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Adenosine deaminases acting on RNA (ADARs) are endogenous enzymes catalyzing the deamination of adenosines to inosines, which are then read as guanosines during translation. This ability to recode makes ADAR an attractive therapeutic tool to edit genetic mutations and reprogram genetic information at the mRNA level. Using the endogenous ADARs and guiding them to a selected target has promising therapeutic potential. Indeed, different studies have reported several site-directed RNA-editing approaches for making targeted base changes in RNA molecules. The basic strategy has been to use guide RNAs (gRNAs) that hybridize and form a double-stranded RNA (dsRNA) structure with the desired RNA target because of ADAR activity in regions of dsRNA formation. Here we report on a novel pipeline for identifying disease-causing variants as candidates for RNA editing, using a yeast-based screening system to select efficient gRNAs for editing of nonsense mutations, and test them in a human cell line reporter system. We have used this pipeline to modify the sequence of transcripts carrying nonsense mutations that cause inherited retinal diseases in the FAM161A, KIZ, TRPM1, and USH2A genes. Our approach can serve as a basis for gene therapy intervention in knockin mouse models and ultimately in human patients.

Tourism growth is an important component for welfare improvement in the host destination, but it can be associated with environmental degradation. The aim of the current study is to assess the environmental impacts of tourism growth in Tanzania, using time series data for the period 1995–2017. It utilizes ecological footprints as a proxy for environmental damage, tourism receipt as an economic indicator, and primary energy consumption, urban population, and trade openness as control variables. The study employs Autoregressive Distributed Lag Bounds Testing, Vector Error Correction Model (VECM), and Granger causality test for analysis and the Wild Bootstrap approach to check the accuracy of the computed statistics. The VECM Granger causality test shows that in the case of Tanzania, international tourism revenue and trade openness compact environmental degradation, while urbanization and primary energy consumption accelerate it. Besides, while long run cointegration exists among the variables, the environmental Kuznets curve hypothesis was not ascertained in Tanzania. Therefore, Tanzania must adopt more proactive urban planning strategies to achieve sustainable urbanization thereby improving the quality of the environment. Additionally, it is important for Tanzania to make strategic use of trade and tourism receipts, such as investment on renewable energy, to lessen dependence on fossil fuels, and improve environmental sustainability. So, the study opens new policy perspectives with wide international relevancy as outlined in the policy implication section.

After the economic liberalization in mid-2000, Tanzania has assumed that tourism growth spars economic growth due to the consistent significant contribution of tourism sector to the country's annual income. However, there are limited empirical studies that investigated tourism-economic growth relationship in Tanzania. This study aims to investigate an empirical insight into the actual nature of tourism-economic growth in Tanzania by applying the Granger causality and Wald test methods where annual time series data on international tourism receipt, real Gross Domestic Product, and real effective exchange rate over the period 1989–2018 are used. Further, the Impulse Response Function approach is utilized to provide insight into the qualitative nature of the relationships and the length of time necessary for the causal effect to take place. The findings confirm a unidirectional causality from tourism development to economic growth. The study concludes that Tanzania ought to focus on economic strategies that encourage sustainable tourism development as a feasible source of economic growth.

Transglutaminases are calcium-dependent enzymes that catalyze the formation of ε-(γ-glutamyl)lysine isopeptide bonds between specific glutamine and lysine residues. Some transglutaminase isoforms are present in the brain and are thought to participate in the protein aggregation characteristic of neurological diseases such as Huntington, Alzheimer's and Parkinson's disease. We have developed a functional proteomics strategy in which biotinylated amine-donor and amine-acceptor probes were used to identify the transglutaminase substrates present in brain. Bioinformatics analyses revealed that most of the 166 brain substrates identified interacted with huntingtin, the amyloid precursor protein or α-synuclein and that neurological disease was the most significant canonical pathway associated with the substrates. The physiological relevance of the substrates identified by mass spectrometry was confirmed by the fact that three of them (actin, β-tubulin and a neurofilament subunit) were polymerized in neuronal cells when cytosolic calcium concentration was raised. We also showed by in-situ immunolabeling that some of the substrates were part of the protein aggregates found in neurological diseases. These results strongly support the idea that the crosslinking activity of brain transglutaminase participates in the formation of the protein aggregates found in diseases of the central nervous system.

