Biological Characterization of Gene Response to Insulin-Induced Hypoglycemia in Mouse Retina.

Glucose is the most important metabolic substrate of the retina and maintenance of normoglycemia is an essential challenge for diabetic patients. Chronic, exaggerated, glycemic excursions could lead to cardiovascular diseases, nephropathy, neuropathy and retinopathy. We recently showed that hypoglycemia induced retinal cell death in mouse via caspase 3 activation and glutathione (GSH) decrease. Ex vivo experiments in 661W photoreceptor cells confirmed the low-glucose induction of death via superoxide production and activation of caspase 3, which was concomitant with a decrease of GSH content. We evaluate herein retinal gene expression 4 h and 48 h after insulin-induced hypoglycemia. Microarray analysis demonstrated clusters of genes whose expression was modified by hypoglycemia and we discuss the potential implication of those genes in retinal cell death. In addition, we identify by gene set enrichment analysis, three important pathways, including lysosomal function, GSH metabolism and apoptotic pathways. Then we tested the effect of recurrent hypoglycemia (three successive 4h periods of hypoglycemia spaced by 48 h recovery) on retinal cell death. Interestingly, exposure to multiple hypoglycemic events prevented GSH decrease and retinal cell death, or adapted the retina to external stress by restoring GSH level comparable to control situation. We hypothesize that scavenger GSH is a key compound in this apoptotic process, and maintaining "normal" GSH level, as well as a strict glycemic control, represents a therapeutic challenge in order to avoid side effects of diabetes, especially diabetic retinopathy

Bis-Retinoid A2E Induces an Increase of Basic Fibroblast Growth Factor via Inhibition of Extracellular Signal-Regulated Kinases 1/2 Pathway in Retinal Pigment Epithelium Cells and Facilitates Phagocytosis.

Age-related macular degeneration (ARMD) is the leading cause of vision loss in developed countries. Hallmarks of the disease are well known; indeed, this pathology is characterized by lipofuscin accumulation, is principally composed of lipid-containing residues of lysosomal digestion. The N-retinyl-N-retinylidene ethanolamine (A2E) retinoid which is thought to be a cytotoxic component for RPE is the best-characterized component of lipofuscin so far. Even if no direct correlation between A2E spatial distribution and lipofuscin fluorescence has been established in aged human RPE, modified forms or metabolites of A2E could be involved in ARMD pathology. Mitogen-activated protein kinase (MAPK) pathways have been involved in many pathologies, but not in ARMD. Therefore, we wanted to analyze the effects of A2E on MAPKs in polarized ARPE19 and isolated mouse RPE cells. We showed that long-term exposure of polarized ARPE19 cells to low A2E dose induces a strong decrease of the extracellular signal-regulated kinases' (ERK1/2) activity. In addition, we showed that A2E, via ERK1/2 decrease, induces a significant decrease of the retinal pigment epithelium-specific protein 65 kDa (RPE65) expression in ARPE19 cells and isolated mouse RPE. In the meantime, we showed that the decrease of ERK1/2 activity mediates an increase of basic fibroblast growth factor (bFGF) mRNA expression and secretion that induces an increase in phagocytosis via a paracrine effect. We suggest that the accumulation of deposits coming from outer segments (OS) could be explained by both an increase of bFGF-induced phagocytosis and by the decrease of clearance by A2E. The bFGF angiogenic protein may therefore be an attractive target to treat ARMD

Associations Between Cardiovascular Risk Factors, Inflammation, and Progression of Carotid Atherosclerosis Among Smokers.

