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The burden of hypoglycaemia is important, particularly in elderly type 2 diabetes (T2D) patients. Unfortunately, however, few studies are available concerning this population. GERODIAB is a prospective, multicentre, observational study that aims to describe the 5-year morbidity and mortality of 987 T2D patients aged 70 years and older. After analyzing the frequency of and factors associated with hypoglycaemia in the 6 months prior to study inclusion, it was found that hypoglycaemia was associated with retinopathy, lower levels of LDL cholesterol and altered mini-Geriatric Depression Scale (GDS) scores.

Objectif Evaluer les modalites d’utilisation et l’efficacite en vie reelle du traitement par injection intravitreenne (IVT) de ranibizumab chez des patients presentant une baisse de l’acuite visuelle (BAV) due a un œdeme maculaire secondaire a une occlusion veineuse retinienne (OM-OVR) qu’elle soit de branche (B) ou centrale (C), a la demande de la Haute Autorite de sante. Methode Etude de cohorte observationnelle nationale de patients initiant un traitement par IVT de ranibizumab pour une BAV due a un OM-OVR, inclus et suivis pendant 24 mois par des retinologues. Le critere principal d’evaluation est la variation de la Meilleure acuite visuelle corrigee (MAVC) a six mois par rapport a l’inclusion. Les criteres secondaires sont la variation de la MAVC, celle de l’epaisseur de la zone centrale de la retine (ECR), la description des modalites du suivi ophtalmologique et les evenements indesirables au cours des 24 mois de suivi. Resultats Entre decembre 2013 et avril 2015, pour les cohortes B/C, 226/196 patients ont ete inclus dans l’etude et 162/139 (71,7/70,9 %) presentaient des donnees de suivi analysables a 24 mois. Les caracteristiques des patients etaient un âge moyen (e-t) de 70,9 ans (11,1)/70,4 (14,3) ans avec 48,7/51,5 % d’hommes, une MAVC moyenne a l’inclusion de 55,2 ans (18,7)/40,4 (25,6) lettres ETDRS et une ECR moyenne de 550 (175)/643 (217) μm. A 6 (± 1,5) mois de suivi, la variation moyenne de la MAVC [IC 95 %] par rapport a l’inclusion etait de +14,1 [11,7 a 16,5]/ + 9,5 [5,5 a 13,5] lettres. Cette evolution se stabilisait au cours du temps avec +13,0 [10,2 a 15,9]/ + 9,2 [4,5 a 13,9] lettres a 12 (± 1,5) mois et +11,4 [7,7 a 15,2]/ + 8,3 [3,7 a 12,8] lettres a 24 (± 1,5) mois, avec 53,1/38,9 % des patients presentant une MAVC superieure a 70 lettres. La variation moyenne de l’ECR etait de −223 [−254 a −192]/−267 [−314 a −220] μm a 6 (±1,5) mois, −225 [−260 a −191]/−284 [−334 a −233] μm a 12 (±1,5) mois et −211 [−251 a −170]/−305 [−356 a −255] μm a 24 (±1,5) mois. A 24 mois, le nombre moyen d’IVT etait de 7,2 (4,3)/7,1 (4,4) par œil etudie et 85,8/85,6 % des yeux etudies ont eu au moins une interruption des IVT de ranibizumab (72,6/62,5 % pour amelioration de la pathologie et 15,2/26,7 % pour manque d’efficacite). A 24 mois, 69,8/62,6 % des yeux etudies ont recu seulement un traitement par ranibizumab et 30,2/37,4 % un autre traitement intravitreen (premier switch : 15,4/12,2 % par dexamethasone, 13,6/20,9 % par aflibercept, 1,2/0 % par triamcinolone et 0/4,3 % par bevacizumab). Aucun nouveau signal de pharmacovigilance n’a ete detecte. Conclusion Les resultats obtenus en vie reelle a 24 mois chez des patients initiant un traitement par IVT de ranibizumab dans l’OM-OVR montrent une relative stabilite par rapport a ceux observes a six mois. Ces resultats sont un peu plus faibles que ceux des essais cliniques a 24 mois avec une intensite plus faible d’injections en vie reelle (7,2/7,1 dans BOREAL contre 11,4/13,1 dans BRIGHTER/CRYSTAL).