Background and Aims: Metabolic syndrome (MetS) definitions in adolescents based on the percentiles of its components are rather complicated to use in clinical practice. The aim of this study was to test the validity of artificial intelligence (AI)-based scores (AI_METS) that do not use these percentiles for MetS screening for adolescents., Methods and Results: This study included 1086 adolescents aged 12 to 18. The cohort underwent anthropometric measurements and blood tests. Mean blood pressure (MBP), and triglyceride glucose index (TyG) were calculated. Explainable AI methods are used to extract the learned function. Gini importance techniques were tested and used to build new scores for the screening of MetS. IDF, Cook, De Ferranti, Viner, and Weiss definitions of MetS were used to test the validity of these scores. MetS prevalence was 0.4%-4.7% according to these definitions. AI_METS used age, waist circumference, MBP, and TyG index. They offer area under the curves (AUCs) 0.91, 0.93, 0.89, 0.93, and 0.98; specificity 81%, 75%, 72%, 80%, and 97%; and sensitivity 90%, 100%, 90%, 100%, and 100%, respectively, for the detection of MetS according to these definitions. Considering only MBP offers a better specificity and sensitivity to detect MetS than considering only TyG index. MBP offers slightly lower performance than AI_METS., Conclusion: AI techniques have proven their ability to extract knowledge from data. They allowed us to generate new scores for MetS detection in adolescents without using specific percentiles for each component. Although these scores are less intuitive than the percentile-based definition, their accuracy is rather effective for the detection of MetS., Competing Interests: Declaration of competing interest Paul Valensi declares having given lectures for Abbott, AstraZeneca, Bayer, Eli-Lilly, Hikma, Merck-Sharp-Dohme, Novo-Nordisk, Novartis, Pfizer, Sanofi, Servier; received research grants from Abbott, Bristol-Myers-Squibb-AstraZeneca, Novo-Nordisk; and participated to Expert Committees for Astra Zeneca, Boehringer Ingelheim, Merck-Serono, Novo-Nordisk, Daiichi-Sankyo, Sanofi, Servier. The other authors have no conflict of interest to declare., (Copyright © 2022 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Studies of dipeptidyl peptidase inhibitors (DPP4is) report heterogeneous effects on cardiovascular targets in type 2 diabetes. This study aimed to investigate, in patients with impaired glucose tolerance (IGT), whether saxagliptin, a DPP4i, had beneficial cardiovascular effects at fasting and during the post-prandial state., Methods and Results: In this randomized, placebo-controlled, double-blind, single-center pilot exploratory study, we included obese individuals with IGT. Twenty-four individuals (BMI 36.8 ± 4.8 kg/m 2 ) were randomized to receive for 12 weeks either saxagliptin 5 mg a day or placebo. They were explored before and after a standardized breakfast for biological markers; microcirculatory blood flow at baseline and after transcutaneous administration of acetylcholine (Periflux System 5000® PERIMED); post-occlusive digital reactive hyperhemia (Endopat2000®); pulse wave velocity, augmentation index, central pulse pressure and subendocardial viability ratio (Sphygmocor®); cardiac hemodynamic parameters and cardiovascular autonomic nervous system activity (Task force monitor®). The results of all the investigations were similar after breakfast in the two groups at Visit 1 (acute post-prandial effects, after the first tablet) and Visit 2 (long-term post-prandial effects), and at fasting at Visit 1 and 2 (long-term effects, after 12 weeks of treatment). Only at Visit 2 the decrease in cardiac vagal activity occurring after breakfast was more sustained in the saxagliptin group than in the placebo group (interaction between treatment and time effect: p = 0.016)., Conclusion: In obese patients with IGT, the effects of saxagliptin on the large set of cardiovascular parameters measured are neutral, except for a more marked post-prandial depression of vagal activity., Clinical Trial Registration Number: NCT01521312., Competing Interests: Declaration of competing interest Amel Rezki, Marinos Fysekidis and Sabrina Chiheb declare they do not have any conflict of interest in relation with this manuscript. Eric Vicaut declares counseling activities for Abbott, Boston, Genomichealth, Celgen, CEMKA, Bristol-Myers-Squibb, CreativPharmaceuticals, Genomic health, and having received research grants from Astra-Zeneca, Bristol-Myers-Squibb and Pfizer. Emmanuel Cosson declares counseling activities for Abbott, AlphaDiab, Ascencia, Lilly, Medtronic, Merck-Sharp-Dohme, Novartis, Novo-Nordisk, Roche Diagnostics, Sanofi-Aventis, YpsoMed; having given lectures for Abbott, Astra-Zeneca, Bezins, Bristol-Myers-Squibb, LifeScan, Lilly, Merck-Sereno, Novartis, Novo-Nordisk, Roche Diagnostics, Sanofi-Aventis; and received research grants from Abbott, Air Liquide, Astra-Zeneca, Lilly, Novo-Nordisk, Roche diagnostics, Sanofi-Aventis, Ypsomed. Paul Valensi declares having given lectures for Abbott, AstraZeneca, Bayer, Eli-Lilly, Hikma, Merck-Sharp-Dohme, Novo-Nordisk, Novartis, Pfizer, Sanofi, Servier; received research grants from Abbott, Bristol-Myers-Squibb-AstraZeneca, Novo-Nordisk; and participated to Expert Committees for Astra Zeneca, Boehringer Ingelheim, Merck-Serono, Novo-Nordisk, Daiichi-Sankyo, Sanofi, Servier., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Dipeptidyl-peptidase inhibitors might be useful in type 2 diabetes prevention. ACCES (ACute and Chronic Effects of Saxagliptin) was a randomized, placebo-controlled, double-blind, controlled phase 2, pilot study aiming to examine in obese patients with impaired glucose tolerance (IGT) the acute effects and the effects after 12 weeks of treatment by saxagliptin on glucose levels at fasting and postprandially after a standard breakfast, and on glucose tolerance., Methods and Results: We included 24 obese patients with IGT. Patients were randomized to receive saxagliptin 5 mg or placebo in the morning. The treatment was taken on Visit 1 before breakfast, then continued for 12 weeks. Biochemical measurements were performed before, one, two and three hours after a standard breakfast including 75 g of carbohydrates, during Visit 1 and Visit 2 (12 weeks). Glucose variability (GV) was evaluated at Visit 1 from 24-h continuous glucose monitoring including the breakfast. A second OGTT was performed at Visit 3 (3-5 days after Visit 2). Compared with placebo-treated patients, saxagliptin-treated patients had lower 1 h and 2 h post-meal plasma glucose levels at Visit 1 and similar changes at Visit 2 (p < 0.01 to p < 0.004), with lower GV indexes after breakfast at Visit 1. At Visit 3, all patients but one in saxagliptin group and only 4 patients in placebo group turned to normal glucose tolerance. Lower glucose response to breakfast at Visit 1 was predictive of recovery of glucose tolerance., Conclusion: Saxagliptin has metabolically beneficial effects in glucose-intolerant obese patients by significantly lowering postprandial blood glucose levels., Clinical Trial Registration Number: NCT01521312: https://clinicaltrials.gov/ct2/show/NCT01521312., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objectives: The objective of this study was to derive a sex- and age-specific definition of the metabolic syndrome (MetS) and its abnormalities for adolescents., Study Design: This is a cross-sectional study., Methods: A total of 1100 adolescent students, aged 12-18 y, were randomly selected from schools and classrooms in the city of Constantine, Algeria; all had anthropometric measurements taken, and 989 had blood tests. Gender-specific growth curves for components of the MetS were derived, using the LMS (lambda-mu-sigma) method, and the percentiles corresponding to the thresholds of the MetS components proposed for adults by the International Diabetes Federation (IDF) were identified., Results: The prevalence of the MetS using this new definition was 4.3% for boys and 3.7% for girls (P = 0.64). Overall, a high waist circumference was the most frequent of the syndrome components, but the frequency was much higher in girls than that in boys, 33.6% and 6.9%, respectively. In contrast, a high systolic blood pressure was seen in 26.8% of the boys and only 11.4% of the girls. The prevalence of the MetS was higher among adolescents with a body mass index (BMI) ≥95th percentile of the study population, 28.8%, against 9.8% in adolescents with a BMI between the 95th and 85th percentile and 1.8% in those with a BMI <85th percentile (P < 0.0001)., Conclusion: MetS during adolescence requires more studies to establish a consensus definition. For clinical practice, we propose a simplified definition for boys and girls based on regression of IDF adult cut-off points. This definition should be tested in further studies with other adolescent populations., (Copyright © 2016 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background and Aims: Arterial stiffness, a measure of macrovascular damage predictive of poor cardio-vascular outcomes, is strongly related to age and hypertension (HT). In diabetic patients peripheral neuropathy (PN) has been found to be associated with increased arterial stiffness, which might be due to the concomitant presence of HT. The aim of this study was to examine in type-2 diabetic patients, the relationship between arterial stiffness and presence or absence of PN and HT separately., Methods and Results: Arterial stiffness was measured with the gold standard carotid-femoral pulse wave velocity (PWV) in 447 type-2 diabetic subjects of whom 66% were hypertensive, 53% had PN, and 40% had both. Patients with PN were older, more often hypertensive and had higher PWV than those free of PN. Patients were separated according to the presence or absence of PN and HT. PWV values above the 90th percentile age- and blood pressure-adjusted reference range (PWV+) were different across these groups (p < 0.005) with the following respective prevalences: 27.2%, 53.4%, 33.3% and 30.6%. Only PWV+ was significantly associated with PN and hypertension in the interaction analysis., Conclusion: Well controlled hypertensive patients did not have elevated arterial stiffness compared to normotensive patients. This might be due to anti-hypertensive treatment although our study design does not allow us to confirm it. A strong association between PN and arterial stiffness was only present in normotensive patients, suggesting that normotensive type 2 diabetic patients with PN and elevated arterial stiffness should be carefully managed to prevent future macrovascular complications., (Copyright © 2015 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Rationale: Some studies suggest that a high heart rate (HR) would be predictive of the incidence of an elevated blood pressure (BP). Cardiac autonomic dysfunction (CAD) affects a high proportion of obese patients. CAD could be involved in BP increase. Our aim was to examine the relationship between CAD, HR and BP in obese patients without known diabetes., Patients and Methods: We included 428 overweight or obese patients. CAD was assessed by analyzing HR variations during three standard tests (Valsalva, deep breathing, lying-to-standing), which are mostly dependent on vagal control. An oral load in glucose was performed and the Matsuda index was calculated., Results: The population was separated in 4 groups according to the grade of CAD (no or only one abnormal test, 2 or 3 abnormal tests) and HR (< or ≥ 75 bpm). Age was similar in the four groups. Systolic (P=0.05), diastolic (P<0.005) and mean BP (P<0.001) differed significantly between the 4 groups, and was the highest in the group of patients who had 2 or 3 abnormal tests and HR ≥ 75 bpm. Matsuda index differed across the groups (P=0.018) and was the lowest in this group., Conclusion: These data indicate that among overweight or obese patients with a defect in cardiac vagal activity BP is elevated only in those with a high heart rate, which is indicative of a more marked insulin resistance and probably an excess in sympathetic activity., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background and Aims: To document the stroke volume to pulse pressure ratio (SV/PP, an index of total arterial compliance) and its correlates in patients with type 2 diabetes (T2DM) aged over 50 years whose peripheral neuropathy and silent myocardial ischemic (SMI) status were known., Methods and Results: A total of 360 patients with T2DM aged ≥ 50 years, without cardiac history or symptom, left ventricular systolic dysfunction, dilatation and hypokinesia, were retrospectively enrolled. The SV/PP was calculated from echocardiographic left ventricular measurements and brachial blood pressure at rest. Peripheral neuropathy was defined as the presence of any two or more of the following: neuropathic symptoms, decreased distal sensation, or decreased or absent ankle reflexes. SMI was defined as an abnormal stress myocardial scintigraphy and/or stress echocardiography. A low SV/PP ratio (<0.53 ml/m²/mmHg, first tertile) was associated with age, creatinine clearance, 24 h urinary albumin excretion rate, peripheral neuropathy, hypertension, serum total cholesterol and triglycerides levels (p < 0.05-0.0001). In multivariate analysis, age (OR 1.1 [1.0-1.2], p < 0.01), triglycerides (OR 1.5 [1.2-2.0], p = 0.01) and peripheral neuropathy (OR 2.2 [1.2-3.9], p = 0.009) were independently associated with a low SV/PP. The patients with peripheral neuropathy had lower SV (p < 0.01) and higher PP (p < 0.05) than those without, and only lower SV after adjustment for age and nephropathy. Similar results were obtained in the patients with and without SMI., Conclusion: Peripheral neuropathy was independently associated with decreased SV/PP, mainly through decreased SV, in patients with T2DM over 50 years., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background and Aims: American Diabetes Association (ADA), French-speaking Societies for diabetes & cardiology (ALFEDIAM-SFC) and Cardiac Radionuclide Imaging (CRI) have proposed guidelines for the screening of silent myocardial ischemia (SMI). The aim of the study was to evaluate their diagnostic values and how to improve them., Methods and Results: 731 consecutive type 2 diabetic patients with ≥1 additional risk factor were screened between 1992 and 2006 for SMI by stress myocardial scintigraphy and for silent coronary artery disease (CAD) by coronary angiography. A total of 215 (29.4%) patients had SMI, and 79 of them had CAD. ADA (Odds Ratio 1.7 [95% Confidence Interval: 1.2-2.5]; p < 0.05), ALFEDIAM-SFC (OR 1.5 [1.0-2.5], p < 0.05) and CRI criteria (OR 2.0 [1.4-2.8], p < 0.01) predicted SMI. Considering the presence of male gender and retinopathy added to the prediction of SMI allowed by ADA criteria (c statistic: area under the curve AROC 0.651 [0.605-0.697] versus 0.582 [0.534-0.630]), p < 0.01 and ALFEDIAM-SFC criteria (AROC 0.672 [0.620-0.719] versus 0.620 [0.571-0.670], p < 0.05). CRI prediction of SMI was improved by considering the presence of macroproteinuria and retinopathy (AROC 0.621 [0.575-0.667] versus 0.594 [0.548-0.641], p < 0.01). Severe retinopathy (OR 3.4 [1.2-9.4], p < 0.05), smoking habits (OR 2.1 [1.1-4.2], p < 0.05) and triglyceride levels (OR 1.3 [1.0-1.6], p < 0.05) were independent predictors of CAD in the patients with SMI., Conclusion: Current guidelines criteria are able to predict SMI but prediction may be improved by considering male gender and the presence of retinopathy. CAD is more frequent in the patients with SMI who are current smokers, have severe retinopathy and higher triglyceride levels., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Biphasic insulin aspart 30 (BIAsp 30) has been shown in randomised controlled trials and the IMPROVE™ observational study to reduce postprandial blood glucose (PPBG) - thought to be an independent risk factor for cardiovascular disease. We used multivariate regression analysis to identify predictors of PPBG reduction in the IMPROVE™ study. A total of 52,419 type 2 diabetes patients were enrolled in the IMPROVE™ study (pre-study therapy subgroups: no pharmaceutical therapy, n = 8966; oral antidiabetic drugs [OADs] only, n = 33,797; insulin ± OADs, n = 9568; missing information on pre-study therapy, n = 88). Mean change from baseline in PPBG (mean of three meals) in the global cohort was -6.3 mmol/L; reductions in subgroups were: no pharmaceutical therapy, -8.8 mmol/L; OADs only, -6.0 mmol/L; insulin ± OADs, -5.1 mmol/L. High baseline PPBG was consistently and strongly predictive of PPBG response; lower baseline HbA1c and body mass index, greater age and shorter diabetes duration were also significant predictors of PPBG change. The novel findings from this study indicate that most patients can be expected to achieve a PPBG response with BIAsp 30 irrespective of baseline characteristics or previous therapy with an expected larger PPBG reduction when baseline PPBG is higher., (Copyright © 2012 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)