The high risk of cardiovascular events in smokers requires adequate control of other cardiovascular risk factors (CVRFs) to curtail atherosclerosis progression. However, it is unclear which CVRFs have the most influence on atherosclerosis progression in smokers. In 260 smokers aged 40-70 included in a smoking cessation trial, we analyzed the association between traditional CVRFs, high-sensitivity C-reactive protein (hs-CRP), smoking cessation and 3-year progression of carotid intima-media thickness (CIMT, assessed by repeated ultrasound measurements) in a longitudinal multivariate model. Participants (mean age 52 years, 47% women) had a mean smoking duration of 32 years with a median daily consumption of 20 cigarettes. Baseline CIMT was 1185 μm (95% confidence interval [CI]: 1082-1287) and increased by 93 μm (95% CI: 25-161) and 108 μm (95% CI: 33-183) after 1 and 3 years, respectively. Age, male sex, daily cigarette consumption, systolic blood pressure (SBP), but neither low-density lipoprotein cholesterol nor hs-CRP, were independently associated with baseline CIMT (all P ≤ .05). Baseline SBP, but neither low-density lipoprotein cholesterol nor hs-CRP, was associated with 3-year atherosclerosis progression (P = .01 at 3 years). The higher the SBP at baseline, the steeper was the CIMT increase over 3-year follow-up. We found an increase of 26 μm per each 10-mmHg raise in SBP at 1 year and an increase of 39 μm per each 10 mmHg raise in SBP at 3 years. Due to insufficient statistical power, we could not exclude an effect of smoking abstinence on CIMT progression. Control of blood pressure may be an important factor to limit atherosclerosis progression in smokers, besides support for smoking cessation. Among 260 smokers aged 40-70 years with a mean smoking duration of 32 years, baseline SBP was associated with atherosclerosis progression over 3 years, as measured by CIMT (P = .01 at 3 years), independently of smoking variables and other CVRFs. The higher the SBP at baseline, the steeper was the CIMT increase over 3-year follow-up. Our findings emphasize the importance of focusing not only on smoking cessation among smokers, but to simultaneously control other CVRFs, particularly blood pressure, in order to prevent future cardiovascular disease

Hospital revascularisation capability and quality of care after an acute coronary syndrome in Switzerland.

BACKGROUND: Patients with acute coronary syndrome (ACS) transferred to regional nonacademic hospitals after percutaneous coronary intervention (PCI) may receive fewer preventive interventions than patients who remain in university hospitals. We aimed at comparing hospitals with and without PCI facilities regarding guidelines-recommended secondary prevention interventions after an ACS. METHODS: We studied patients with ACS admitted to a university hospital with PCI facilities in Switzerland, and either transferred within 48 hours to regional nonacademic hospitals without PCI facilities or directly discharged from the university hospital. We measured prescription rates of evidence-based recommended therapies after ACS including reasons for nonprescription of aspirin, statins, β-blockers, angiotensin converting-enzyme inhibitors (ACEI) / angiotensin II receptor blockers (ARB), along with cardiac rehabilitation attendance and delivery of a smoking cessation intervention. RESULTS: Overall, 720 patients with ACS were enrolled; 541 (75.1%) were discharged from the hospital with PCI facilities, 179 (24.9%) were transferred to hospitals without PCI facilities. Concomitant prescription of aspirin, β-blockers, ACEI/ARB and statins at discharge was similar in hospitals with and without PCI facilities, reaching 83.9% and 85.5%, respectively (p = 0.62). Attendance at cardiac rehabilitation reached 55.5% for the hospital with PCI facilities and 65.7% for hospitals without PCI facilities (p = 0.02). In-hospital smoking cessation interventions were delivered to 70.8% patients exclusively at the hospital with PCI facilities. CONCLUSION: Quality of care for patients with ACS discharged from hospitals without PCI facilities was similar to that of patients directly discharged from the hospital with PCI facilities, except for in-hospital smoking cessation counselling and cardiac rehabilitation attendance

A Just-in-Time Document Retrieval System for Dialogues or Monologues

The Automatic Content Linking Device is a just-in-time document retrieval system that monitors an ongoing dialogue or monologue and enriches it with potentially related documents from local repositories or from theWeb. The documents are found using queries that are built from the dialogue words, obtained through automatic speech recognition. Results are displayed in real time to the dialogue participants, or to people watching a recorded dialogue or a talk. The system can be demonstrated in both settings

Comparative Study on Sentence Boundary Prediction for German and English Broadcast News

We present a comparative study on sentence boundary prediction for German and English broadcast news that explores generalization across different languages. In the feature extraction stage, word pause duration is firstly extracted from word aligned speech, and forward and backward language models are utilized to extract textual features. Then a gradient boosted machine is optimized by grid search to map these features to punctuation marks. Experimental results confirm that word pause duration is a simple yet effective feature to predict whether there is a sentence boundary after that word. We found that Bayes risk derived from pause duration distributions of sentence boundary words and non-boundary words is an effective measure to assess the inherent difficulty of sentence boundary prediction. The proposed method achieved F-measures of over 90% on reference text and around 90% on ASR transcript for both German broadcast news corpus and English multi-genre broadcast news corpus. This demonstrates the state of the art performance of the proposed method

Uptake and efficacy of a systematic intensive smoking cessation intervention using motivational interviewing for smokers hospitalised for an acute coronary syndrome: a multicentre before-after study with parallel group comparisons.