Resume Les nodules thyroidiens sont tres frequents, et moins de 10 % d'entre eux sont des cancers. La cytoponction a l'aiguille fine est une procedure simple et peu onereuse dont la sensibilite (estimee entre 95 et 99 %) en fait un examen de depistage efficace ; sa specificite est plus faible (55 a 75 %) mais permet cependant de reduire le nombre d'interventions inutiles sur nodules benins. Les caracteristiques histologiques et cytologiques des principales lesions thyroidiennes sont detaillees en insistant sur les difficultes diagnostiques de chacune. Ces difficultes sont d'ordres differents selon le type de pathologie ; histologie et cytologie peuvent dans certains cas se completer utilement. Les limites de l'examen cytologique sont rappelees, notamment dans les tumeurs vesiculaires et oncocytaires. Les techniques immunocyto- et histochimiques permettent d'affiner les diagnostics et d'augmenter la specificite. Leur apport dans chaque type de lesion thyroidienne est discute, en rappelant l'interet des methodes de recueil cytologique en milieu liquide pour ce type d'examens complementaires.

Resumen Los nodulos tiroideos constituyen un cuadro muy frecuente. Menos del 10% corresponden a un cancer. La puncion aspiracion con aguja fina es una eficaz tecnica de deteccion, simple, poco invasiva y con una sensibilidad entre el 95 y el 99%. Aunque su especificidad es inferior (55 a 75%), permite disminuir el numero de intervenciones quirurgicas innecesarias sobre nodulos benignos. En este articulo se detallan las caracteristicas histologicas y citologicas de las principales lesiones tiroideas haciendo hincapie en las dificultades diagnosticas de cada una. Estas dificultades diagnosticas varian en funcion del tipo de enfermedad, resultando util en ciertos casos la combinacion de la histologia y la citologia. Tambien se estudian las limitaciones del examen citologico, sobre todo en el caso de tumores foliculares y oncociticos. Las tecnicas inmunocitoquimicas e histoquimicas contribuyen a precisar el diagnostico aumentando la especificidad, aunque su aportacion en cada tipo de lesion tiroidea es controvertida. Cabe destacar la toma de celulas en medio liquido para este tipo de pruebas complementarias.

Introduction Les anti-inflammatoires non steroidiens (AINS) sont parmi les medicaments les plus prescrits en ambulatoire, notamment chez les sujets âges malgre leurs effets indesirables nombreux et frequents. Nous avons conduit une analyse retrospective de la prescription des AINS par 6 medecins generalistes travaillant au sein du meme centre de sante Francilien chez des patients âges de 65 ans et plus. Notre hypothese principale etait que les AINS etaient largement prescrits chez ces patients, pas toujours dans le respect des recommandations de bonne pratique cliniques. Patients et methodes Chaque medecin generaliste a ete interroge au moyen d’un questionnaire afin de determiner les habitudes de prescription des AINS, la connaissance des AINS par les medecins et de leurs recommandations de prescriptions. Avec l’accord de chaque medecin, une etude retrospective observationnelle a ete conduite chez 154 patients âges de 65 ans et plus, recevant au moins un AINS prescrit entre le 1er octobre et le 31 decembre 2014, a l’aide d’un questionnaire comportant 34 criteres d’evaluations valides et conformes aux recommandations. Resultats D’apres les resultats des entretiens individuels, les 6 medecins generalistes ne prescrivent que rarement des AINS a leurs patients âges de 65 ans et plus, principalement en raison des nombreux traitements associes, des comorbidites notamment renales et hepatiques, et du risque eleve d’effet indesirable chez ces patients. Leurs connaissances des effets indesirables, des contre-indications et des precautions d’emploi des differents AINS disponibles etaient en revanche heterogenes et aucun d’entre eux n’avait connaissance de l’existence de recommandations de prescriptions et prevention des effets indesirables des AINS chez les patients âges. Concernant notre etude retrospective, 10,5 % des 154 patients etudies avaient une prescription d’au moins un AINS. Cette prescription etait conforme recommandations de l’autorisation de mise sur le marche des AINS concernes dans seulement 72 % des cas. Les recommandations de bonne pratique concernant la prescription d’AINS n’etaient en general pas respectees, a l’exception des recommandations concernant les effets secondaires gastro-intestinaux et les contre-indications des AINS, qui etaient en revanche parfaitement respectees. Conclusion Les recommandations de bonne pratique en termes de prescription et surveillances des AINS chez les sujets âges en ambulatoires sont inconnues des prescripteurs, conformement aux etudes anterieures publiees sur le sujet. Le respect de ces recommandations devrait etre optimise par le biais de formations dediees et, en pratique quotidienne, un fichier de surveillance informatise de chaque patient prenant des AINS pourrait etre propose afin d’optimiser la prise en charge et la prevention des evenements indesirables potentiels ou averes chez ces patients.

