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International audience; There is a continued unmet need for treatments that can slow Parkinson's disease progression due to the lack of understanding behind the molecular mechanisms underlying neurodegeneration. Since its discovery, ferroptosis has been implicated in several diseases and represents a therapeutic target in Parkinson's disease. Here, we use two highly relevant human dopaminergic neuronal models to show that endogenous levels of α-synuclein can determine the sensitivity of dopaminergic neurons to ferroptosis. We show that reducing α-synuclein expression in dopaminergic neurons leads to ferroptosis evasion, while elevated α-synuclein expression in patients' small-molecule-derived neuronal precursor cells with SNCA triplication causes an increased vulnerability to lipid peroxidation and ferroptosis. Lipid profiling reveals that ferroptosis resistance is due to a reduction in ether-linked phospholipids, required for ferroptosis, in neurons depleted of α-synuclein (α-syn). These results provide a molecular mechanism linking α-syn levels to the sensitivity of dopaminergic neurons to ferroptosis, suggesting potential therapeutic relevance.

International audience; In the liver, contact sites between the endoplasmic reticulum (ER) and mitochondria (named MAMs) may be crucial hubs for the regulation of lipid metabolism, thus contributing to the exacerbation or prevention of fatty liver. We hypothesized that tether proteins located at MAMs could play a key role in preventing triglyceride accumulation in hepatocytes and nonalcoholic fatty liver disease (NAFLD) occurrence. To test this, we explored the role of two key partners in building MAM integrity and functionality, the glucose-regulated protein 75 (Grp75) and mitofusin 2 (Mfn2), which liver contents are altered in obesity and NAFLD. Grp75 or Mfn2 expression was either silenced using siRNA or overexpressed with adenoviruses in Huh7 cells.Silencing of Grp75 and Mfn2 resulted in decreased ER-mitochondria interactions, mitochondrial network fusion state and mitochondrial oxidative capacity, while overexpression of the two proteins induced mirror impacts on these parameters. Furthermore, Grp75 or Mfn2 silencing decreased cellular cholesterol content and enhanced triglyceride secretion in ApoB100 lipoproteins, while their overexpression led to reverse effects. Cellular phosphatidylcholine/phosphatidylethanolamine ratio was decreased only upon overexpression of the proteins, potentially contributing to altered ApoB100 assembly and secretion. Despite the opposite differences, both silencing and overexpression of Grp75 or Mfn2 induced triglyceride storage, although a fatty acid challenge was required to express the alteration upon protein silencing. Among the mechanisms potentially involved in this phenotype, ER stress was closely associated with altered triglyceride metabolism after Grp75 or Mfn2 overexpression, while blunted mitochondrial FA oxidation capacity may be the main defect causing triglyceride accumulation upon Grp75 or Mfn2 silencing. However, further studies are required to decipher the link between modulation of Grp75 or Mfn2 expression, change in MAM integrity and alteration of cholesterol content of the cell.In conclusion, Grp75 or Mfn2 silencing and overexpression in Huh7 cells contribute to altering MAM integrity and cholesterol storage in opposite directions, but all promote triglyceride accumulation through distinct cellular pathways. This study also highlights that besides Mfn2, Grp75 could play a central role in hepatic lipid and cholesterol metabolism in obesity and NAFLD.

Mutations in the LKB1 (also known as STK11) tumor suppressor are the third most frequent genetic alteration in non–small cell lung cancer (NSCLC). LKB1 encodes a serine/threonine kinase that directly phosphorylates and activates 14 AMPK family kinases (“AMPKRs”). The function of many of the AMPKRs remains obscure, and which are most critical to the tumor-suppressive function of LKB1 remains unknown. Here, we combine CRISPR and genetic analysis of the AMPKR family in NSCLC cell lines and mouse models, revealing a surprising critical role for the SIK subfamily. Conditional genetic loss of Sik1 revealed increased tumor growth in mouse models of Kras-dependent lung cancer, which was further enhanced by loss of the related kinase Sik3. As most known substrates of the SIKs control transcription, gene-expression analysis was performed, revealing upregulation of AP1 and IL6 signaling in common between LKB1- and SIK1/3-deficient tumors. The SIK substrate CRTC2 was required for this effect, as well as for proliferation benefits from SIK loss. Significance: The tumor suppressor LKB1/STK11 encodes a serine/threonine kinase frequently inactivated in NSCLC. LKB1 activates 14 downstream kinases in the AMPK family controlling growth and metabolism, although which kinases are critical for LKB1 tumor-suppressor function has remained an enigma. Here we unexpectedly found that two understudied kinases, SIK1 and SIK3, are critical targets in lung cancer. This article is highlighted in the In This Issue feature, p. 1469

Past research has demonstrated the effectiveness of teacher-implemented, function-based treatments for problem behavior, but no studies have evaluated the impact of distractions on teachers' procedural integrity. In this proof-of-concept study, the experimenters employed a laboratory analog to examine the impact of distractions on levels of integrity when 5 teachers implemented 3 different treatments. Although integrity was similar across treatments when the setting was free of distractions, integrity declined for all teachers in the presence of student-driven distractions. In general, distractions had a greater impact on the integrity of differential negative reinforcement of alternative behavior (DNRA) compared to differential negative reinforcement of other behavior (DNRO) and noncontingent escape (NCE), particularly for the delivery of reinforcement. However, teachers tended to have lower levels of integrity when responding to problem behavior during DNRO. These findings support the potential viability of this approach for studying factors that impede procedural integrity in the classroom.

Carboxylesterase 1d (Ces1d) is a crucial enzyme with a wide range of activities in multiple tissues. It has been reported to localize predominantly in ER. Here, we found that Ces1d levels are significantly increased in obese patients with type 2 diabetes. Intriguingly, a high level of Ces1d translocates onto lipid droplets where it digests the lipids to produce a unique set of fatty acids. We further revealed that adipose tissue–specific Ces1d knock-out (FKO) mice gained more body weight with increased fat mass during a high fat-diet challenge. The FKO mice exhibited impaired glucose and lipid metabolism and developed exacerbated liver steatosis. Mechanistically, deficiency of Ces1d induced abnormally large lipid droplet deposition in the adipocytes, causing ectopic accumulation of triglycerides in other peripheral tissues. Furthermore, loss of Ces1d diminished the circulating free fatty acids serving as signaling molecules to trigger the epigenetic regulations of energy metabolism via lipid-sensing transcriptional factors, such as HNF4α. The metabolic disorders induced an unhealthy microenvironment in the metabolically active tissues, ultimately leading to systemic insulin resistance.

Background/Objectives Infantile hemangioma (IH) is the most frequent benign tumor of infancy resulting from vascular proliferation. Data regarding the burden on families of children with IHs are limited. This study aimed to characterize IHs and provide a comprehensive evaluation of the burden of IHs on parents of children requiring systemic treatment in the United States and Europe. Methods This noninterventional cross-sectional study included infants with newly diagnosed IH requiring systemic treatment. A parent or family member completed two questionnaires (Family Member questionnaire; Hemangioma Family Burden [HFB] questionnaire). Results A total of 693 individuals were evaluable in five countries. IHs were observed in more girls than boys (66%–83% female) and the mean age at inclusion was 0.44 to 1.4 years. Approximately half of patients had superficial IHs, approximately 70% of cases affected the head, and approximately 80% of cases were moderate or severe. Most patients received propranolol treatment. Their child's IH affected more than 70% of parents in each country, but fewer than 10% were offered psychological support. Approximately half of all parents reported that their child's IH affected their professional life. The global HFB score was significantly (p

Background Early prognostication is a major challenge after out-of-hospital cardiac arrest (OHCA). Aims We hypothesized that a genome-wide analysis of blood gene expression could offer new prognostic tools and lines of research. Methods Sixty-nine patients were enrolled from an ancillary study of the clinical trial NCT00999583 that tested the effect of erythropoietin (EPO) after OHCA. Blood samples were collected in comatose survivors of OHCA at hospital admission and 1 and 3 days after resuscitation. Gene expression profiles were analyzed (Illumina HumanHT-12 V4 BeadChip; >34,000 genes). Patients were classified into two categories representing neurological favorable outcome (cerebral performance category [CPC] = 1-2) vs unfavorable outcome (CPC > 2) at Day 60 after OHCA. Differential and functional enrichment analyses were performed to compare transcriptomic profiles between these two categories. Results Among the 69 enrolled patients, 33 and 36 patients were treated or not by EPO, respectively. Among them, 42% had a favorable neurological outcome in both groups. EPO did not affect the transcriptomic response at Day-0 and 1 after OHCA. In contrast, 76 transcripts differed at Day-0 between patients with unfavorable vs favorable neurological outcome. This signature persisted at Day-1 after OHCA. Functional enrichment analysis revealed a down-regulation of adaptive immunity with concomitant up-regulation of innate immunity and inflammation in patients with unfavorable vs favorable neurological outcome. The transcription of many genes of the HLA family was decreased in patients with unfavorable vs favorable neurological outcome. Concomitantly, neutrophil activation and inflammation were observed. Up-stream regulators analysis showed the implication of numerous factors involved in cell cycle and damages. A logistic regression including a set of genes allowed a reliable prediction of the clinical outcomes (specificity = 88%; Hit Rate = 83%). Conclusions A transcriptomic signature involving a counterbalance between adaptive and innate immune responses is able to predict neurological outcome very early after hospital admission after OHCA. This deserves confirmation in a larger population.