The effect of the insulin sensitizer rosiglitazone (RSG) on biological markers of endothelial dysfunction in subjects with type 2 diabetes mellitus (T2DM) was investigated in a 12-week, multi-center, randomized, double-blind study. One hundred and thirty-six subjects aged 40-70 years, with FPG > or = 7.0 and < or = 15.0 mmol/l, previously treated with a single oral anti-diabetic agent or diet/exercise, were randomized to RSG 8 mg/day (n=65) or placebo (PBO, n=71). Results revealed that RSG significantly reduced soluble (s)E-selectin by -10.9% (P=0.004) compared with PBO, but did not significantly alter soluble vascular cell adhesion molecule-1 (+0.6%, P=NS). Compared with PBO, RSG also significantly reduced plasminogen activator inhibitor-1 (-36.9%, P<0.001), tissue plasminogen activator antigen (-22.7%, P<0.001), FPG (-2.8 mmol/l, P<0.001), fasting fructosamine (-42.0 mg/dl, P<0.001). Post-prandial AUC(0-4h) for free fatty acids (FFAs) reduced by -6.5 mg/dl*h from baseline (P=0.03), a change that positively and significantly correlated with changes in sE-selectin (r=0.22, P=0.05). The incidence of adverse events was similar in the two groups (RSG: 35.4%; PBO: 40.8%); the majority mild or moderate. These data support the hypothesis that, in patients with T2DM, rosiglitazone has beneficial effects on biological markers of endothelial dysfunction. Improvements in insulin sensitivity and decreases in FFAs may play a role in these effects.