This study had several purposes: to define cytomorphological features of thyroid cells that might be modified by alcohol fixation; to optimize May-Grunwald-Giemsa (MGG) staining on ThinPrep(R) (TP; Cytyc Inc., Bexborough, MA, USA) slides and to compare the diagnostic accuracy of slides prepared by a liquid-based method with those obtained by conventional technique. This study included 120 cases of ultrasound-guided fine needle aspiration (FNA) of the thyroid and 55 FNAs performed on surgically resected thyroid specimens. Histological control was available in 80 cases. In the first group of 120 FNAs, a split-sample technique was used for the TP. Three screenings were performed: first, an individual screening of the conventional smears (CS) and of the TP, a second screening to compare cells observed on the TP with the histological control and a third screening to assess the previously defined diagnostic criteria. Twenty-seven TP cases (22%) were considered unsatisfactory for diagnosis compared with 10 in CS (8%). The high rate of unsatisfactory cases with TP is likely to be due to the use of the split-sample technique. The sensitivity was 94% for CS and 81% for TP. The specificity was 67% and 60% for CS and TP, respectively. Two occult papillary carcinomas were missed by both methods. As for the MGG staining, the modified technique used for TP resulted in the same quality as the standard procedure. Conversely, TP did however induce uncommon morphological features. In this study, sensitivity and specificity levels are higher for CS than for TP; the difference may be explained by the fact that the methanol fixative used for TP induces some cytological alterations, especially in oncocytic tumours and lymphocytic thyroiditis.

Resume Propos. — Le diabete de type 2 dans sa forme « commune » est une maladie multifactorielle. L’hyperglycemie est due a une reduction du captage du glucose et a une production glucosee hepatique excessive, liees a une diminution de l’insulinosecretion et de l’insulinosensibilite. Les anomalies de l’insulinosecretion sont multiples : perte du caractere pulsatile de la secretion basale, perte du pic precoce induit par l’administration intraveineuse de glucose, insulinopenie basale et stimulee par le glucose, secretion excessive de prohormones, reduction progressive de l’insulinosecretion avec le temps. Ces anomalies, dont l’origine genetique est vraisemblable, apparaissent precocement. L’insulinoresistance touche le muscle, le foie et le tissu adipeux : a concentration d’insuline egale, les patients ont un plus faible captage peripherique du glucose et une moindre « freinabilite » de la production glucosee hepatique. Le vieillissement de la population, les habitudes de vie des societes industrialisees, responsables d’une augmentation croissante du poids moyen du fait d’apports energetiques excessifs, de depenses reduites et d’une sedentarite de plus en plus complete et precoce, sont en cause dans le determinisme de l’insulinoresistance. Actualites. – Le role du deficit de l’insulinosecretion, ainsi que l’interface entre insulinopenie et insulinoresistance jusque la non elucidee, sont actuellement mieux compris. Chez des sujets sans predisposition genetique a un diabete de type 2, l’augmentation des besoins en insuline qui resulte de l’insulinoresistance est compensee par une insulinosecretion accrue, ce qui permet de garder une glycemie normale. En revanche, chez les sujets predisposes a un diabete de type 2, l’incapacite de la cellule β a repondre a l’augmentation des besoins conduit a une elevation progressive de la glycemie puis a un diabete franc. Ce mecanisme d’adaptation est appele phenomene de compensation de l’insulinoresistance par la cellule β, et c’est sa defaillance qui est a l’origine du diabete de type 2. Une fois l’hyperglycemie installee, l’insulinosecretion decline avec le temps du fait de la glucotoxicite et de la lipotoxicite. Perspectives. – Des modifications simples des habitudes de vie, activite physique reguliere, controle ponderal, devraient permettre de juguler l’epidemie annoncee de diabete de type 2. Le bien fonde de cette approche a ete demontre par les resultats d’etudes prospectives d’intervention qui visaient a diminuer le nombre d’evolutions de l’intolerance au glucose en diabete. Chez les patients dont l’hyperglycemie n’est pas controlee par les modifications des habitudes de vie, les anomalies metaboliques representent autant de cibles pour une utilisation rationnelle des differentes classes d’antidiabetiques oraux, insulinosecretagogues, insulinosensibilisateurs, et inhibiteurs du debit glucose hepatique.