International audience; AIM: Current questionnaires designed to evaluate the burden of haemorrhoidal disease ignore symptoms such as bleeding, pain and itching. A specific questionnaire is needed to evaluate the global impact of anal disorders on patients' daily lives.METHOD: We developed a questionnaire (HEMO-FISS-QoL) to assess the symptom burden of anal disorders and administered it to 256 patients (mean age 46.2 years; men 60.4%) with haemorrhoidal disease (67.2%), anal fissure (29.3%) or both (3.5%). Psychometric properties were evaluated by testing the acceptability, construct validity and reliability of the questionnaire. Principal components and multi-trait analyses were used to identify dimensions and to assess construct validity. Backward Cronbach alpha curves and a graded response model were used to reduce the number of items and modalities. External validity was evaluated against SF-12 and the Psychological Global Well-Being Index (PGWBI) using Spearman's correlation coefficient.RESULTS: Principal component analysis defined four dimensions: physical disorders, psychology, defaecation and sexuality. The number of questions was reduced from 38 to 23. The HEMO-FISS-QoL scores correlated well with those of the SF-12 and PGWBI (P < 0.001). Cronbach's coefficients (all > 0.7) reflected good internal reliability of the different dimensions. The total score increased with the severity of the anal disorders and with their consequences (days off work and personal spending related to the disease).CONCLUSION: The HEMO-FISS-QoL questionnaire reliably evaluates the global impact of haemorrhoids and anal fissures on patients' daily lives. This simple tool may prove useful for treatment evaluation in clinical trials and daily practice.

The mitochondrial translocator protein (TSPO) is a high affinity cholesterol binding protein which is primarily located in the outer mitochondrial membrane where it has been shown to interact with proteins implicated in mitochondrial permeability transition pore (mPTP) formation. TSPO is found in different species and is expressed at high levels in tissues that synthesize steroids but is also present in other peripheral tissues especially in the heart. TSPO has been involved in the import of cholesterol into mitochondria, a key step in steroidogenesis. This constitutes the main established function of the protein which was recently challenged by genetic studies. TSPO has also been associated directly or indirectly with a wide range of cellular functions such as apoptosis, cell proliferation, differentiation, regulation of mitochondrial function or porphyrin transport. In the heart the role of TSPO remains undefined but a growing body of evidence suggests that TSPO plays a critical role in regulating physiological cardiac function and that TSPO ligands may represent interesting drugs to protect the heart under pathological conditions. This article briefly reviews current knowledge regarding TSPO and discusses its role in the cardiovascular system under physiological and pathologic conditions. More particularly, it provides evidence that TSPO can represent an alternative strategy to develop new pharmacological agents to protect the myocardium against ischemia-reperfusion injury.

Carbon monoxide (CO) is generated by heme oxygenase-1 (HO-1) and displays important signaling, anti-apoptotic and anti-inflammatory activities, indicating that pharmacological agents mimicking its action may have therapeutic benefit. This study examined the biochemical and pharmacological properties of CORM-401, a recently described CO-releasing molecule containing manganese as a metal center. We used in vitro approaches, ex-vivo rat aortic rings and the EA.hy926 endothelial cell line in culture to address how CORM-401 releases CO and whether the compound modulates vascular tone and pro-angiogenic activities, respectively. We found that CORM-401 released up to three CO/mole of compound depending on the concentration of the acceptor myoglobin. Oxidants such as H2O2, tert-butyl hydroperoxide or hypochlorous acid increased the CO liberated by CORM-401. CORM-401 also relaxed pre-contracted aortic rings and vasorelaxation was enhanced in combination with H2O2. Consistent with the release of multiple CO molecules, CORM-401-induced vasodilation was three times higher than that elicited by CORM-A1, which exhibits a similar half-life to CORM-401 but liberates only one CO/mole of compound. Furthermore, endothelial cells exposed to CORM-401 accumulated CO intracellularly, accelerated migration in vitro and increased VEGF and IL-8 levels. Studies using pharmacological inhibitors revealed HO-1 and p38 MAP kinase as two independent and parallel mechanisms involved in stimulating migration. We conclude that the ability of CORM-401 to release multiple CO, its sensitivity to oxidants which increase CO release, and its vascular and pro-angiogenic properties highlight new advances in the design of CO-releasing molecules that can be tailored for the treatment of inflammatory and oxidative stress-mediated pathologies.

Background Experimental studies suggest that morphine may protect the myocardium against ischemia-reperfusion injury by activating salvage kinase pathways. The objective of this two-center, randomized, double-blind, controlled trial was to assess potential cardioprotective effects of intra-coronary morphine in patients with ST-segment elevation myocardial infarction (STEMI) referred for primary percutaneous intervention. Methods Ninety-one patients with STEMI were randomly assigned to intracoronary morphine (1 mg) or placebo at reperfusion of the culprit coronary artery. The primary endpoint was infarct size/left ventricular mass ratio assessed by magnetic resonance imaging on day 3–5. Secondary endpoints included the areas under the curve (AUC) for troponin T and creatine kinase over three days, left ventricular ejection fraction assessed by echocardiography on days 1 and 6, and clinical outcomes. Results Infarct size/left ventricular mass ratio was not significantly reduced by intracoronary morphine compared to placebo (27.2% ± 15.0% vs. 30.5% ± 10.6%, respectively, p = 0.28). Troponin T and creatine kinase AUCs were similar in the two groups. Morphine did not improve left ventricular ejection fraction on day 1 (49.7 ± 10.3% vs. 49.3 ± 9.3% with placebo, p = 0.84) or day 6 (48.5 ± 10.2% vs. 49.0 ± 8.5% with placebo, p = 0.86). The number of major adverse cardiac events, including stent thrombosis, during the one-year follow-up was similar in the two groups. Conclusions Intracoronary morphine at reperfusion did not significantly reduce infarct size or improve left ventricular systolic function in patients with STEMI. Presence of comorbidities in some patients may contribute to explain these results. Trial registration ClinicalTrials.gov, NCT01186445 (date of registration: August 23, 2010).

Revue non répertoriée dans le JCR.; International audience; Lipids are key molecules in various biological processes, thus their quantification is a crucial point in a lot of studies and should be taken into account in lipidomics development. This family is complex and presents a very large diversity of structures, so analyzing and quantifying all this diversity is a real challenge. In this review, the different techniques to analyze lipids will be presented: from nuclear magnetic resonance (NMR) to mass spectrometry (with and without chromatography) including universal detectors. First of all, the state of the art of quantification, with the definitions of terms and protocol standardization, will be presented with quantitative lipidomics in mind, and then technical considerations and limitations of analytical chemistry's tools, such as NMR, mass spectrometry and universal detectors, will be discussed, particularly in terms of absolute quantification.