To compare the efficacy of a proactive approach with a reactive approach to offer intensive smoking cessation intervention using motivational interviewing (MI). Before-after comparison in 2 academic hospitals with parallel comparisons in 2 control hospitals. Academic hospitals in Switzerland. Smokers hospitalised for an acute coronary syndrome (ACS). In the intervention hospitals during the intervention phase, a resident physician trained in MI systematically offered counselling to all smokers admitted for ACS, followed by 4 telephone counselling sessions over 2 months by a nurse trained in MI. In the observation phase, the in-hospital intervention was offered only to patients whose clinicians requested a smoking cessation intervention. In the control hospitals, no intensive smoking cessation intervention was offered. The primary outcome was 1 week smoking abstinence (point prevalence) at 12 months. Secondary outcomes were the number of smokers who received the in-hospital smoking cessation intervention and the duration of the intervention. In the intervention centres during the intervention phase, 87% of smokers (N=193/225) received a smoking cessation intervention compared to 22% in the observational phase (p<0.001). Median duration of counselling was 50 min. During the intervention phase, 78% received a phone follow-up for a median total duration of 42 min in 4 sessions. Prescription of nicotine replacement therapy at discharge increased from 18% to 58% in the intervention phase (risk ratio (RR): 3.3 (95% CI 2.4 to 4.3; p≤0.001). Smoking cessation at 12-month increased from 43% to 51% comparing the observation and intervention phases (RR=1.20, 95% CI 0.98 to 1.46; p=0.08; 97% with outcome assessment). In the control hospitals, the RR for quitting was 1.02 (95% CI 0.84 to 1.25; p=0.8, 92% with outcome assessment). A proactive strategy offering intensive smoking cessation intervention based on MI to all smokers hospitalised for ACS significantly increases the uptake of smoking cessation counselling and might increase smoking abstinence at 12 months

Identification and molecular characterisation of Lausanne Institutional Biobank participants with familial hypercholesterolaemia - a proof-of-concept study.

We aimed to identify familial hypercholesterolaemia mutation carriers among participants to the Lausanne Institutional Biobank (BIL). Our experimental workflow was designed as a proof-of-concept demonstration of the resources and services provided by our integrated institutional clinical research support platform. Familial hypercholesterolaemia was used as a model of a relatively common yet often underdiagnosed and inadequately treated Mendelian disease. Clinical and laboratory information was extracted from electronic hospital records. Patients were selected using elevated plasma cholesterol levels (total cholesterol ≥7.5 mM or low-density lipoprotein cholesterol ≥5 mM), premature coronary artery disease status and age (18-60 yr) as main inclusion criteria. LDLR, APOB and PCSK9 were analysed by high-throughput DNA sequencing. The most relevant mutations were confirmed by Sanger sequencing. Of 23 737 patients contacted by the BIL, 17 760 individuals consented to participate and 13 094 wished to be recontacted if there were findings requiring clinical action. Plasma cholesterol records were available for 5111 participants, of whom 94 were selected for genetic screening. Twenty-five of the tested patients presented with premature coronary artery disease while 69 had no such diagnosis. Seven heterozygous carriers of eight rare coding missense variants were identified. Three mutations were pathogenic (APOB p.R3527Q) or likely pathogenic (LDLR p.C27W, LDLR p.P526S) for hypercholesterolaemia, while the others were either benign or of unknown significance. One patient was a double heterozygote for variants APOB p.R3527Q and LDLR p.P526S. This work illustrates how clinical and translational research can benefit from a dedicated platform integrating both a hospital-based biobank and a data support team

Automatic Speech Indexing System of Bilingual Video Parliament Interventions

This paper presents the development and evaluation of an automatic audio indexing system designed for a special task: work in a bilingual environment in the Parliament of the Canton of Valais in Switzerland, with two official languages, German and French. As several speakers are bilingual, language changes may occur within speaker or even within utterance. Two audio indexing approaches are presented and compared: in the first, speech indexing is based on bilingual automatic speech recognition; in the second, language identification is used after speaker diarization in order to select the corresponding monolingual speech recognizer for decoding. The approaches are later combined. Speaker adaptive training is also addressed and evaluated. Accuracy of language identification and speech recognition for the monolingual and bilingual cases are presented and compared, in parallel with a brief description of the system and the user interface. Finally, the audio indexing system is also evaluated from an information retrieval point of view