Many patients at high cardiovascular risk still fail to achieve recommended LDL-C goals. Showing evidence of a difference between two statins at the same dose can significantly contribute to selecting the most appropriate strategy to reduce cardiovascular risk in these patients. ARIANE study was a randomized, open-label comparative study. 844 patients at high cardiovascular risk were recruited by primary care cardiologists in France. They were randomized to receive once-daily dose of 10 mg of rosuvastatin or atorvastatin. The primary objective of this study was to compare the efficacy of rosuvastatin with that of atorvastatin in achieving an LDL-C goal of < 1.00 g/1 at 12 weeks. High cardiovascular risk was defined by either history of cardiovascular event, or a type IIa or IIb dyslipidemia associated with more than 2 other cardiovascular risk factors or 2 risk factors and a 10-year coronary risk > 20% based on Framingham score. 790 patients were available for intention-to-treat analysis. At 12 weeks, LDL-C goal was reached by 211 of the 411 patients treated with rosuvastatin (51.3%) and 119 of 379 patients treated with atorvastatin (31.4%), the difference being statistically significant (p < 0.0001). Both treatments were well tolerated. Adverse events were equally observed in the 2 groups, one patient in the rosuvastatin group showed a CK elevation without clinical consequence. The risk profile for the patients in this study matched that which, in 2005, had led to the Afssaps lowering the LDL-C target below 1.00g/l. The doses of the two statins compared here correspond to the doses most commonly used in day-to-day clinical practice. The greater efficacy of rosuvastatin versus atorvastatin at the same dose demonstrated here confirms previous data. Therefore, in high risk patients treated by primary care cardiologists, rosuvastatin allows a significantly greater proportion to reach the LDL-C goal of < 1.00 g/l compared to atorvastatin at the same dose. However, many patients remain not at goal.

