Proportionate universalism intervention is effective for tackling nutritional social gradient in adolescents: the PRALIMAP-INÈS mixed randomised trial.

OBJECTIVE: This study aimed to investigate the effectiveness of proportionate universalism intervention to reduce the slope of the nutritional social gradient in adolescents. STUDY DESIGN: A mixed (experimental and quasi-experimental) multicentre trial. METHODS: Data from 985 adolescents of the PRALIMAP-INÈS trial (North-eastern France, 2012-2015) were analysed. For this, adolescents were split into five social classes according to the Family Affluence Scale: Highly Less Advantaged (H.L.Ad; n = 33), Less Advantaged (L.Ad; n = 155), Intermediate (Int; n = 404), Advantaged (Ad; n = 324) and Highly Advantaged (H.Ad; n = 69). The overweight care management was a standard care for all and a strengthened one adapted to the social class of adolescents. The main outcome was the 1-year change of the body mass index z-score (BMIz) slope. Other nutritional outcomes were BMI, ΔBMIp95 (BMI minus 95th percentile of the WHO reference), %BMIp95 (percent of 95th percentile of the WHO reference), leisure-time sport, consumption of fruits and vegetables and consumption of sugary foods and drinks. RESULTS: The inclusion data confirmed a weight social gradient expressed by a significant BMIz linear regression coefficient (ß = -0.09 [-0.14 to -0.04], P < 0.0001). The higher the social class, the lower the BMIz. The 1-year BMIz linear regression coefficient was -0.07 [-0.12 to -0.02], corresponding to a significant weight social gradient reduction of 23.3% (ß = 0.021 [0.001 to 0.041]; P = 0.04). Consistent results were found for other nutritional outcomes. CONCLUSIONS: PRALIMAP-INÈS shows that proportionate universalism intervention is effective to reduce the adolescents' nutritional social gradient and suggests that equitable health programmes and policies are a realistic goal.

Altered DNA methylation at age-associated CpG sites in children with growth disorders: impact on age estimation?

Age estimation based on DNA methylation (DNAm) can be applied to children, adolescents and adults, but many CG dinucleotides (CpGs) exhibit different kinetics of age-associated DNAm across these age ranges. Furthermore, it is still unclear how growth disorders impact epigenetic age predictions, and this may be particularly relevant for a forensic application. In this study, we analyzed buccal mucosa samples from 95 healthy children and 104 children with different growth disorders. DNAm was analysed by pyrosequencing for 22 CpGs in the genes PDE4C, ELOVL2, RPA2, EDARADD and DDO. The relationship between DNAm and age in healthy children was tested by Spearman's rank correlation. Differences in DNAm between the groups "healthy children" and the (sub-)groups of children with growth disorders were tested by ANCOVA. Models for age estimation were trained (1) based on the data from 11 CpGs with a close correlation between DNAm and age (R ≥ 0.75) and (2) on five CpGs that also did not present significant differences in DNAm between healthy and diseased children. Statistical analysis revealed significant differences between the healthy group and the group with growth disorders (11 CpGs), the subgroup with a short stature (12 CpGs) and the non-short stature subgroup (three CpGs). The results are in line with the assumption of an epigenetic regulation of height-influencing genes. Age predictors trained on 11 CpGs with high correlations between DNAm and age revealed higher mean absolute errors (MAEs) in the group of growth disorders (mean MAE 2.21 years versus MAE 1.79 in the healthy group) as well as in the short stature (sub-)groups; furthermore, there was a clear tendency for overestimation of ages in all growth disorder groups (mean age deviations: total growth disorder group 1.85 years, short stature group 1.99 years). Age estimates on samples from children with growth disorders were more precise when using a model containing only the five CpGs that did not present significant differences in DNAm between healthy and diseased children (mean age deviations: total growth disorder group 1.45 years, short stature group 1.66 years). The results suggest that CpGs in genes involved in processes relevant for growth and development should be avoided in age prediction models for children since they may be sensitive for alterations in the DNAm pattern in cases of growth disorders.

Evidence for differences in DNA methylation between Germans and Japanese.