Objectif Evaluer les modalites d’utilisation et l’efficacite en vie reelle du traitement par injection intravitreenne (IVT) de ranibizumab chez des patients presentant une baisse de l’acuite visuelle secondaire a un œdeme maculaire diabetique (OM-D), a la demande de la Haute Autorite de sante (HAS). Methode Etude de cohorte observationnelle nationale de patients initiant un traitement par IVT de ranibizumab pour une baisse de l’acuite visuelle due a un OM-D inclus et suivis pendant 36 mois par des ophtalmologistes specialistes de la retine (retinologues). Le critere principal d’evaluation est la variation de la meilleure acuite visuelle corrigee (MAVC) a 12 mois par rapport a l’inclusion (304 patients attendus pour avoir une precision de ± 1 lettre). Les criteres secondaires sont la variation de la MAVC, celle de l’epaisseur de la zone centrale de la retine (ECR), la description des modalites du suivi ophtalmologique ainsi que les evenements indesirables au cours du suivi. Resultats Entre decembre 2013 et avril 2015, 290 patients ont ete inclus dans l’etude et 242 (83,4 %) presentaient des donnees de suivi analysables a 12 mois. Les caracteristiques des patients etaient un âge moyen (ET) de 66,1 (11,0) ans avec 56,6 % d’hommes, 43,8 % avec un OM-D de plus de 6 mois, 13,2 % deja traites pour leur OM-D (8,3 % par laser maculaire, 4,5 % par corticotherapie intravitreenne, 2,5 % par un anti-VEGF autre que le ranibizumab) et 66,5 % avec une atteinte bilaterale. A l’inclusion, la MAVC moyenne etait de 59,2 (15,0) lettres d’ETDRS avec 13,2 % des patients qui presentaient une MAVC superieure a 70 lettres. L’ECR moyenne etait de 457 (144) μm. Au cours des trois premiers mois, 83,9 % des patients avaient recu les trois premieres injections recommandees (traitement d’induction). A 12 mois de suivi, le nombre moyen d’IVT etait de 5,1 (2,3) par œil etudie et 83,1 % des patients avaient eu au moins une interruption des IVT de ranibizumab (45,4 % pour amelioration de la pathologie et 27,7 % pour manque d’efficacite). A 12 (± 1,5) mois de suivi, la variation moyenne de la MAVC [IC 95 %] par rapport a l’inclusion etait de 7,4 [5,4 a 9,4] lettres avec 36,8 % des patients presentant une MAVC superieure 70 lettres. En parallele, l’evolution de l’ECR etait de −125 [−146 a 103] μm. Conclusion Cette etude en vie reelle chez des patients initiant un traitement par IVT de ranibizumab dans l’OM-D montre une amelioration de l’acuite visuelle proche de celle de l’essai clinique pre-AMM RESTORE avec en moyenne un peu moins d’IVT realisees (5,1 dans BOREAL contre 7 injections en moyenne dans RESTORE sur 12 mois).