Aims: We determined the 6-year incidence of peripheral arterial disease (PAD) in a French population and assessed the association of glucose metabolism, smoking, cardiovascular risk factors and physical activity with incident PAD., Methods: Participants from the French Data from a Epidemiological Study on the Insulin Resistance Syndrome (DESIR) were studied. Participants analysed were 30-65 years (at baseline) and had complete data (n=3805) after 6 years of follow-up. Diabetes was diagnosed according to the 1999 WHO criteria on the basis of fasting plasma glucose results or previous diagnosis of diabetes mellitus. The ankle brachial pressure index (ABPI) and a claudication question were used to classify PAD., Results: The 6-year incidence of PAD (defined by ABPI<0.9 and or claudication present) among those with normal fasting glucose (NFG) and free of PAD at baseline was 5.1%. Among those with impaired fasting glucose (IFG) at baseline the incidence of PAD was 4.9% and among those with diabetes mellitus at baseline the incidence of PAD was 9.8%. The incidence of PAD among those who maintained NFG over 6 years was 4.7% and among those who progressed to diabetes over 6 years was 10.2%. Those who progressed from NFG or IFG to diabetes over 6 years were twice as likely to develop PAD compared to those who maintained NFG over 6 years, after adjustment for age and sex (OR (95% CI), 2.22 (1.12-4.42)). Independent risk factors for incident PAD using baseline population characteristics were diabetes (OR (95% CI) 2.11 (1.25-3.55)), systolic BP 122-135mmHg 1.06 (0.70-1.60), >135mmHg 1.54 (1.04-2.27) and current smoking 1.60 (1.10-2.34) after multivariate adjustment for age, sex, cholesterol, triglycerides and waist circumference., Conclusions: This French study shows that those who progress to diabetes are twice as likely to develop PAD, compared to those who maintain NFG. Peripheral arterial disease is a treatable condition and more aggressive management of atherosclerotic risk factors could reduce the numbers of people who develop PAD.

Objective: To investigate the smoking cessation period during pregnancy., Patients and Methods: Questionnaire-based, descriptive study of 979 pregnant women in four regions of France. The variables analysed included the characteristics of the mother and neonate at delivery, the smoking habits of the mother before and during pregnancy, the perception of risk linked to smoking, and the reasons for giving up smoking., Results: Eighteen percent of women smoked until delivery. Forty-five percent of women gave up smoking during pregnancy, usually in the first trimester. More precisely, about one woman who smoked out of 50 gives up in order to prepare pregnancy. The proportion of women who stop smoking in each of the three trimesters of pregnancy is 84,1, 8,8 and 7,1% respectively., Discussion and Conclusion: Most women appear to stop smoking before any intervention therapy is possible. The first contact with a midwife or an obstetrician takes place whereas smoking cessation is already successful.

Objectives: To evaluate whether ultrasound screening during pregnancy increases the ability to stop or reduce smoking., Materials and Methods: This multicenter questionnaire study was performed to describe smoking characteristics among pregnant women and evaluate the factors that influence the ability to reduce smoking during pregnancy. Questionnaire-based, descriptive study of 979 pregnant women in four regions of France. The variables analyzed included the characteristics of the mother and neonate at delivery, the smoking habits of the mother before and during pregnancy, and the reasons for giving up smoking., Results: We report only results about ultrasound scan. One third of women, who smoked at the start of pregnancy, reported that ultrasound was a positive tool to enhance motivation to reduce smoking., Conclusion: Ultrasound screening may be a positive factor to reduce smoking. Our study focused on motivation could give a tool in this way. However most women who stop smoking during pregnancy do so in the first trimester (84%) mainly before the first ultrasound exam. Thus, the routine ultrasound scan itself does not seem to influence attitudes to stop smoking any further. But it may be included in comprehensive and individualised anti-smoking support.