As a contribution to the discussion about the possible effects of ethnicity/ancestry on age estimation based on DNA methylation (DNAm) patterns, we directly compared age-associated DNAm in German and Japanese donors in one laboratory under identical conditions. DNAm was analyzed by pyrosequencing for 22 CpG sites (CpGs) in the genes PDE4C, RPA2, ELOVL2, DDO, and EDARADD in buccal mucosa samples from German and Japanese donors (N = 368 and N = 89, respectively).Twenty of these CpGs revealed a very high correlation with age and were subsequently tested for differences between German and Japanese donors aged between 10 and 65 years (N = 287 and N = 83, respectively). ANCOVA was performed by testing the Japanese samples against age- and sex-matched German subsamples (N = 83 each; extracted 500 times from the German total sample). The median p values suggest a strong evidence for significant differences (p < 0.05) at least for two CpGs (EDARADD, CpG 2, and PDE4C, CpG 2) and no differences for 11 CpGs (p > 0.3).Age prediction models based on DNAm data from all 20 CpGs from German training data did not reveal relevant differences between the Japanese test samples and German subsamples. Obviously, the high number of included "robust CpGs" prevented relevant effects of differences in DNAm at two CpGs.Nevertheless, the presented data demonstrates the need for further research regarding the impact of confounding factors on DNAm in the context of ethnicity/ancestry to ensure a high quality of age estimation. One approach may be the search for "robust" CpG markers-which requires the targeted investigation of different populations, at best by collaborative research with coordinated research strategies.

Obstructive sleep apnoea syndrome in patients living with diabetes: Which patients should be screened?

AIM: Because type 2 diabetes (T2D) is related to obesity, it is often associated with obstructive sleep apnoea syndrome (OSAS), although OSAS is also frequently diagnosed in patients with type 1 diabetes (T1D) and may promote gestational diabetes. Thus, this systematic review of the scientific evidence aimed to evaluate the epidemiological association between OSAS and all forms of diabetes, the current understanding of the pathophysiological mechanisms behind these associations, the expected benefits and limitations of OSAS treatment in patients with diabetes and, finally, to propose which patients require screening for OSAS. METHODS: A panel comprising French expert endocrinologists and pneumologists was convened. Two of these experts made a search of the relevant literature for each subpart of the present report; all panel experts then critically reviewed the entire report separately as well as collectively. RESULTS: There is little evidence to support the notion that OSAS treatment improves glycated haemoglobin, although it may improve nighttime blood glucose control and insulin sensitivity. However, there is robust evidence that OSAS treatment lowers 24-h blood pressure. CONCLUSION: The high prevalence of OSAS in patients with T1D and T2D justifies screening for the syndrome, which should be based on clinical symptoms, as the benefits of OSAS treatment are mainly improvement of symptoms related to sleep apnoea. There are also several clinical situations wherein screening for OSAS seems justified in patients with diabetes even when they have no symptoms, particularly to optimalize control of blood pressure in cases of resistant hypertension and microvascular complications.

Endothelial dysfunction and type 2 diabetes. Part 1: physiology and methods for exploring the endothelial function.

Coronary artery, cerebrovascular and peripheral vascular disease, are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy. Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. The endothelium is a major organ involved by cardiovascular risk factors, such as hypercholesterolemia, hypertension, inflammation, ageing, postmenopausal status, and smoking. Changes in endothelium function may lead to the coronary artery circulation being unable to cope with the increased metabolism of myocardial muscle independently of a reduced coronary artery diameter. The way endothelial function is altered in diabetic patients is not yet fully understood, but the loss of normal endothelial function could be involved in the pathogenesis of diabetic angiopathy, as endothelial dysfunction is associated with diabetic microangiopathy and macroangiopathy. Finally, recent reports indicate that an improved metabolic control in diabetic patients, whatever the treatment used, is associated with near normalization or restoration of normal endothelial function.

Endothelial dysfunction and type 2 diabetes. Part 2: altered endothelial function and the effects of treatments in type 2 diabetes mellitus.

Coronary artery, cerebrovascular and peripheral vascular disease, are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy. Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. The endothelium is a major organ involved by cardiovascular risk factors, such as hypercholesterolemia, hypertension, inflammation, ageing, postmenopausal status, and smoking. Changes in endothelium function may lead to the coronary artery circulation being unable to cope with the increased metabolism of myocardial muscle independently of a reduced coronary artery diameter. The way endothelial function is altered in diabetic patients is not yet fully understood, but the loss of normal endothelial function could be involved in the pathogenesis of diabetic angiopathy, as endothelial dysfunction is associated with diabetic microangiopathy and macroangiopathy. Finally, recent reports indicate that an improved metabolic control in diabetic patients, whatever the treatment used, is associated with near normalization or restoration of normal endothelial function.

Fatty acid abnormalities in chronic pancreatitis: effect of concomitant diabetes mellitus.