Human oncocytic tumors of the thyroid gland may be either adenomas or carcinomas. The morphology and the ultrastructure of these oncocytes are well-known. Numerous studies have demonstrated the role of gap and tight junctions in experimental and human carcinogenesis; however, the junctional complexes of the oncocytic tumors have never been studied. The aim of this study is to analyze gap and tight junctions in the oncocytic tumors of the thyroid. Because they are morphologically similar, whether benign or malignant, they offer an attractive model for studying the junctional complexes in both benign and malignant lesions. Eight oncocytic human thyroid tumors were collected and studied by freeze-fracture. Four of these cases were benign and four were malignant. Four cases of normal gland were also studied to represent the control group. Normal tight and gap junctions were described for the control group. No gap junctions could be found for the oncocytic tumors. Furthermore, alterations of the tight junctions were described; especially focal tights in the oncocytic adenomas and well organized and labyrinthic tight junctions in the oncocytic carcinomas. The lack of gap junction in the benign as well as in the malignant oncocytomas may suggest that the absence of gap junction is not sufficient for malignancy. The alterations of the tight junctions found in the oncocytic tumors of the thyroid are similar to those observed in poorly differentiated tissues or tumors, and may suggest a cellular regression rather than a tumorogenic factor.

Monitoring of metabolic control in patients with non-insulin-dependent (Type 2) diabetes (NIDDM) is usually based upon blood glucose assay in the morning (after an overnight fast) and in the postprandial state (breakfast or lunch). However, this schedule does not seek low blood glucose values, especially in the evening. We have conducted a prospective study of laboratory blood glucose profiles (8 am, 9.30 am after a 35 g carbohydrate breakfast and in the evening between 5 and 7 pm). We have included 58 consecutive NIDDM patients regularly followed in our clinic (39 men, age 60 ± 11.5 years, diabetes duration 8.6 ± 6.5 years, BMI 25.5 ± 3 kg m−2 ), treated with the sulphonylurea gliclazide, alone (40–320 mg 24 h−1 , mean 170 ± 110 mg) (group 1, n = 32) or in combination with metformin (1000–3000 mg 24 h−1 , 2400 ± 620 mg) (group 2, n = 26). All patients were stable, with no change in dosage for at least 3 months. Mean glycaemic control was good (group 1 HbA1c : 6.5 ± 1.1 %, group 2: 6.9 ± 0.7 %). Evening blood glucose values were the lowest of the day in 26 patients of group 1 (81.3 %) and in 22 of group 2 (84.6 %). Mean evening blood glucose levels were lower (p = 0.001) than 8 am values (group 1: 5.8 ± 1.4 vs 6.1 ± 1.6 mmol l−1 , group 2: 6.5 ± 1.8 vs 6.9 ± 1.9) and than 9.30 am values (group 1: 7.6 ± 1.5, group 2: 12.3 ± 2.8). No blood glucose values in the hypoglycaemic range were observed. HbA1c was strongly correlated (p = 0.002 to 0.0001) in the whole group with 8 am (r = 0.39), 9.30 am (r = 0.56), and evening blood glucose values (r = 0.42). These results indicate that, in patients treated with the sulphonylurea gliclazide, alone or in combination with metformin, the lowest blood glucose values occur in the evening more frequently (4/5) than in the morning. Therefore, evening blood glucose determination should be performed systematically in the course of the metabolic evaluation of NIDDM patients on oral hypoglycaemic agents. © 1997 John Wiley & Sons, Ltd.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since jeudi 31 octobre 2013

Vascular dysfunction is one of the major complications in diabetes mellitus. The extended interaction of proteins with aldoses results in non enzymatic glycation, ultimately leading to formation of Advanced Glycation End Products (AGEs). We previously showed that increased adhesion of diabetic red blood cells (RBCs) was statistically correlated with the vascular severity and the glycated hemoglobin level. We demonstrated that diabetic erythrocytes bear cell surface AGE which enhance their binding to endothelium, resulting in oxidative stress through generation of thiobarbituric acid reactive substances (TBARS) and activation of the transcription factor N FKB, both of which were prevented by preincubating of endothelial cells with anti-RAGE IgG or the antioxidant probucol. Incubation of diabetic erythrocytes with endothelial cells increased the diffusional transit of 1251 albumin, an effect prevented by preincubation of endothelial cells with anti­ RAGE antibodies or an antioxidant compound. These data indicate that the interaction of diabetic erythrocytes with endothelium results in oxidative stress one consequence of which is increased vascular permeability. Copyright © 1996 Elsevier Science Ltd