Diabetes and arterial hypertension are major cardiovascular risk factors. Coronary endothelial dysfunction is frequently observed in diabetic and hypertensive patients. This study was designed to compare cardiovascular outcome of hypertensive (HT) and type 2 diabetic patients (D2) with angiographically normal coronary arteries on the basis of their epicardial coronary endothelial function. Coronary reactivity assessment by cold-pressor test (CPT) using quantitative coronary angiography was achieved in 65 HT (45 males, 20 females) aged 51.9+/-7.6 years, and in 59 D2 (32 males, 27 females) aged 48.9+/-7.3 years, with angiographically normal coronary arteries and without other major coronary risk factor. Cardiovascular events (CVE) were recorded with a mean follow-up of 108+/-15 months in HT, and 113+/-10 months in D2. During CPT, in HT coronary artery dilation occurred in 10.8% of the patients, no change in 21.5%, and constriction in 67.7%. In D2, dilation occurred in 3.4% of the patients, no change in 18.6%, and constriction in 78.0%. During follow-up, in HT there were nine CVE in 6/65 patients (9.2%), all in the 6/44 (13.6%) patients with coronary artery constriction. In D2, there were 18 CVE in 16/59 patients (27.1%, P<0.01 versus HT), with 17 CVE in the 15/46 patients with coronary artery constriction, and one CVE in the 1/13 patients without constriction (32.6% versus 7.7%). In patients with coronary artery constriction, CVE were more frequent in D2 than in HT (P<0.05). Last, CVE were more severe and occurred earlier in D2 than in HT. In conclusion, epicardial coronary endothelial dysfunction is predictive of long-term CVE in HT and D2 with angiographically normal coronary arteries. Cardiovascular outcome of patients with coronary constriction is worse in D2 than in HT. At the opposite, patients without constriction have good cardiovascular prognosis in both subgroups.

Numerous mechanisms contribute to impaired arterial wall in insulin resistant subjects and in type 2 diabetic patients. Endothelial dysfunction appears at an early stage of atherosclerosis progression, an accelerated process in diabetic patients. At a more advanced stage, arterial stiffness and thickening contribute to development of macroangiopathies. Inflammation plays a key role in these phenomena, particularly through growth factors and cytokines secretion in arterial wall cells. Thiazolidinediones, are pharmacological ligands of nuclear receptor PPARgamma and appear to act favorably on several pathophysiological mechanisms involved in these vascular dysfunctions and complications. Thiazolidinediones decrease plasma levels of C reactive protein, possess antiinflammatory effects through a reduction of inflammatory cytokines production, decrease free fatty acids levels, antagonize angiotensin II effects, increase adiponectin expression and production, etc. Pathophysiological mechanisms leading to vascular function impairment and their evaluation techniques are described, as well as the main thiazolidinediones beneficial effects on these mechanisms, which may lead to vascular prevention and/or protection in high cardiovascular risk insulin resistant and/or type 2 diabetic patients.

This study forms part of a research project seeking to develop a standardized questionnaire by which clinicians can assess the impact of growth hormone (GH) deficiency and its treatment on the "perceived health" or health-related quality of life of adults. The specific aim of this study was to translate and adapt for French patients the AGHDA (Adult Growth Hormone Deficiency Assessment) a standardized health-related quality of life measure for use with GH-deficient adults, initially developed in the United Kingdom, and to collect data which could be used to assess the main psychometric characteristics of its French version the ISPA-HC (Indicateur de Santé Perceptuelle Adulte-Hormone de Croissance). The main properties analyzed are: 1/ The scale's acceptability, as determined by means of face-to-face interviews with a small number of subjects, then by an ad hoc questionnaire administered during a test-retest study; 2/ The scale's reliability, as determined by a test-retest study (with a 15-days interval between tests); 3/ The scale's concurrent validity, as expressed by comparison with scores obtained by means of a generic quality of life scale, the ISPN (the French version of the Nottingham Health Profile). The results of this first trial with the ISPA-HC are conforming to what one can expect from a good instrument. The ISPA-HC has been shown to have very good levels of reliability and internal consistency. Its scores show a close correlation with those of the ISPN (the French version of the Nottingham Health Profile). This instrument can be used to measure variations in the perceived health of subjects with growth hormone deficiency. Its responsiveness to change is to be examined in subsequent studies.

Type 2 diabetes is a recognized independent cardio-vascular risk factor, which adds to other known risk factors. In in vitro or animal models, rosiglitazone and/or other thiazolidinediones induced favourable effects on the various mechanisms involved in atherosclerosis. In type 2 diabetic patients, rosiglitazone and/or other thiazolidinediones have shown beneficial effects on blood pressure, arterial wall, vasomotricity, PAI-1 levels and urinary albumin excretion. These data are briefly reviewed. They justify carrying out a large program of prospective studies aimed to assess the effects of rosiglitazone on cardiovascular morbidity and mortality in type 2 diabetic patients.

Aim: To examine the evolution of different parameters of the nutritional status after short-term oral protein-energy supplementation in moderately malnourished geriatric patients., Methods: Seventeen hospitalized malnourished elderly patients and 12 healthy adults received dietary supplements for 10 days. A group of six malnourished elderly subjects served as controls. Spontaneous oral intakes, biological and biophysical markers of the nutritional status were measured. Fat-free mass (FFM) was assessed using Dual energy X-ray absorptiometry (DXA), bio-impedance analysis (BIA) and anthropometry., Results: In elderly subjects, the supplementation significantly increased both dietary intake (energy +32%, protein +65%) and FFM (+1.3 kg, P<0.001) as assessed using DXA. BIA and anthropometric data correlated with DXA measurements in the elderly (BIA: r=0.68--0.80, anthropometry: r=0.80--0.89), but failed to reflect accurately the changes measured in FFM. Supplementation had no notable effect on biological markers in any of the groups. IGF-I and hand-grip strength were not significantly influenced by the supplementation despite trends towards an improvement., Conclusions: Monitoring short-term changes in nutritional status in malnourished elderly individuals is a problem in routine clinical management. Our data put in the limelight the changes in IGF-I values related to dietary supplementation, and, chiefly, suggest a prime role for the assessment of dietary intake and FFM, as assessed by DXA, as indicators of short-term efficacy of refeeding. Nevertheless larger studies are necessary to confirm the clinical and prognostic significance of the changes., (Copyright 2001 Harcourt Publishers Ltd.)