Fat perception during eating is a complex sensation that involves various sensory modalities, such as texture, aroma and taste. Taste is supported by the discovery of fatty acid receptors in the tongue papillae. Dietary fat is mainly composed of esterified fatty acids, whereas only free fatty acids can bind to taste receptors. Some authors have mentioned the necessity and efficiency of salivary lipolytic activity to hydrolyse the esterified fatty acids present in foods and enable fat perception. Our hypothesis is that salivary lipolytic activity is also involved in regulating the basal level of salivary fatty acids in humans. To test this hypothesis, total fatty acid (TFA) and free fatty acid (FFA) concentrations and selected salivary characteristics (such as lipolytic activity) were analysed in the resting saliva of 54 subjects. The results show differences in the TFA and FFA profiles, with TFA and FFA concentrations of 8.99 and 3.56 µg/mL of saliva, respectively. Interestingly, lipolytic activity had a significant positive correlation with FFA concentration (0.51, p

Cytochromes P450 (CYP) are a large family of enzymes widely involved in hepatic drug metabolism. While most CYP are extensively expressed in the liver, some of them are also detected in the heart where they participate through arachidonic acid metabolism to a variety of eicosanoids synthesis with different cardiovascular effects. Studies performed in the last years reported that several isoenzymes of microsomal CYP (i.e. CYP 2J2, CYP 2C8, CYP 2C9, CYP 4F) can play a role in the pathogenesis of ischemia-reperfusion. Moreover, various data indicate that microsomal CYP could represent a relevant target to develop pharmacological therapies to attenuate ischemia-reperfusion injury in the heart. As mitochondria appear to play a central role during ischemia-reperfusion, mitochondrial CYP, mainly involved in steroid hormone biosynthesis, could also become potential therapeutic target for cardioprotective strategies. Indeed, CYP 11A1 and CYP 27A1 could contribute to the preservation of the mitochondrial integrity by limiting the formation and enhancing elimination of toxic oxysterols. Further studies are required to explore whether modulation of these mitochondrial CYP could really produce cardioprotection in the human heart.

The hepatitis C virus may lead to cirrhosis, liver cancer, liver transplant, and increased mortality. With standard treatment peginterferon-alpha and ribavirin (PR), sustained viral response (SVR) was less than 50 %. SVR rates improve greatly when PR is combined with telaprevir or boceprevir. The aim of this study was to assess the cost utility of telaprevir-peginterferon-ribavirin (TPR) versus PR and boceprevir-peginterferon-ribavirin (BPR) in treatment-naive (TN) and treatment-experienced (TE) adults with chronic hepatitis C in the Netherlands. A Markov model with a lifelong time horizon and annual cycles was developed. Clinical data stemmed from phase III trials (TPR vs PR, BPR vs PR). A mixed treatment comparison (MTC) was developed to compare TPR and BPR indirectly. Unit costs and utilities based on EQ-5D were established in a Dutch cross-sectional study. Cost per quality-adjusted life-years (QALYs) was calculated according to the societal perspective. Treating TN patients with TPR generates 1.12 additional QALYs with €333 additional cost compared with PR, resulting in an incremental cost–utility ratio of €299/QALY. In TE patients, TPR dominates PR with cost savings (−€7,819) and 1.63 additional QALYs. TPR dominates BPR yielding additional QALYs (0.26 in TN; 0.71 in TE) and cost savings (−€7,296, −€18,144, respectively). TPR seems a cost-effective alternative to PR in TN patients and dominant in TE patients. TPR was a dominant, more effective and less costly alternative to BPR in both patient types. The cost effectiveness of both TPR and BPR is well below generally accepted willingness-to-pay thresholds and may be considered cost effective.

cAMP signaling can both promote and inhibit myogenic differentiation, but little is known about the mechanisms mediating promyogenic effects of cAMP. We previously demonstrated that the cAMP response element-binding protein (CREB) transcriptional target salt-inducible kinase 1 (SIK1) promotes MEF2 activity in myocytes via phosphorylation of class II histone deacetylase proteins (HDACs). However, it was unknown whether SIK1 couples cAMP signaling to the HDAC-MEF2 pathway during myogenesis and how this response could specifically occur in differentiating muscle cells. To address these questions, we explored SIK1 regulation and function in muscle precursor cells before and during myogenic differentiation. We found that in primary myogenic progenitor cells exposed to cAMP-inducing agents, Sik1 transcription is induced, but the protein is rapidly degraded by the proteasome. By contrast, sustained cAMP signaling extends the half-life of SIK1 in part by phosphorylation of Thr475, a previously uncharacterized site that we show can be phosphorylated by PKA in cell-free assays. We also identified a functional PEST domain near Thr475 that contributes to SIK1 degradation. During differentiation of primary myogenic progenitor cells, when PKA activity has been shown to increase, we observe elevated Sik1 transcripts as well as marked accumulation and stabilization of SIK1 protein. Depletion of Sik1 in primary muscle precursor cells profoundly impairs MEF2 protein accumulation and myogenic differentiation. Our findings support an emerging model in which SIK1 integrates cAMP signaling with the myogenic program to support appropriate timing of differentiation.

To assess the burden of disease associated with advanced breast cancer (ABC) treated with oral (VinO) or intravenous vinorelbine (VinIV) from the perspective of patients and caregivers in five European countries.This was an observational, prospective, international, multicenter study. Patients were included in the study at the beginning of their second cycle of chemotherapy with vinorelbine and categorized into two groups depending on whether they received VinO or VinIV. At baseline (V0) and at the end of the second cycle of chemotherapy (V1), patients and caregivers were asked to complete self-administered questionnaires: SF-12 and burden of disease.At baseline, the two groups were well balanced in demographic and clinical characteristics. However, while HER2+ (human epidermal growth factor receptor 2) disease was significantly more frequent in patients receiving VinIV, patients receiving VinO were predominantly treated with single-agent therapy and were older than those treated with VinIV (67.1 years versus 57.7 years [p = 0.05]). As measured with SF-12, patients with VinO had, at end of cycle 1 and end of cycle 2, significantly more favorable outcomes in physical summary score, role physical, role emotional and mental health (all p 0.05) than those treated with VinIV. Trends for a better caregiver mental score and social functioning were also observed with VinO (cycle 1 and 2; p 0.10). From a patient perspective, no major difference was reported on the burden of disease between the two groups, however, a trend for a better" overall impact on daily life" was observed in VinO patients. Major significant differences, showing a lower burden of disease with VinO, were also reported from caregivers. In addition, in patients treated with VinO, mental score was almost similar to the one of the general population.VinO showed benefits over VinIV for both patients and caregivers, particularly in health related quality of life and burden of disease. Because of its observational design, results are only informative.

Summary The cardioprotective effect of therapeutic hypothermia (32–34 °C) has been well demonstrated in animal models of acute myocardial infarction. Beyond infarct size reduction, this protection was associated with prevention of the no-reflow phenomenon and long-term improvement in terms of left ventricular remodelling and performance. However, all these events were observed when hypothermia was induced during the ischaemic episode, and most benefits virtually vanished after reperfusion. This is consistent with clinical findings showing a lack of benefit from hypothermia in patients presenting acute myocardial infarction in most trials. In these studies, hypothermia was most often achieved too far into the reperfusion phase (i.e. possibly too late to reduce infarct size); this is supported by meta-analyses and subgroup analyses suggesting that the benefits of hypothermia could still be observed in patients with a large infarction and more rapid cooling before reperfusion. Novel strategies for ultra-fast induction of hypothermia and/or prehospital cooling might therefore be more beneficial.

Purpose: Gangliosides are glycosphingolipids that are particularly abundant in the nervous system, including the retina. However, their precise role in this tissue and its pathologies remain poorly understood. The objective of the present study was to characterize the ganglioside profile of human plasma and to determine whether it is affected in age-related macular degeneration (AMD). Methods: Eighty-three subjects were included: control subjects (n = 25), atrophic AMD patients (n = 27) and exudative AMD patients (n = 31). For each subject, gangliosides were extracted from plasma and analyzed by liquid chromatography coupled to mass spectrometry. Results: GM3 appeared to be by far the major ganglioside of human plasma, associated with GD3. No specific ganglioside class was detected in the plasma of AMD patients. Fourteen molecular species of GM3 and 9 species of GD3, accounting for the variability of the ceramide moiety of the ganglioside molecule, were identified and characterized. Analyses revealed no significant differences in the proportion of these species between control, atrophic and exudative AMD patient groups. Total GM3 levels did not differ either. Conclusion: Although gangliosides are considered important for the retina's structure and function, it seems that circulating gangliosides are not associated with the retinal damage occurring during the course of AMD.