Dysfunctional endothelium is associated with and, likely, predates clinical complications of diabetes mellitus, by promoting increased vascular permeability and thrombogenicity. Irreversible advanced glycation end products (AGEs), resulting from nonenzymatic glycation and oxidation of proteins or lipids, are found in plasma, vessel wall, and tissues and have been linked to the development of diabetic complications. The principal means through which AGEs exert their cellular effects is via specific cellular receptors, one of which, receptor for AGE (RAGE), is expressed by endothelium. We report that blockade of RAGE inhibits AGE-induced impairment of endothelial barrier function, and reverse, in large part, the early vascular hyperpermeability observed in diabetic rats. Inhibition of AGE- and diabetes-mediated hyperpermeability by antioxidants, both in vitro and in vivo, suggested the central role of AGE-RAGE-induced oxidant stress in the development of hyperpermeability. Taken together, these data support the concept that ligation of AGEs by endothelial RAGE induces cellular dysfunction, at least in part by an oxidant-sensitive mechanism, contributing to vascular hyperpermeability in diabetes, and that RAGE is central to this pathologic process.

Aims This study aimed to assess the relationship between blood pressure and cognitive function in elderly patients with diabetes mellitus (DM). Methods A total of 32 patients with DM aged≥65 years (seven women and 25 men; mean±SD age: 74.3±6.4 years) were included in this cross-sectional study. Relationships between blood pressure and neuropsychological tests were determined using Spearman's rank correlations (ρ) and multivariable linear regression models. Results Lower diastolic blood pressure was associated with lower scores on the Frontal Assessment Battery (ρ=0.32, P =0.02), longer times to complete the Trail Making Test Part B (ρ=0.51, P =0.003), lower scores for the Finger Tapping Test (ρ=0.36, P =0.046) and less verbal fluency (ρ=0.36, P =0.047). In multivariable models, these relationships were attenuated after adjusting for levels of education. Conclusion There was an association between lower diastolic blood pressure and poorer executive function in this cohort of elderly DM patients. These results underline the importance of systematic cognitive evaluation in elderly patients with DM, and suggest that a too-low diastolic blood pressure may have deleterious effects on mental function. Larger studies in the future are required to confirm these preliminary results.

Synthesis, storage, secretion, delivery, and utilization of thyroid hormones are dependent upon specific enzymatic activity; inherited disorders may cause thyroid disease.

Aim Type 2 diabetes mellitus (T2DM) is often associated with chronic kidney disease. For this reason, this article reviews the relationship between treatment of T2DM and renal disease. Method The review presents the recent French data on the management of diabetes in patients with renal impairment, and discusses the implications of renal disease for the treatment of such patients. Prescribing data are presented for various antidiabetic treatments, and the use of the more commonly prescribed medications is discussed with reference to T2DM patients with renal disease. Results In France, it is estimated that 4–5% of the general population has T2DM and that almost 40% of patients with end-stage renal failure have diabetes. Diabetes and renal disease are both risk factors for cardiovascular morbidity and mortality. Glycaemic control is pivotal in T2DM patients for minimizing the risk of vascular complications and hypoglycaemic episodes, particularly in patients with renal disease who also have a higher risk of hypoglycaemia. Whereas poorly controlled glycaemia increases the risk of renal disease and its progression, the risk is diminished in patients treated intensively for diabetes and in those who achieve stable glycaemic control. Intensive multitargeted treatment can also help to decrease cardiovascular morbidity and mortality, especially if started early in patients who have not yet developed macrovascular complications. Conclusion In recent years, considerable improvement has been observed in France regarding the follow-up of diabetic patients. Less extensive, but nonetheless significant, improvement has also been observed in glycaemic control. However, even though treatment decisions generally take renal function into account, some at-risk treatments are often still being used in patients with renal insufficiency.