Background: An increase in protein intake exerts a stimulating effect on protein kinetics in children, young adults, and healthy elderly persons. However, there are few data on the response to such dietary changes in malnourished elderly subjects, despite important medical implications in this population., Objective: The objective of this study was to determine the metabolic response to short-term nutritional supplementation in moderately malnourished elderly subjects., Design: The influence of 10 d of supplementation (1.67 MJ/d and 30 g protein/d) on body composition, resting energy expenditure, and whole-body protein kinetics was studied in 17 malnourished elderly patients and 12 healthy young adults. A control group of 6 malnourished elderly patients received no supplementation., Results: Supplemented elderly subjects had a significantly greater fat-free mass gain than did unsupplemented elderly subjects (1.3 and 0.1 kg, respectively; age effect, P < 0.05; diet effect, P < 0.02) and a significantly greater increase in fasting rate of protein synthesis than did young supplemented subjects (0.6 and 0.2 g*kg FFM(-1)*11 h(-1); age effect, P < 0.05). The net protein balance in the supplemented elderly subjects in the fed state was positively correlated with protein intake (r(2) = 0.46) and in the fasted state was negatively correlated with protein intake (r(2) = 0.27). The sum of these regressions is a line with increasingly positive net diurnal protein balance produced by increasing protein intake., Conclusion: These data provide evidence of a short-term anabolic response of protein metabolism to dietary supplementation in malnourished elderly patients that is likely to improve muscle strength and functional status.

Benzo[a]pyrene is a cigarette smoke component that is metabolized in the human body to the diol-epoxide derivative benzo[a]pyrene-trans- 7,8-dihydrodiol-9,10-epoxide (BPDE-I), which is the final carcinogen. BPDE-I binds covalently to DNA, producing BPDE-I-DNA adducts. A competitive immunoenzymetric assay was used to measure BPDE-I-DNA adducts in blood samples from 58 heavy smokers, 32 men and 26 women, attending a smoking cessation clinic. Cigarette consumption was evaluated based on urinary continine levels. None of the subjects worked in jobs involving exposure to polycyclic aromatic hydrocarbons (e.g., benzo[a]pyrene). Concentrations of BPDE-I-DNA adducts varied with cigarette consumption, ranging from 10.00 to 28.20 fmol/50 micrograms of DNA.

The bioavailability of rapid-acting insulin administered as a nasal spray was studied in 6 type 1 (insulin-dependent) diabetic patients. They received long-acting bovine insulin (Ultratardum 40 U/ml, Organon) as basal treatment at 8 a.m. Rapid-acting insulin was also administered at 8 a.m., then at noon and 6 p.m, subcutaneously on day 1 as a 100 U/ml solution and intranasally by aerosol spray as a 100 U/ml and 500 U/ml with 1% (w/v) 9 lauryl ether solution on day 2 and day 3 respectively. On days 2 and 3, the dose of insulin was at least nine times higher than the subcutaneous dose on day 1. Free and total plasma insulin concentrations were assayed after the noon insulin administration. The peaks of the free and total plasma insulin levels were reached earlier and the return to basal levels was obtained earlier after nasal insulin administration than after insulin injected subcutaneously. The bioavailability of nasal spray insulin versus subcutaneous insulin with a 100 U/ml insulin solution was similar to that with a 500 U/ml insulin solution: 5.14 +/- 0.38% (m +/- SEM) and 4.64 +/- 0.46% according to the total plasma insulin level. This study suggests that the bioavailability of nasal spray insulin is not increased by increasing insulin concentration in our experimental conditions.

Anti-thyroid hormone autoantibodies are occasionally found in Hashimoto's disease. They can interfere with thyroid hormone assays. The authors report the case of a 35-year-old hypothyroid (TSH between 29 and 46 microIU/ml) female patient with Hashimoto's disease and surprisingly high free and total levels of plasma T4 and T3 assayed with different solid phase radio-immunologic kits. Two immunoenzymologic assay kits gave a T4 level close to the one expected. The presence of circulating anti-T4, T3 and reverse T3 autoantibodies was demonstrated by precipitating the corresponding tracers with the patient's serum in the presence of polyethylene glycol without heterologous antibodies. The replacement treatment of 150 micrograms l-thyroxine allowed normalization of TSH at 3.4 microIU/ml, but the patient remained tired and anxious, with headaches and tachycardia. After discontinuing treatment for one month a series of four plasma exchanges was carried out in six days. After the first exchange the binding percentages were already much lower and went even lower after the other exchanges. After the fourth one, the free T4 and T3 levels were closer to the expected levels:7.3 pmol/l (N:10-30 pmol/l) and 4.3 pmol/l (N:3-9 pmol/l). Treatment by prednisone made it possible to maintain the percentages of binding to the three tracers for two weeks at the levels reached after the fourth plasma exchange. Two months after discontinuing corticosteroid treatment they returned to the initial levels and were again interfering with the free T4 and T3 assays. This finding suggests that usefulness of the thyroid hormone immuno-enzymologic assay, which apparently is not affected by the anti-thyroid hormone autoantibody interference.(ABSTRACT TRUNCATED AT 250 WORDS)