Among organ systems, skeletal muscle is perhaps the most structurally specialized. The remarkable subcellular architecture of this tissue allows it to empower movement with instructions from motor neurons. Despite this high degree of specialization, skeletal muscle also has intrinsic signaling mechanisms that allow adaptation to long-term changes in demand and regeneration after acute damage. The second messenger adenosine 3′,5′-monophosphate (cAMP) not only elicits acute changes within myofibers during exercise but also contributes to myofiber size and metabolic phenotype in the long term. Strikingly, sustained activation of cAMP signaling leads to pronounced hypertrophic responses in skeletal myofibers through largely elusive molecular mechanisms. These pathways can promote hypertrophy and combat atrophy in animal models of disorders including muscular dystrophy, age-related atrophy, denervation injury, disuse atrophy, cancer cachexia, and sepsis. cAMP also participates in muscle development and regeneration mediated by muscle precursor cells; thus, downstream signaling pathways may potentially be harnessed to promote muscle regeneration in patients with acute damage or muscular dystrophy. In this review, we summarize studies implicating cAMP signaling in skeletal muscle adaptation. We also highlight ligands that induce cAMP signaling and downstream effectors that are promising pharmacological targets.

International audience; The objective of this work was to detect and identify phosphatidylserine plasmalogen species in human ocular neurons represented by the retina and the optic nerve. Plasmalogens (vinyl-ether bearing phospholipids) are commonly found in the forms of phosphatidylcholine and phosphatidylethanolamine in numerous mammalian cell types, including the retina. While their biological functions are still unclear, the alteration of cellular plasmalogen content has been associated with several human disorders such as Rhizomelic Chondrodysplasia Punctata Type 2 and Primary Open-Angle Glaucoma.By using liquid-chromatography coupled to high resolution and tandem mass spectrometry, we have identified for the first time several species of phosphatidylserine plasmalogens including atypical forms having moieties with odd numbers of carbons and unsaturation in sn-2 position. Structural elucidation of the potential phosphatidylserine ether linked species was pursued by performing MS3 experiments and three fragments are proposed as marker ions to deduce which fatty acid is linked as ether or ester on the glycerol backbone. Interpretation of the fragmentation patterns based on this scheme enabled the assignment of structures to the m/z values this way identifying the phosphatidylserine plasmalogens.

Background— Increased permeability, predominantly controlled by endothelial junction stability, is an early event in the deterioration of vascular integrity in ischemic disorders. Hemorrhage, edema, and inflammation are the main features of reperfusion injuries, as observed in acute myocardial infarction (AMI). Thus, preservation of vascular integrity is fundamental in ischemic heart disease. Angiopoietins are pivotal modulators of cell–cell junctions and vascular integrity. We hypothesized that hypoxic induction of angiopoietin-like protein 4 (ANGPTL4) might modulate vascular damage, infarct size, and no-reflow during AMI. Methods and Results— We showed that vascular permeability, hemorrhage, edema, inflammation, and infarct severity were increased in angptl4 -deficient mice. We determined that decrease in vascular endothelial growth factor receptor 2 (VEGFR2) and VE-cadherin expression and increase in Src kinase phosphorylation downstream of VEGFR2 were accentuated after ischemia-reperfusion in the coronary microcirculation of angptl4 -deficient mice. Both events led to altered VEGFR2/VE-cadherin complexes and to disrupted adherens junctions in the endothelial cells of angptl4 -deficient mice that correlated with increased no-reflow. In vivo injection of recombinant human ANGPTL4 protected VEGF-driven dissociation of the VEGFR2/VE-cadherin complex, reduced myocardial infarct size, and the extent of no-reflow in mice and rabbits. Conclusions— These data showed that ANGPTL4 might constitute a relevant target for therapeutic vasculoprotection aimed at counteracting the effects of VEGF, thus being crucial for preventing no-reflow and conferring secondary cardioprotection during AMI.

Mild hypothermia, 32-35° C, is very potent at reducing myocardial infarct size in rabbits, dogs, sheep, pigs, and rats. The benefit is directly related to reduction in normothermic ischaemic time, supporting the relevance of early and rapid cooling. The cardioprotective effect of mild hypothermia is not limited to its recognized reduction of infarct size, but also results in conservation of post-ischaemic contractile function, prevention of no-reflow or microvascular obstruction, and ultimately attenuation of left ventricular remodelling. The mechanism of the anti-infarct effect does not appear to be related to diminished energy utilization and metabolic preservation, but rather to survival signalling that involves either the extracellular signal-regulated kinases and/or the Akt/phosphoinositide 3-kinase/mammalian target of rapamycin pathways. Initial clinical trials of hypothermia in patients with ST-segment elevation myocardial infarction were disappointing, probably because cooling was too slow to shorten normothermic ischaemic time appreciably. New approaches to more rapid cooling have recently been described and may soon be available for clinical use. Alternatively, it may be possible to pharmacologically mimic the protection provided by cooling soon after the onset of ischaemia with an activator of mild hypothermia signalling, e.g. extracellular signal-regulated kinase activator, that could be given by emergency medical personnel. Finally, the protection afforded by cooling can be added to that of pre- and post-conditioning because their mechanisms differ. Thus, myocardial salvage might be greatly increased by rapidly cooling patients as soon as possible and then giving a pharmacological post-conditioning agent immediately prior to reperfusion.

To compare 2-year neodymium:YAG (Nd:YAG) laser capsulotomy rates after bilateral implantation of hydrophobic or hydrophilic multifocal intraocular lenses (IOLs).Private practice, southwest France.This retrospective study included patients with cataract or clear lenses who had bilateral implantation of AcrySof ReSTOR hydrophobic or Acri.LISA hydrophilic acrylic multifocal IOLs between May 2004 and June 2009 by the same surgeon at 1 clinic. Data were extracted from patients' files maintained by the surgeon and ophthalmologists involved in postoperative care. Time from IOL implantation to Nd:YAG laser capsulotomy was analyzed with Kaplan-Meier survival curves. Imbalances in confounding variables were adjusted with a Cox model.The hydrophobic IOL group comprised 80 patients and the hydrophilic IOL group, 76 patients. There were significantly more men in the hydrophobic group (51.3%) than in the hydrophilic group (30.7%) and patients were significantly younger in the hydrophobic group (63.0 years versus 65.8 years) (both P.01). Eighteen months postoperatively, 4.4% of eyes in the hydrophobic group and 14.6% of eyes in the hydrophilic group required Nd:YAG laser capsulotomy. After 24 months, the respective rates were 8.8% and 37.2% (P.0001). Eyes in the hydrophilic group had a 4.50-fold (2.28 versus 8.91) higher risk for Nd:YAG laser capsulotomy (P.0001) that persisted after adjusting for age (relative risk 4.64, 2.32 to 9.29) (P.0001). Patients younger than 63.5 years in the hydrophilic group were more likely to require Nd:YAG laser capsulotomy.Capsulotomy was significantly less frequent after hydrophobic IOL implantation than after hydrophilic IOL implantation 24 months postoperatively.No author has a financial or proprietary interest in any material or method mentioned. An additional disclosure is found in the footnotes.

Purpose: To develop a patient self-administered questionnaire assessing the added value of complete independence from spectacles (hereafter referred to as glasses) after multifocal intraocular lens (IOL) surgery. Methods: Exploratory interviews with five cataract patients and six presbyopic patients with AcrySof ReSTOR IOLs (Alcon Laboratories Inc) implanted in both eyes for at least 6 months were conducted. The questionnaire’s conceptual framework was developed after interview analysis. Based on the identified concepts, items were generated simultaneously in French and Spanish using patients’ own words, and comprehension tested with six French patients; the Spanish questionnaire underwent clinician review and was further tested with four Spanish patients. French and Spanish versions were accordingly refined. The questionnaire was linguistically validated in UK English and Danish. Results: Interview analysis resulted in the identification of 9 global concepts: global vision, practical constraints related to wearing glasses, impact of eye surgery on the patient’s life, improvement of practical issues without glasses, improvement of psychological constraints without glasses, physical appearance/aesthetic aspect, self-image and in the eyes of others, eyesight problems left behind after surgery, and recommendation of surgery to others. The initial version of the test questionnaire contained 23 items; 2 items were deleted and changes were made after clinician review and patient testing. The final questionnaire named Freedom from Glasses Value Scale (FGVS) contained 21 items and four general additional questions. Conclusions: Beyond functional aspects, this qualitative study identified additional benefits in cataract and presbyopic patients living free of glasses after receiving multifocal IOLs. The FGVS now needs to be psychometrically validated (eg, construct validity and reliability).