OBJECTIVE: Patients with chronic pancreatitis suffer from malabsorption and nutritional deficiencies. However there is little data available concerning the fatty acid profile in chronic pancreatitis. Diabetes mellitus, a common complication of this disease, could interfere with the metabolism of fatty acids. SUBJECTS: We therefore compared the fatty acid composition of LDL from four groups of male patients with (a) chronic pancreatitis without diabetes (ND-CP; n=12), (b) diabetes secondary to chronic pancreatitis and insulin-treated (CP-D; n=35); (c) type 1 diabetes (n=25); and (d) controls (n=20). RESULTS: The patients in both groups of chronic pancreatitis (ND-CP and CP-D) had lower mean values for linoleic acid than that seen in the type 1 DM and control groups, whereas monounsaturated fatty acids (MUFA; 18 : 1(n-9) and (16 : 1(n-7)) were significantly increased in these two groups (ND-CP and CP-D). Docosa-hexaenoic-acid (22 : 6(n-3)) was significantly decreased in the CP-D group (P>0.05), a response that could be explained by the effects of diabetes mellitus and by selenium deficiency. In this way, diabetes was associated with a decrease in the docosa-hexaenoic-acid (22 : 6(n-3); r=0.30, P=0.005), and selenium was correlated with DHA (r=0.28, P=0.029) and with the 22 : 6(n-3)/20 : 5(n-3) ratio (evaluating the delta 4 desaturation); r=0.31, P=0.022), independently of the diabetes effect. Selenium was negatively correlated with 20 : 4(n-6)/20 : 3(n-6) ratio (evaluating the delta 5 desaturase; r=-0.30; P=0.025). These results suggest that these two factors may have a role in the regulation of the desaturation process. If we consider that a ratio of 16 : 1(n-7)/18 : 2(n-6) greater than 0.086 in plasma indicates an EFAn-6 deficiency, 40% of our CP patients, 57.6% of CP-D patients and 13.6% of type 1 DM patients were involved. CONCLUSIONS: The consequences of these deficiencies are not evaluated in this disease. However, correction of the fundamental deficiencies in essential fatty acids and in selenium seems desirable in chronic pancreatitis.

[Urinary lithiasis: between metabolism and dietetics]. / La lithiase urinaire: entre métabolisme et diététique.

Prevalence and incidence of urinary lithiasis are increasing in western countries. Oxalocalcic stone is the major form of urinary calculi but other forms are not unusual. Caracteristics of the collected stone may improve the diagnosis investigations. Rationnal blood and urine examinations are essential for this medical managment. Most of the various metabolic abnormalities in cause can be corrected from specific dietary measures.

Fear of hypoglycaemia in patients with type 1 diabetes: do patients and diabetologists feel the same way?

AIM: This study described and compared the perception of hypoglycaemia in both patients with type 1 diabetes and diabetologists. METHODS: This was an observational cross-sectional study undertaken in France in 2011. Data for what hypoglycaemia represents and practices related to it were collected using a questionnaire completed by patients with type 1 diabetes (all>12 years of age) and their diabetologists. Agreement between patients and physicians was evaluated by the intraclass correlation coefficient (ICC) and Gwet's coefficient (GC). RESULTS: A total of 485 patients were enrolled by 118 diabetologists. Half the patients thought that hypoglycaemia was always symptomatic. According to both patients and diabetologists, hypoglycaemia impaired quality of life, caused anxiety and was disturbing, especially at night. Clinical symptoms of hypoglycaemia (sweating, shakiness, anxiety) were linked to patient's age and diabetes duration. Regarding hypoglycaemia frequency, agreement was good for severe hypoglycaemia (GC: 0.61 and 0.72 for diurnal and nocturnal hypoglycaemia, respectively) and poor for mild hypoglycaemia (ICC: 0.44 and 0.40, respectively). Diabetologists correctly evaluated the impact of hypoglycaemia on quality of life, but overestimated the hypoglycaemia-induced burden and anxiety. Counteractive behaviours were frequent: 23% of patients decreased their insulin dose, 20% increased their sugar intake and 12% ate extra snacks. Diabetologists were generally aware of these measures, but not of how often patients used them. CONCLUSION: Diabetologists and patients do not share enough information about hypoglycaemia. Fear of hypoglycaemia and counteractive behaviours should be looked for by diabetologists. Systematic advice and specially adapted education should also be provided to increase patients' awareness of hypoglycaemia.

Gastric electrical stimulation for the treatment of diabetic gastroparesis.

