > grade 2 was 69.7+/-9.5% at 5 years., Conclusions: The mechanisms of ischemic mitral valve prolapse were variable and tightly linked to the PM anatomy. A reliable mitral valve repair could be achieved in most cases with acceptable mid-term results.

The subventricular zone (SVZ) in the forebrain is the largest source of neural stem cells and progenitor cells in the adult CNS. To assess the ability of adult neural stem cells to survive, differentiate and migrate, we have compared the behavior of dissociated, neurosphere-derived stem cells with that of progenitor cells in transplantation experiments. This ability was first tested in vivo, offering the stem cells the possibility to migrate along the rostral migratory stream (RMS), their specific pathway. In addition, the differential behaviors of the two classes of cells were also compared in vitro by grafting them into organotypic slice cultures containing either tangential (embryonic cerebral cortex) or radial (early postnatal cerebellar cortex) migratory routes. Most of the grafted adult neurosphere-derived stem cells survived and integrated in vivo, and a proportion of them differentiate into neurons, oligodendrocytes or astrocytes. However, they were unable to migrate along the RMS and remained in the vicinity of the injection site. In contrast, SVZ progenitor cells were able to migrate toward the olfactory bulb and, once there, to acquire the phenotype of granule cells, as previously reported. In vitro, neural stem cells exhibited a better migratory ability, although they only migrated for short distances, particularly, in forebrain slices. Nevertheless, the average distance covered by progenitor cells was a two-fold longer than that covered by neural stem cells, corroborating that this class of more specified cells has higher migratory ability. These results suggest that the in vitro conditions of expanding SVZ-derived stem cells, required to maintain them in an immature stage might modify their intrinsic properties, preventing their differentiation into neuroblasts and their subsequent migration.

Oxidative stress is implicated in age-related diseases and is a possible determinant in the loss of lung function. The aim of our study was to examine the association between blood indicators of oxidative metabolism and lung function in an old population. The relationships of three antioxidant indicators (selenium, total carotenoids and alpha-tocopherol) and of a marker of lipid peroxidation (thiobarbituric acid-reactive substances (TBARs)) with age and height-adjusted PEF were assessed in 688 subjects aged 59-71 years (61% never smokers, 30% ex-smokers, 9% current smokers). Stratified analyses according to gender and smoking were performed. Gender, age, tobacco and alcohol consumption, educational level and body mass index were taken into account as potential confounders. Regarding antioxidant markers, PEF was significantly positively associated with total carotenoids in the whole group (P = 0.03), and with selenium among ex-smokers only (P = 0.008). Regarding lipid peroxidation, PEF was significantly negatively associated with TBARs in men only (P = 0.02). Consistent results were observed when analyzing quantitative values and quartiles of biological markers. Results are consistent with the hypothesis of the role of both oxidants and antioxidants on lung function in elderly. Research is needed to better understand the effect of former smoking in the surviving elderly subjects.

Object: Although a growing number of authors currently advocate surgery to treat low-grade gliomas, controversy still persists, especially because of the risk of inducing neurological sequelae when the tumor is located within eloquent brain areas. Many researchers performing preoperative neurofunctional imaging and intraoperative electrophysiological methods have recently reported on the usefulness of cortical functional mapping. Despite the frequent involvement of subcortical structures by these gliomas, very few investigators have specifically raised the subject of fiber tracking. The authors in this report describe the importance of mapping cortical and subcortical functional regions by using intraoperative real-time direct electrical stimulations during resection of low-grade gliomas., Methods: Between 1996 and 2001, 103 patients harboring a corticosubcortical low-grade glioma in an eloquent area, with no or only mild deficit, had undergone surgery during which intraoperative electrical mapping of functional cortical sites and subcortical pathways was performed throughout the procedure. Both eloquent cortical areas and corresponding white fibers were systematically detected and preserved, thus defining the resection boundaries. Despite an 80% rate of immediate postoperative neurological worsening, 94% of patients recovered their preoperative status within 3 months--10% even improved--and then returned to a normal socioprofessional life. Eighty percent of resections were classified as total or subtotal based on control magnetic resonance images., Conclusions: The use of functional mapping of the white matter together with cortical mapping allowed the authors to optimize the benefit/risk ratio of surgery of low-grade glioma invading eloquent regions. Given that preoperative fiber tracking with the aid of neuroimaging is not yet validated, we used intraoperative real-time cortical and subcortical stimulations as a valuable adjunct to the other mapping methods.

We report the case of a 47-year-old woman with a left anterior interosseous nerve palsy. Surgical release of the anterior interosseous nerve was initially proposed, but electrodiagnostic evaluation demonstrated that the neuropathy was due not to compression or to neuralgic amyotrophy but to a proximal conduction block. At that time, the conduction block could be defined only by indirect electrodiagnostic criteria. A multifocal motor neuropathy with persistent conduction block was subsequently diagnosed, and the patient was treated with intravenous immunoglobulins. The efficacy of this treatment and the subsequent disclosure of conduction block in the right posterior interosseous and peroneal nerves definitively confirmed the multifocal motor neuropathy., (Copyright 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 841-844, 2002)

Purpose: To report patients with neuralgic amyotrophy (NA) and abnormal sensory nerve action potentials (SNAP)., Methods: A retrospective study of NA cases diagnosed in electrodiagnostic evaluation during a 5-year period found 18 patients with 23 abnormal SNAP. Clinical and neurophysiological records were reviewed. NA was diagnosed according to clinical features and disease course. Radiologic and laboratory investigations were conducted to rule out other disorders., Results: The 23 individual sensory nerve lesions were 8 median, 5 radial, 4 ulnar, and 6 lateral antebrachial nerves., Conclusions: Our findings suggest that clinical and electrodiagnostic sensory involvement in NA is not uncommon and may be a prominent feature. They confirm that the most typical pattern of NA is mononeuritis or mononeuritis multiplex, and that the frequent lack of sensory deficit is because the lesions usually affect pure motor proximal or distal nerves.

Episodic memories are characterized by a specific state of awareness, conscious recollection, which allows subjects to mentally relive past events. They are not a literal reproduction of the past but instead depend on constructive processes. Patients with schizophrenia exhibit a specific impairment of conscious recollection. The aim of this study was to investigate the role of constructive processes into defective conscious recollection of patients with schizophrenia. An experiential approach to false recognition and related states of awareness was used. Thirty patients with schizophrenia, who were matched with 30 normal subjects, studied lists of words semantically related to a non-presented theme word (critical lure). On a recognition memory task with both previously presented words and non presented critical lures, they were asked to give Remember, Know or Guess responses to items that were recognized on the basis of conscious recollection, familiarity or guessing, respectively. Patients with schizophrenia recognized fewer studied words and critical lures than normal subjects. This deficit was restricted to memories associated with conscious recollection as indicated by a decrease in Remember responses, but not Know and Guess responses. Our results indicate that patients with schizophrenia exhibit an impaired conscious recollection, whether memories are true or false. They provide evidence that schizophrenia impairs the mere construction of conscious recollection.