Purpose To estimate the lifetime cost consequences for society and the National Health Service (NHS) of bilateral monofocal (SI40NB) or multifocal (ReSTOR or Array-SA40) intraocular lense (IOL) implantation after cataract surgery. Setting Public hospital in the Netherlands. Methods A Markov model simulated three cohorts of patients followed 69 until 100 years of age, or death. Spectacle independence rates for each IOL were adjusted to the results of a randomized clinical trial that compared monofocal and multifocal Array-SA40 IOL implants, together with a prospective cohort of patients implanted with ReSTOR. Adjustment was performed using the propensity score method in a multivariate analysis. Resource consumption was estimated from a dedicated Dutch survey. Dutch unit costs were applied to spectacles, cataract surgery, IOLs, visits to ophthalmologists, optometrists, transport, and spectacle cleaning materials. Cost discounted at 4% and undiscounted economic results were calculated. Results Spectacle independence rates were 86.0% for ReSTOR, 8.7% for monofocal IOLs, and 8.5% for Array-SA40. Patients lived without needing spectacles for 12.9 years after ReSTOR, for 1.4 years after monofocal IOLs, and 1.3 years after Array-SA40. ReSTOR patients bought 6.4 fewer pairs of spectacles than monofocal patients. Lifetime discounted cost consequences for the society were ReSTOR (sic)3969, monofocal IOLs (sic)4123, and Array-SA40 (sic)5326. Corresponding costs for the NHS were (sic)2415, (sic)2555, and (sic)2556, respectively. Conclusions ReSTOR IOLs provided higher levels of spectacle independence than monofocal SI40NB or multifocal Array-SA40 IOLs resulting in savings, compared to a monofocal, over the period modelled of (sic)315 for society and (sic)140 for the NHS. Eye (2010) 24, 663-672; doi:10.1038/eye.2009.151; published online 3 July 2009

To compare the lifetime costs of freeing astigmatic patients from spectacles after bilateral cataract surgery implanting toric intraocular lenses (IOLs: i.e., Acrysof Toric) versus monofocal IOLs, in France, Italy, Germany and Spain.A Markov model followed patient cohorts from cataract surgery until death. Prevalence rates of patients not needing spectacles and the types of spectacles prescribed for those requiring them were obtained from clinical trials and national surveys. The economic perspective was societal. Mortality rates were incorporated into the model. Discount rates were applied. A sensitivity analysis was performed on non-discounted costs.Fewer patients with toric IOLs needed spectacles for distance vision than patients with monofocal IOLs. With monofocal IOLs more than 66% of patients needed complex spectacles compared to less than 25% implanted with toric IOLs. In France and Italy, toric IOLs reduced overall costs relative to otherwise high spectacle costs after cataract surgery. Savings were 897.0 euros (France), 822.5 euros (Germany), 895.8 euros (Italy) and 391.6 euros (Spain), without discounting. On applying a 3% discount rate the costs became 691.7 euros, 646.4 euros, 693.9 euros and 308.2 euros, respectively.Bilateral toric IOL implants in astigmatic patients decreased spectacle dependence for distance vision and the need for complex spectacles. The economic consequences for patients depended on the national spectacle costs usually incurred after cataract surgery.

PURPOSE: To report results of the National French Observational Database for Endophthalmitis (Observatoire National Des Endophtalmies [ONDE]). SETTING: Departments of ophthalmology at universities, general hospitals, and private clinics. METHODS: In this multicenter national interventional case series, data were collected prospectively between March 1, 2003, and November 1, 2004, from French ophthalmologists who answered a standardized 175-item questionnaire. The data were from patients with acute-onset endophthalmitis after cataract surgery. Before surgery, all 105 patients had received an official information card from the French Ophthalmological Society and provided written informed consent. RESULTS: The study comprised 105 patients. The median time from cataract extraction to endophthalmitis was 4 days (range 1 to 39 days). All but 1 patient had symptoms, with blurred vision being the most common. Initial visual acuity was 5/200 or better in 18.9% (18/95) of patients. Intraocular samples from 90.5% (95/105) of patients yielded 45 pathogens, of which 86.7% were gram positive. Treatments included intraocular antibiotic injections in 95.1% (98/103) of patients, intraocular steroid injections in 41.4% (41/99) of patients, and immediate vitrectomy in 14.0% (14/100) of patients. Visual acuity at 3 months was 20/100 in 64% of patients. CONCLUSIONS: The ONDE study disclosed important changes in French ophthalmic surgical practice 15 years after the first prospective endophthalmitis survey and 12 years after a United States study were published. Progress toward standardization of preventive methods (eg, patient information, increased systemic antibiotic efficacy, more frequent corticosteroid use) has contributed to fewer vitrectomies.

To estimate the lifetime economic consequences of glaucoma in France.A Markov model estimated the average discounted outcome and cost of glaucoma treatment over a patient's lifetime. Clinical states were defined as first- to fourth-line drugs, no treatment, laser therapy, surgery, blindness and death. After each failure (always after the fourth-line drug) patients could receive either laser treatment or surgery followed by no treatment, or a new treatment. A societal perspective was adopted. Sensitivity analyses were performed.Discounted medical costs were euro 7,322 for ocular hypertension treatment (OHT) and euro 8,488 for a glaucoma patient. Social costs of OHT and glaucoma patients exceeded medical costs. First-line use of the most effective drug would reduce medical and social costs. Societal willingness to pay for the vision benefit would equal the medical costs. Treatment initiated with the most effective drug is a cost saving strategy.Public health decisions in glaucoma treatment should take a broad economic view embracing the lifetime duration of the disease. There is still a place both within and outside the healthcare system for therapeutic innovations with important economic consequences that bring high added value to patients.

To compare the lifetime cost consequences, in France, Italy, Germany and Spain, of liberating presbyopic patients from spectacles by implanting the multifocal intraocular lens ReSTOR.A Markov model was created to compare a patient cohort implanted with ReSTOR at age 45 years, with a cohort using spectacles, until death or age 100 years. Prevalence rates of patients not requiring spectacles after surgery were obtained from clinical trials. Resource utilisation included implant surgery, spectacles, visits to ophthalmologists and optic centres, transport and time lost by patients. Economic perspectives were those of society and sickness funds. Mortality rates were introduced into the model. Cataract surgery was allowed just for the spectacles-only cohort.Rate of spectacle independence was fixed at 80% for ReSTOR. When time spent to care for refraction was not taken into account, lifelong ReSTOR cost was higher than spectacles in all countries (293 euro; 1013 euro), according to the societal perspective. When time was included, cost saving was observed in Italy (136 euro) and the incremental cost to be free of spectacles comprised between \[euro]11 and \[euro]816. According to the NHS perspective, ReSTOR is a cost saving strategy (-274 euro; -605 euro).At a 3% discount rate, savings achieved by liberating patients from spectacles counterbalanced partially the initially higher cost of ReSTOR according to the society perspective. ReSTOR could be considered as cost-effective in the four countries provided that the willingness to pay of patients to be free of spectacles would be lower than 23.65 euro/year.

To compare the effectiveness and associated costs of carbonic anhydrase inhibitors + beta-blocker versus alpha-2 adrenergic agonists + beta-blocker in glaucoma therapy, as documented by The United Kingdom General Practitioner Research Database (UK-GPRD).Patient chart analysis.Patient records were screened for diagnoses of ocular hypertension or glaucoma, and for surgery, laser therapy or medication specific to glaucoma. Selected patients were those prescribed either carbonic anhydrase inhibitors + beta-blocker or alpha-2 adrenergic agonists + beta-blocker. Treatment failure was defined as a glaucoma prescription change, i.e. addition, cessation or replacement of medication, surgery or laser therapy. Times to treatment failure were compared with an adjusted Cox model.Treatment persistence and cost.Included patients were those treated with either carbonic anhydrase inhibitors + beta-blocker (n = 5581) or alpha-2 adrenergic agonists + beta-blocker (n = 1164). The average age at diagnosis was 68.1 years and 48.2% were male. Treatment failure at one year was significantly (p0.001) less frequent after carbonic anhydrase inhibitors + beta-blocker (57% of patients) than after alpha-2 adrenergic agonists + beta-blocker (64.3%). The hazard ratio for failure was lower (0.82: p0.0001) with carbonic anhydrase inhibitors + beta-blocker following adjustment for age, gender, comorbidities and duration of follow-up. Adjusted annual costs of glaucoma management were pound 348.04 for carbonic anhydrase inhibitors + beta-blocker and pound 356.80 for alpha-2 adrenergic agonists + beta-blocker.According to UK-GPRD information, glaucoma therapy with carbonic anhydrase inhibitors + beta-blocker is more persistent than with alpha-2 adrenergic agonists + beta-blocker at a similar cost.