This study evaluated the incidence of diabetic retinopathy (DR) over a 3-year period in a French population that was followed by OPHDIAT®, and assessed the clinical and biological risk factors associated with incident retinopathy.The studied patients were screened for DR during hospitalization for their annual diabetes check-up in the endocrinology department by two examinations three years apart. DR screening used the OPHDIAT® telemedical network, and the examination included clinical and biological data.A total of 254 patients were studied. At the 3-year follow-up, the incidence was 14.0%, (CI: 9.5-18.4%). Longer duration of diabetes and the presence of micro- or macroalbuminuria were significantly associated with incident retinopathy (P0.05). Other potential risk factors were not statistically significantly related to DR progression, and only treatment with insulin showed a trend towards significance (P0.20).This study provides the first French data on the incidence of DR, which was estimated after a 3-year follow-up at 14.0%. Longer duration of time from the onset of diabetes and higher baseline albuminuria were the only statistically significant risk factors found for the incidence of DR after our 3-year study. Nevertheless, microalbuminuria should be more widely used in ophthalmological practice in the assessment of DR, as is already the case for both blood pressure and HbA(1c).

Mitochondrial diabetes affects up to 1% of patients with diabetes and is often unrecognised by the physicians. Maternally inherited diabetes and deafness (MIDD) resulting from the mutation 3243AG of the mitochondrial DNA is the most frequent mutation associated with mitochondrial diabetes. This review summarizes the range of clinical phenotypes associated with MIDD and outlines the advances in genetic diagnosis, pathogenesis and management of these patients.

Few cases of myopathy have been reported in patients treated with ezetimibe as monotherapy or in association with a statin. We report on two cases of elevation of CKP that occurred upon monotherapy with ezetimibe, which were reversible after discontinuation of the drug. In both cases, patients previously experienced intolerance with other lipid-lowering agents. The pathogenesis of muscle toxicity associated with ezetimibe is not known yet. An interaction with statin or a toxicity mechanism common to several lipid-lowering drugs have been suggested. A potential role of induction of glucuronidation by numerous associated drugs can also be involved Although association of ezetimibe with myopathy seems to be uncommon, special attention should be given to patients treated with ezetimibe who had a previous intolerance to other lipid-lowering drugs and who received several drugs.

Maternal diabetes associated with neural deafness is designated as MIDD (maternal inherited diabetes and deafness); it is linked to a A3243G tRNA leucine gene mutation. The disease course is progressive and involvement of other systems is frequent. In most cases, macular pattern dystrophy is present. Muscular lesions are characteristic of mitochondrial myopathies. Mitochondrial abnormalities have also been observed in pancreas, heart, kidney, smooth muscle of the digestive tract with variable heteroplasmy levels. MIDD may present as a single syndrome or is part of MELAS or Kearns-Sayre syndrome.

This study had several purposes: to define cytomorphological features of thyroid cells that might be modified by alcohol fixation; to optimize May-Grünwald-Giemsa (MGG) staining on ThinPrep(R) (TP; Cytyc Inc., Bexborough, MA, USA) slides and to compare the diagnostic accuracy of slides prepared by a liquid-based method with those obtained by conventional technique. This study included 120 cases of ultrasound-guided fine needle aspiration (FNA) of the thyroid and 55 FNAs performed on surgically resected thyroid specimens. Histological control was available in 80 cases. In the first group of 120 FNAs, a split-sample technique was used for the TP. Three screenings were performed: first, an individual screening of the conventional smears (CS) and of the TP, a second screening to compare cells observed on the TP with the histological control and a third screening to assess the previously defined diagnostic criteria. Twenty-seven TP cases (22%) were considered unsatisfactory for diagnosis compared with 10 in CS (8%). The high rate of unsatisfactory cases with TP is likely to be due to the use of the split-sample technique. The sensitivity was 94% for CS and 81% for TP. The specificity was 67% and 60% for CS and TP, respectively. Two occult papillary carcinomas were missed by both methods. As for the MGG staining, the modified technique used for TP resulted in the same quality as the standard procedure. Conversely, TP did however induce uncommon morphological features. In this study, sensitivity and specificity levels are higher for CS than for TP; the difference may be explained by the fact that the methanol fixative used for TP induces some cytological alterations, especially in oncocytic tumours and lymphocytic thyroïditis.