Objectives: Thyroid disorders, particularly euthyroid goiters and hyperthyroidism, can be observed in sarcoidosis. The aim of this study was to analyze the presence of thyroid stimulating antibodies (TSAb) in 21 patients with sarcoidosis. 12 patients out of 21 had simultaneous euthyroid goiter. The others were euthyroid and free of goiter., Methods: The TSAb testing was carried out using the rat thyroid fragment perifusion technique. Thyroid response to IgG was determined by the mean rate of T4 release (R) during a 30-min perifusion and the secretion peak (Imax). Antibodies inhibiting TSH binding to its receptors were also looked for., Results: Ten patients were TSAb+ and eleven were TSAb-. There was no difference between the TSAb+ and TSAb- groups in the clinical parameters for sarcoidosis, nor in the number of goiters found (n = 6 for both groups). In 5 out of the 6 cases where goiter was present in the TSAb+ group it was homogeneous and diagnosed at the same time as or after the first signs of sarcoidosis, whereas in 5 out of the 6 cases of goiter in TSAb- patients, it was nodular, diagnosed before sarcoidosis in 3 of them, endemic in one of them, and familial in another. The search for antibodies inhibiting TSH binding to its receptors was negative in 10 out of 21 patients tested., Conclusion: Although the presence of thyroid-stimulating antibodies in the serum of patients with sarcoidosis, found here for the first time, remains to be explained, it pleads in favor of the immunologic nature of the association of sarcoidosis with thyroid disorders.

This prospective study compared two weaning modalities in COPD patients requiring mechanical ventilation (MV) for acute respiratory failure. Nineteen patients with COPD were studied when their precipitating illness was controlled. Although they satisfied the conventional bedside weaning criteria, they could not tolerate any reduction in the respirator rate below 10 cycles/min. At this time, patients were randomized into two groups receiving either synchronized intermittent mandatory ventilation (SIMV) with pressure support ventilation (PSV) (group 1) or SIMV alone (group 2). The volumetric support of ventilation (SIMV rate) was progressively decreased in both groups according to the patient's tolerance with a concurrent decrease in the barometric support of ventilation (PSV levels from 15 cm H2O to 6 cm H2O). At each step of SIMV rate, we found no difference between group 1 and group 2 in arterial blood gases, blood pressure, heart rate, airway occlusion pressure, maximal inspiratory pressure, and oxygen cost of breathing (OCB). At each step, however, group 1 patients showed significantly higher spontaneous tidal volume and lower spontaneous breathing frequency than did group 2 patients. We found a slight but not significant tendency to a shorter weaning period with than without PSV, but no difference in the weaning success. We concluded that (1) conventional weaning criteria might be inaccurate in COPD patients, (2) SIMV appeared very useful in weaning COPD patients from MV, (3) PSV marginally reduced the weaning period when added to SIMV, and (4) the OCB was not significantly improved with PSV.

There have been few studies examining the relationship between NOD and mortality in patients with COPD and none examining this relationship in those patients with a daytime PaO2 greater than 60 mm Hg. Is NOD related to early death, and if so, should nocturnal supplemental oxygen be considered as therapy for altering survival? We examined survival in 169 COPD subjects. Two definitions were used to classify subjects as NOD and non-NOD, one considering episodic desaturation associated mainly with REM sleep (definition 1) and one considering greater than 30 percent of time in bed spent below an SaO2 of 90 percent (definition 2) to be significant. Survival corrected for age was significantly better in non-NOD subjects. However, when stratified for supplemental oxygen use, survival remained better only in subjects separated by definition 1. There was a trend toward increased survival in 35 oxygen-treated vs 38 non-oxygen-treated NOD subjects (definition 1), but this difference was not statistically significant.

The aim of this study was to determine, with a rat thyroid fragment perifusion system, the short-term (20 min) effect of forskolin (FK), an adenylate cyclase activator, on T4 secretion, the effect of forskolin on T4 secretion stimulated by theophylline and TSH, and the role played by calcium in the forskolin effect. A dose-dependent effect on T4 secretion was obtained with forskolin, from 10(-8) to 10(-4) mol/l, with a maximal effect between 10(-6) and 10(-5) mol/l. The effect of forskolin was not increased by theophylline. The combined stimulation with forskolin and theophylline induced a T4 release which remained significantly lower than the effect of 22 or 65 mIU/ml TSH. Forskolin slightly increased the stimulating effect of 22 mIU/ml TSH but significantly decreased the effect of 65 mIU/ml TSH. A reduction in the buffer calcium concentration slightly decreased the effect of the forskolin and theophylline stimulations and the effect of the combined stimulation with forskolin and theophylline without suppressing completely the effect of these stimulations. This study demonstrates that 1) low concentrations of forskolin are able to induce a significant T4 release during short-term stimulations; 2) calcium is necessary in order to obtain a maximum effect of adenylate cyclase activation on T4 release; 3) the part of the thyroid hormone response to TSH which is mediated by adenylate cyclase activation is relatively small.

The computerization of SaO2 recording during polysomnographic monitoring allows the construction of a diagram expressing the percentage of TIB spent at different steps in saturation. We studied the value of this diagram in three groups of male patients: (1) nine healthy subjects (all volunteers); (2) 25 patients with COPD who had a mean daily SaO2 of 92.3 +/- 1.3 percent; and (3) 25 patients with SAS who had a mean daily SaO2 of 92.1 +/- 1.4 percent. The results show the existence of a discriminating quality in the diagram's morphology, the existence of strong correlations (p less than 0.01) between the percentage of TIB spent at SaO2 less than 85 percent, and the total duration of the desaturation dips.