Control of intraocular pressure (IOP) is a major factor in avoiding visual impairment related to glaucoma. Both the cost and the effectiveness of therapy should be considered when initiating this lifelong treatment. The aim of this study was to assess the cost effectiveness of travoprost versus latanoprost as single agents for the treatment of glaucoma in France.Two surveys, one documenting efficacy and the other costs, were used to provide data for a Markov model. The model reproduced the 5-year course of patients receiving a prostaglandin analogue, travoprost or latanoprost, as monotherapy. The effectiveness criterion was fitted with a Weibull distribution from a national study. Transition probabilities and costs per treatment line were extracted from two French observational databases. Bootstrap techniques were implemented to drive the probabilistic sensitivity analyses. The study compared both treatments given once daily as monotherapy to ambulatory patients with primary open-angle glaucoma or ocular hypertension. The main outcome measure was mean time to treatment change (MTTC). Possible treatment changes were the addition of adjunctive medication, treatment substitution, laser therapy or surgery. After laser therapy or surgery, patients could continue with no treatment or proceed to prostaglandin analogue as monotherapy or treatment substitution. IOP was stratified at treatment onset asor =20, 21-23 andor =24 mmHg, respectively. All costs were expressed in 2005 euros.MTTC was 44.3 months for travoprost and 37.8 for latanoprost. Additional 5-year costs for travoprost were euro51, resulting in an incremental cost-effectiveness ratio without treatment change of euro95 per year. Of patients treated with latanoprost, 1.9% underwent laser therapy or surgery, compared with 1.2% of patients treated with travoprost. The results differed with baseline IOP values, such that 55.6%, 53.9% and 50.4% of patients with pretreatment IOP values ofor =20, 21-23 andor =24 mmHg, respectively, continued to receive travoprost treatment at 5 years, compared with 32.3%, 26.1% and 26.1% of patients, respectively, receiving latanoprost. Thus, incremental cost-effectiveness ratios (ICERs) without treatment change were euro140, euro45 and euro123 per year, respectively.Travoprost demonstrated a longer effectiveness profile than latanoprost and minimized early treatment changes. The smaller proportion of patients needing a new treatment, laser therapy or surgery virtually compensated for the higher travoprost acquisition cost. Overall, travoprost is cost effective compared with latanoprost, and is most cost effective in patients with pretreatment IOPs between 21 and 23 mmHg.

The aim of this study was to confirm randomized clinical trial results showing that a fixed timolol/travoprost combination (TT; DuoTrav) controls intraocular pressure (IOP) better than a fixed timolol/latanoprost combination (TL; Xalacom) in everyday ophthalmic practice, when measured in the morning and24 hours after instillation.Patients with ocular hypertension or primary open angle glaucoma stabilized on TT or TL were included in this retrospective cross-sectional study. Data on demographics, medical history and previous treatments were extracted from the patients' medical records. Last treatment instillation times and IOP values were recorded at clinic visits. Treatments were compared by analyses of variance, logistic regressions and propensity scores adjusted for confounding factors.Out of 316 patients included, 124 instilled TT, 192 instilled TL and 266 (84.2%) overall had instilled their eye drops within 24 hours. The patients' mean age was 64.5 years and 51.6% were female. Treatment groups were comparable except for longer disease and treatment durations in TL recipients. Worse eye mean IOPs were 25.8 mmHg at diagnosis and 21.9 mmHg on starting their designated fixed combination treatment. The best IOP control was provided by TT instillations (mean IOP 17.1 and 19.0 mmHg in the TT and TL groups, respectively; p0.001). This difference was reinforced by results in the subgroup of patients who instilled treatment24 hours prior to IOP measurement (mean IOP 17.0 and 20.3 mmHg in the TT and TL groups, respectively; p0.004). Also, 82.6% of TT patients satisfied their ophthalmologists' IOP targets versus 51.1% of TL patients (p0.001). All significant differences persisted after adjustment for confounding factors.This study, conducted in routine ophthalmic practice, confirmed published clinical trial results showing that TT provides better IOP control than TL when measured in the morning, and that travoprost has longer-lasting residual effects than latanoprost when IOP is measured24 hours after instillation. However, readers should interpret these findings in the context of a cross-sectional observational study conducted in a naturalistic setting.

AIM: The MITOCARE study evaluated the efficacy and safety of TRO40303 for the reduction of reperfusion injury in patients undergoing revascularization for ST-elevation myocardial infarction (STEMI).METHODS: Patients presenting with STEMI within 6 h of the onset of pain randomly received TRO40303 (n = 83) or placebo (n = 80) via i.v. bolus injection prior to balloon inflation during primary percutaneous coronary intervention in a double-blind manner. The primary endpoint was infarct size expressed as area under the curve (AUC) for creatine kinase (CK) and for troponin I (TnI) over 3 days. Secondary endpoints included measures of infarct size using cardiac magnetic resonance (CMR) and safety outcomes.RESULTS: The median pain-to-balloon time was 180 min for both groups, and the median (mean) door-to-balloon time was 60 (38) min for all sites. Infarct size, as measured by CK and TnI AUCs at 3 days, was not significantly different between treatment groups. There were no significant differences in the CMR-assessed myocardial salvage index (1-infarct size/myocardium at risk) (mean 52 vs. 58% with placebo, P = 0.1000), mean CMR-assessed infarct size (21.9 g vs. 20.0 g, or 17 vs. 15% of LV-mass) or left ventricular ejection fraction (LVEF) (46 vs. 48%), or in the mean 30-day echocardiographic LVEF (51.5 vs. 52.2%) between TRO40303 and placebo. A greater number of adjudicated safety events occurred in the TRO40303 group for unexplained reasons.CONCLUSION: This study in STEMI patients treated with contemporary mechanical revascularization principles did not show any effect of TRO40303 in limiting reperfusion injury of the ischaemic myocardium.

Intraocular pressure (IOP) is known to be subject to daily fluctuations, the occurrence of which is a risk factor for progression of glaucoma. Control of IOP during the day by drugs is an important therapeutic target. We set out to compare the IOP control of travoprost and latanoprost taking into account the time since last instillation and the time of IOP measurement.This was a prospective, cross-sectional observational study with some retrospective data collection. Private ophthalmologists were selected to each recruit ten patients with primary open-angle glaucoma and/or ocular hypertension receiving either travoprost or latanoprost as monotherapy. Clinical endpoints included IOP measurements and percentage of patients attaining predefined target IOPs. Six patient subgroups were defined according to: (a) IOP measurement time: before 1200h, 1200h-1600h and after 1600h, and (b) time since last intake (24 hours,24 hours). Analyses comprised chi(2) and Wilcoxon tests, ANOVA, logistic regressions and adjustment by propensity score.In total, 2052 patients treated with travoprost (n = 1704) or latanoprost (n = 348) participated in the study. Treatment groups were comparable at baseline, except for a longer treatment duration in latanoprost-treated patients. When the interval between the last treatment instillation and IOP measurement (treatment/IOP interval) was24 hours (n = 1241), 82% of travoprost-treated patients attained pre-defined target IOP versus 67% with latanoprost (p0.0001). This difference was greatest after 1600 h, when the mean IOP was 16.5 mm Hg for travoprost-treated patients and 17.7 mm Hg for latanoprost-treated patients (p = 0.0025). When the treatment/IOP interval was24 hours (n = 461), travoprost was superior to latanoprost, i.e. more patients using travoprost attained the predefined target IOP (78.5% vs 68.3%; p = 0.0344), and the mean IOP value was lower in the travoprost group (16.8 vs 17.8 mm Hg; p = 0.0016). After adjustments for confounding factors, similar results were obtained.According to this observational survey, travoprost appears to reduce evening and mean diurnal IOP more effectively than latanoprost. Latanoprost IOP control appears to be more sensitive to time since the last dose.

The treatment of Parkinson's disease (PD) with l-DOPA leads to involuntary movements (dyskinesias). This 6-month observational study in three European countries in PD patients with various degrees of motor complications examined the effects of dyskinesias on the quality of life (QoL) of patients and health care costs. Retrospective and prospective health economic data were collected, and QoL of patients was measured using the Short Form-36 (SF-36) and the PD Quality of Life (PDQL) Scale. Regression analysis was used to estimate the adjusted effects of dyskinesias on QoL and costs, whilst accounting for the potentially confounding effects of disease progression, motor fluctuations and country. Increasing dyskinesia scores on either the Unified PD Rating Scale or the Goetz Dyskinesia Rating Scale were associated with significant reductions in QoL scores on the SF-36 and PDQL Scale. Increasing dyskinesia severity was also associated with increased depression scores on the Montgomery-Asberg Depression Rating Scale along with significant increases in health care costs. The effects of dyskinesia on QoL, depression and costs decreased but remained significant after adjustment for the confounding effects of disease progression and motor fluctuations. In conclusion, dyskinesias may adversely affect QoL and increase health care costs in patients with PD. Future studies should evaluate the potentially beneficial effects in terms of QoL and health care costs of strategies to delay the onset of, or the treatment of, dyskinesias.