Diabetic gastroparesis is a component of autonomic neuropathy, and is the most common manifestation of gastrointestinal neuropathy. Diabetes is responsible for about one quarter of gastroparesis. The upper gastrointestinal symptoms are often non-specific and dominated by nausea, vomiting, early satiety, fullness, bloating. We also have to look for diabetic gastroparesis in case of metabolic instability, such as postprandial hypoglycaemia. The pathophysiology of diabetic gastroparesis is complex, partly due to a vagus nerve damage, but also to changes in secretion of hormones such as motilin and ghrelin. A decrease in the stem cell factor (SCF), growth factor for cells of Cajal (gastric pacemaker), was found in subjects with diabetic gastroparesis. These abnormalities lead to an excessive relaxation in the corpus, a hypomotility of antrum, a desynchronization antrum-duodenum-pylorus, and finally an abnormal duodenal motility. The treatment of diabetic gastroparesis is based on diabetes control, and split meals by reducing the fiber content and fat from the diet. The antiemetic and prokinetic agents should be tested primarily in people with nausea and vomiting. Finally, after failure of conventional measures, the use of gastric neuromodulation is an effective alternative, with well-defined indications. Introduced in the 1970s, this technology works by applying electrical stimulation continues at the gastric antrum, particularly in patients whose gastric symptoms are refractory to other therapies. Its efficacy has been recently reported in different causes of gastroparesis, especially in diabetes. Gastric emptying based on gastric scintigraphy, gastrointestinal symptoms, biological markers of glycaemic control and quality of life are partly improved, but not normalized. Finally, a heavy nutritional care is sometimes necessary in the most severe forms. The enteral route should be preferred (nasojejunal and jejunostomy if possible efficiency). However, in case of failure especially in patients with small bowel neuropathy, the long-term parenteral nutrition is sometimes required.

Myocardial collagen turnover in normotensive obese patients: relation to insulin resistance.

OBJECTIVES: The present study was undertaken to assess the differential impact of insulin resistance, leptin and body composition on myocardial mass and serum markers of cardiac fibrosis in obese subjects, within a small range of elevated BMI (30-40 kg/m(2)), without pulmonary disease, cardiovascular disease, hypertension, cardiac hypertrophy or other cardiovascular disease. BACKGROUND: Obesity is an independent predictor of left ventricular mass (LVM) and is associated with disturbances in cardiac structure. The extent of the interstitial fibrosis in obese patients is not known, especially in the absence of cardiac hypertrophy. METHODS AND RESULTS: We included 160 obese subjects. The LVM was obtained using the Devereux formula. Body composition was estimated from a total body scan. Insulin sensitivity was assessed by homeostasis model assessment (HOMA), and cardiac collagen turnover by measurement of procollagen type III aminopeptide (PIIINP). PIIINP was correlated to the E/A ratio (r=0.24; P=0.012), a marker of ventricular function. PIIINP was independently correlated with glucose concentration (r=0.27; P=0.004), indexes of insulin resistance (HOMA (r=0.27; P=0.003), insulin (r=0.24; P=0.008)), and parameters associated with the insulin-resistance syndrome (HDL-cholesterol r=-0.27; P=0.004) and fat trunk/fat leg ratio (r=0.24; P=0.053)). The variable most correlated with PIIINP was HDL-cholesterol, followed by HOMA (r (2)=0.13). When HOMA was substituted for blood glucose concentration and insulinemia (Model 2), HDL-cholesterol was strongly related to lower PIIINP levels, followed by higher glucose concentration (r (2)=0.21). Regression analyses showed that LVM had the strongest independent positive correlation with fat-free mass (FFM) (r=0.39; P=0.0002), followed by systolic blood pressure (r=0.19; P=0.034). Neither adipose mass nor height independently added information to multivariate models. The ratio leptin/fat mass was correlated with LVM (r=-0.27; P=0.004), but not independently of the FFM. Markers for fibrosis were not significantly correlated with LVM. As a result, FFM was the most predictive factor of LVM in obese subjects. CONCLUSION: We found that serum levels of markers of cardiac collagen synthesis were significantly associated with insulin resistance in normotensive, nondiabetic obese subjects, and not related to the LVM. As a result, PIIINP could be a very early marker of ventricular dysfunction in these patients. Furthermore, we suggest that, for better detection of left ventricle hypertrophy in obese subjects, LVM should be indexed to FFM rather than to body surface area, or height.

[Results of surgical treatment of colorectal cancers in patients over 70]. / Ergebnisse der chirurgischen Behandlung kolorektaler Karzinome bei über 70jährigen Patienten.

276 patients older than 70 years suffering from colorectal cancer underwent surgery during the past 12 years. Several of these patients had additional diseases and often advanced tumour stages. The overall postoperative mortality rate came up to 18%. The results of better preoperative preparation of the bowel by irrigation and antibiotics as well as advanced operative techniques (EEA-stapler) with regard to infection rate, postoperative course and time of hospitalisation are discussed. Extensive follow-up care of treated patient is necessary.

[Thyroid gland surgery in elderly patients (author's transl)]. / Schilddrüsenchirurgie im hohen Lebensalter

In our hospital during the last 8 years, 583 operations on the thyroid gland were performed. 95 patients were aged between 61 and 90, and there was an increased risk in more than half of these cases. Our observations show that thyroid gland surgery is relatively harmless with insignificant complications, except for cancer of the thyroid, which has a high lethality.