To quantify the clinical outcome of glaucoma treatment over a patient's lifetime to identify treatment parameters that would preserve vision across a population.A Markov model was used to reproduce glaucoma treatments and clinical responses over a patient's lifetime. Markov states comprised first-line to fourth-line pharmacological treatments, no treatment, laser therapy, surgery, blindness, and death. All patients began with first-line treatment and passed to the next treatment in line following a failure. After each failure, and always after a fourth-line failure, patients could receive laser therapy or surgery, followed by no treatment or a new first-line treatment. Transitional probabilities came from a cross-sectional study and national statistics. Sensitivity analyses were based on second order Monte-Carlo simulation.Cohort demographics were average age 59.7 years, life expectancy 22.5 years, females 54.0%. Treatment durations (months) for a patient with ocular hypertension were first-line (89), second-line (49), third-line (41), and no treatment (44); laser interventions numbered 1.251 and surgical 0.882. For a patient with glaucoma the corresponding values were 70, 44, 40, 18, 42, 1.197, and 0.842. First-line or second-line drugs best at controlling intraocular pressure (IOP) reduced laser therapy, surgery, and the prevalence of blindness. The most effective drug should be prescribed first-line. According to our model drugs specifically able to arrest disease progression would be more beneficial than intraocular pressure control.More powerful glaucoma medication (first-line or second-line) would contribute to the preservation of long-term vision.

To compare the cost-effectiveness of different intra-ocular lens (IOL) materials (Hydrophobic acrylic, Polymethylmethacrylate (PMMA), Hydrophilic acrylic and Silicone) implanted after cataract surgery with reference to Nd:YAG laser capsulotomy and Nd:YAG-related complications in four European countries (France, Italy, Germany and Spain).A retrospective review of 1,525 patients (eyes), aged 50 to 80 years, operated with phacoemulsification for cataract in 1996 or 1997 in 16 surgical centres (4 per country).The study was conducted using a cost-effectiveness approach. Medical charts were reviewed to collect retrospective information during the 3-year period following cataract surgery in order to identify patients who underwent Nd:YAG laser capsulotomy post-operatively. Clinical data were combined with unit costs assessed by experts for Nd:YAG laser capsulotomy and their complications. A cost-effectiveness ratio (cost per patient without Nd:YAG laser capsulotomy intervention) was estimated in relation to each IOL material used in each of the four European countries.Hydrophobic acrylic, specifically Acrysof, was the most cost-effective IOL material in all the countries except Germany where it was second. PMMA had the best ratio in Germany, was second in Spain and only third in Italy and France. Silicone was second in France and ranked third in the other countries, while hydrophilic acrylic had the worst ratio overall in all countries.Cost-effectiveness ratios of hydrophobic acrylic (Acrysof) were better than those of other types of IOL materials used in most of the countries. Sensitivity analyses were performed to vary the base case analysis to demonstrate the economic importance of the assumptions. In all cases, hydrophobic acrylic IOL material was shown to be a highly cost-effective option.

This paper reviews the burden and economic consequences of glaucoma upon healthcare systems and patients, especially elderly patients. An extensive review of the literature was conducted, primarily using MEDLINE, but also by examining selected article reference lists, relevant websites and the proceedings of specialised conferences. All relevant articles and documents were analysed. Glaucoma is characterised by destruction of the optic nerve. It is most often a continuous, chronic eye disease and the most frequent diagnosis is primary open angle glaucoma (POAG). POAG is mostly associated with intraocular hypertension which can be delayed by medication, surgery or laser therapy. The prevalence rate of glaucoma is about 1% in the population50 years of age. The rate increases with age and is higher in Black and Hispanic populations. Glaucoma affects more than 67 million people worldwide. Cost-of-illness studies have shown the importance of this disease, on which more than pound300 million was spent in the UK in 2002. Most of the costs (45%) were associated with direct medical costs, but direct nonmedical costs (20%) and indirect costs (35%) were also not negligible. Recent economic studies have shown a dramatic increase in the number of patients with glaucoma receiving treatment but a reduction in use of surgical procedures to treat the condition, especially as first-line therapy. The greater part of medical expenditure is now on medication, with new, more potent, better tolerated, but more costly drugs replacing older and less expensive medications. Treatment costs are directly related to the severity of disease and the number of different treatments used; they are also negatively correlated with treatment efficacy in reducing intraocular pressure. However, long-term economic benefits that may be associated with use of more potent new drugs (by delaying institutionalisation) have never been documented. Glaucoma screening has also been found not to be cost effective, although these results should be reconsidered in the light of new data.

Transformation of fibroblasts by oncogenic Src causes disruption of actin stress fibers and formation of invasive adhesions called podosomes. Because the small GTPase Rho stimulates stress fiber formation, Rho inactivation by Src has been thought to be necessary for stress fiber disruption. However, we show here that Rho[GTP] levels do not decrease after transformation by activated Src. Inactivation of Rho in Src-transformed fibroblasts by dominant negative RhoA or the Rho-specific inhibitor C3 exoenzyme disrupted podosome structure as judged by localization of podosome components F-actin, cortactin, and Fish. Inhibition of Rho strongly inhibited Src-induced proteolytic degradation of the extracellular matrix. Furthermore, development of an in situ Rho[GTP] affinity assay allowed us to detect endogenous Rho[GTP] at podosomes, where it colocalized with F-actin, cortactin, and Fish. Therefore, Rho is not globally inactivated in Src-transformed fibroblasts, but is necessary for the assembly and function of structures implicated in tumor cell invasion.

Objective: Physicians need reliable, valid and sensitive questionnaires to assess QOL related to glaucoma or ocular hypertension. This article presents the psychometric properties of the French version of the National Eye Institute Visual Function Questionnaire — 25 (NEI VFQ-25). Methods: A mail survey was sent to 20 000 households. The survey identified 581 residents with glaucoma or ocular hypertension. Of these a random sample (n = 204) took part in a telephone survey during which the NEI VFQ-25 was completed by eligible patients (those taking at least one topical treatment for glaucoma or ocular hypertension on the day of the interview). Multi-trait analysis was performed to assess the construct validity of the questionnaire. Internal consistency reliability was assessed using Cronbach’s α and the average inter-item correlation. Known groups validity was assessed by comparing patients grouped by duration of glaucoma, adjusted for age and gender. Results: One hundred and seventy-three patients participated in the survey. Analysis of convergent validity showed that all of the items in each scale correlated above 0.40 with their own scale except for the ‘driving’ scale. The success rate of the discriminant validity ranged from 57.1% to 100% except for the ‘driving’ scale, which was 7.1%. Cronbach’s α coefficients were all above 0.70 except the ‘driving’ score. Participants with glaucoma for less than 20 years consistently had better ‘global’, ‘near vision’, ‘distant vision’, ‘driving’, ’social function’ and ‘peripheral vision’ scores than those with disease of 20+ years duration, indicating better QOL in patients with a shorter disease duration. Conclusion: The NEI VFQ-25 is a validated instrument to measure vision-targeted QOL in French populations with glaucoma.

The oxidised derivatives of phytosterols (oxyphytosterols) were identified in plasma samples from thirteen healthy human volunteers, using MS. All the samples contained noticeable quantities of (24R)-5b,6b-epoxy-24-ethylcholestan-3b-ol (b-epoxysitostanol) and (24R)-ethylcholestan-3b,5a,6b-triol (sitostanetriol) and also trace levels of (24R)-5a,6a-epoxy-24-ethylcholestan-3b-ol (a-epoxysitostanol), (24R)-methylcholestan-3b,5a,6b-triol (campestanetriol) and (24R)-ethylch olest-5-en-3b-ol-7-one(7-ketositosterol). The amounts of these oxyphytosterols in plasma varied from 4·8 to 57·2 ng/ml. There are two possibilities concerning the origin of these compounds. First, they could come from the small amounts of oxyphytosterols in food. Second, they could originate from the in vivo oxidation of phytosterols in plasma. Very few data actually exist concerning these compounds. Their identification in human samples suggests that further research is necessary in this field. Oxyphytosterols: Phytosterols: Human plasma: Mass spectrometry

Since several years, the interest for chloride channels and more particularly for the enigmatic swelling-activated chloride channel (I(Cl,swell)) is increasing. Despite its well-characterized electrophysiological properties, the I(Cl,swell) structure and pharmacology are not totally elucidated. These channels are involved in a variety of cell functions, such as cardiac rhythm, cell proliferation and differentiation, cell volume regulation and cell death through apoptosis. This review will consider different aspects regarding structure, electrophysiological properties, pharmacology, modulation and functions of these swelling-activated chloride channels.

Objective: Cost is an issue when prescribing two drugs with equivalent efficacy. We compared the direct medical costs of topical brinzolamide 1% (twice a day or three times daily) with topical dorzolamide 2% (twice a day or three times daily) in France, Italy, Portugal and Spain in patients with ocular hypertension or primary open-angle glaucoma. Design and setting: Three double-blind, controlled, randomised trials (with a study duration of 3 months) compared the response rate of brinzolamide twice a day or three times daily versus dorzolamide three times daily, and the response rate of brinzolamide-timolol twice a day versus a dorzolamide-timolol combination twice a day. A fourth double-blind randomised trial (with a duration of 12 months) compared brinzolamide twice a day and three times daily with timolol monotherapy. Local tolerance was compared in two dedicated studies. Rates of switching to a new medication regimen were evaluated through a US health maintenance organisation database. In case of treatment failure, the patients were treated with latanoprost. A model was developed to value direct medical costs over 3 months. The economic perspective was that of the third-party payer and the patient, and included direct medical costs (reimbursed part plus co-payment). Patients: Patients with ocular hypertension and/or primary open-angle glaucoma who had not responded to or could not tolerate β-blocker therapy. Outcome measure: The daily direct medical costs of therapy with the two drugs. Results: As monotherapy, brinzolamide twice daily and three times daily was found to be as efficacious as dorzolamide three times a day. Brinzolamide twice daily plus timolol was also as efficacious as a combination of dorzolamide and timolol twice a day. Stinging of the eye upon instillation with brinzolamide was experienced by fewer patients than with dorzolamide (p < 0.0001). The likelihood of patients treated with dorzolamide changing therapy was 1.28 times greater than that for those treated with brinzolamide. The size of the brinzolamide drop is 18.7% smaller than that of dorzolamide allowing seven more therapy days per bottle with brinzolamide twice daily than with dorzolamide monotherapy, and five more days when brinzolamide is used three times a day. The direct medical costs for patients treated with brinzolamide were lower in all four European countries when drop size was taken into account than for those treated with dorzolamide. Sensitivity analyses confirmed the robustness of our findings. Conclusion: Because brinzolamide can be prescribed twice daily in monotherapy and because fewer patients treated with brinzolamide switch therapy due to local intolerance, our model suggests that brinzolamide is a cost-saving alternative to dorzolamide.

Purpose To compare the societal costs and consequences of 3 strategies to correct mild to moderate myopia: laser in situ keratomileusis (LASIK), eyeglasses, and contact lenses (CLs). Setting Instituto Oftalmologico de Alicante, Alicante, Spain. Methods A Markov model was set up to compare the present value of LASIK, eyeglasses, and CLs. A structured questionnaire was administered to 40 consecutive patients with mild to moderate myopia to collect resource information including direct medical and nonmedical costs as well as indirect costs (transportation, time spent, hotel, eyeglasses, CLs, LASIK, cleaning products, visits to ophthalmologist/optometrist/optical center, and adverse events linked to LASIK and CLs). The time period ranged from 10 to 30 years with a 5% discount rate. The Spanish population was used as the basis for the economic data. Full sensitivity analyses were conducted. Results Based on the time period, LASIK saved from 18 to 278 km in distance to care centers compared with eyeglasses and from 405 to 1436 km compared with CLs. The time to care for visual acuity was similar between LASIK and CLs, but up to 1180 additional hours were spent by CL users. Laser in situ keratomileusis saved from 4.69 to 12.07 eyeglasses and from 28 to 84 eyeglass cleaning packs. With LASIK, there were 18 to 50 visits to the optical center compared with 41 to 117 visits with CLs. Laser in situ keratomileusis saved 4.7 to 12.2 visits to correct visual acuity compared with eyeglasses and CLs. It prevented 95 to 295 per 10 000 cases of CL-related keratitis. Contact lenses were always more costly than LASIK, which was always more costly than eyeglasses. The 2 sensitivity parameters were time period and discount rate. Conclusion Laser in situ keratomileusis was less costly than CLs and more expensive than eyeglasses, although the potential nonmonetary benefit of LASIK over eyeglasses was not taken into account.

Treatments for allergic conjunctivitis have various mechanisms of action. Cromolyn sodium stabilizes conjunctival mast cells by preventing calcium influx across the cell membrane, whereas olopatadine hydrochloride is both an antihistamine and a mast cell stabilizer.This study compared the efficacy and tolerability of olopatadine and cromolyn in controlling the ocular signs and symptoms of seasonal allergic conjunctivitis.This was a multicenter, randomized, double-masked, parallel-group trial. One group instilled olopatadine 0.1% ophthalmic solution and placebo BID, and the other instilled cromolyn 2% ophthalmic solution QID, both for 6 weeks. The formulation of cromolyn used in this study is currently available only in Europe and Australia.The intent-to-treat efficacy and safety analyses included 185 patients, 91 in the olopatadine group and 94 in the cromolyn group. At 30 minutes after the first instillation, respective decreases of approximately 30% and approximately 20% were reported in self-rated ocular itching and redness with both treatments; by 4 hours, itching had decreased by approximately 38% in both groups. Differences between treatments were not statistically significant. At 4 hours, redness had decreased by approximately 38% and approximately 26% in the respective treatment groups. By day 42, both treatments had produced significant reductions from baseline in ocular signs and symptoms; however, the reductions in itching and redness were significantly greater with olopatadine compared with cromolyn (both variables, P0.05). The difference in physicians' impression of overall improvement on days 30 and 42 significantly favored olopatadine over cromolyn (both days, P0.05). Most patients (62.2%) had reacted positively to grass pollen at baseline. The regression slopes correlating itching and redness with pollen count were 5 times lower for olopatadine compared with cromolyn (P = 0.002 and P = 0.016, respectively), indicating that olopatadine's efficacy increased as the pollen count increased.Six weeks' instillation of olopatadine 0.19% ophthalmic solution BID had a significantly greater effect on the ocular signs and symptoms of allergic conjunctivitis compared with 6 weeks' instillation of cromolyn 2% ophthalmic solution QID. Both treatments were well tolerated by patients in all age groups; however, olopatadine appeared to have better local tolerability in children aged11 years.

Background: Long chain polyunsaturated fatty acids (LCPUFAs) including docosahexaenoic acid and arachidonic acid are suspected to play a key role in the pathogenesis of diabetes. LCPUFAs are known to be preferentially concentrated in specific phospholipids termed as plasmalogens. This study was aimed to highlight potential changes in the metabolism of phospholipids, and particularly plasmalogens, and LCPUFAs at various stages of diabetic retinopathy in humans. Methodology and Principal Findings: We performed lipidomic analyses on red blood cell membranes from controls and mainly type 2 diabetes mellitus patients with or without retinopathy. The fatty acid composition of erythrocytes was determined by gas chromatography and the phospholipid structure was determined by liquid chromatography equipped with an electrospray ionisation source and coupled with a tandem mass spectrometer (LC-ESI-MS/MS). A significant decrease in levels of docosahexaenoic acid and arachidonic acid in erythrocytes of diabetic patients with or without retinopathy was observed. The origin of this decrease was a loss of phosphatidyl-ethanolamine phospholipids esterified with these LCPUFAs. In diabetic patients without retinopathy, this change was balanced by an increase in the levels of several phosphatidyl-choline species. No influence of diabetes nor of diabetic retinopathy was observed on the concentrations of plasmalogen-type phospholipids. Conclusions and Significance: Diabetes and diabetic retinopathy were associated with a reduction of erythrocyte LCPUFAs in phosphatidyl-ethanolamines. The increase of the amounts of phosphatidyl-choline species in erythrocytes of diabetic patients without diabetic retinopathy might be a compensatory mechanism for the loss of LC-PUFA-rich phosphatidyl-ethanolamines.