"Common" type 2 diabetes mellitus is a multifactorial disease. Hyperglycemia is related to a decrease in glucose peripheral uptake, and to an increase in hepatic glucose production, due to reduced insulin secretion and insulin sensitivity. Multiple insulin secretory defects are present, including loss of basal pulsatility, lack of early phase of insulin secretion after intravenous glucose administration, decreased basal and stimulated plasma insulin concentrations, excess in prohormone secretion, and progressive decrease in insulin secretory capacity with time. These genetically determined abnormalities appear early in the course of the disease. Insulin resistance affects muscle, liver, and adipose tissue. For the same plasma insulin levels, peripheral glucose uptake and hepatic glucose production suppressibility are lower in diabetic patients than in controls. It results from aging of the population and from "western" lifestyle, with progressive increase in mean body weight, due to excess in energy intake, decreased energy expenses and low physical activity level.The role of beta-cell dysfunction, as well as the interplay between insulin secretory defect and insulin resistance are now better understood. In subjects with normal beta-cell function, increase in insulin needs secondary to insulin resistance is compensated by an increase in insulin secretion adjusted to maintain plasma glucose levels to normal. In subjects genetically predisposed to type 2 diabetes, failure of beta-cell to compensate for increased needs is responsible for a progressive elevation in plasma glucose levels, then for overt type 2 diabetes. This adaptative phenomenon is called beta-cell compensation of insulin resistance. The lack of compensation is responsible for type 2 diabetes. When permanent hyperglycemia is present, progressive insulin secretory failure with time ensues, due to glucotoxicity and to lipotoxicity.Simple changes in lifestyle, such regular moderate physical activity, and control of body weight, should permit to avoid the explosion in prevalence of type 2 diabetes. This has been evidenced by the results of prospective studies aiming at preventing conversion from impaired glucose tolerance to diabetes. In patients with permanent hyperglycemia not controlled by lifestyle changes, metabolic defects are the targets of specific therapy intervention with antidiabetic oral agents, such as insulin secretagogues, insulin sensitizers, and inhibitors of hepatic glucose production.

The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established by intervention studies. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. This review focuses on the consequences of hyperglycemia on the formation of advanced glycation end-products (AGEs), and on the role of AGEs and of their specific receptors (RAGE) in the functional and anatomical alterations of the vascular wall. AGEs are formed during the Maillard reaction by the binding of aldoses on free NH(2) groups of proteins, which, after a cascade of molecular rearrangements, result in molecules of brown color and specific fluorescence. Experimental studies have indicated that the binding of AGEs to RAGE activates cells, particularly monocytes and endothelial cells. Activated endothelial cells produce cytokines, and express adhesion molecules and tissue factor. The role of AGEs in increased oxidative stress, and in the functional alterations in vascular tone control observed in diabetes, in part related to a reduction in nitric oxide, is also discussed. The microvascular retinal, glomerular and nerve lesions induced by experimental diabetes in animals are prevented by an inhibitor of AGEs formation, aminoguanidine. The administration in diabetic animals of recombinant RAGE, which hinders AGEs-RAGE interaction, prevents hyperpermeability and vascular lesions. These data suggest a central role of AGEs and RAGE in the development of chronic complications of diabetes.

The aim of this study was to investigate circulating soluble Fas (sFas) and Fas ligand (sFasL), two transmembrane glycoproteins involved in apoptosis, in the serum of diabetic patients.We assessed sFas and sFasL serum levels in normal controls (n=15), and in both 42 diabetic patients without complications, or with predominant retinopathy or neuropathy, using sFas and sFasL specific ELISA method.sFasL serum levels were less than 0.1 ng/ml in normal controls and in each group of diabetic patients. In diabetic patients with a predominant neuropathy, sFas serum levels were significantly increased not only when compared with normal controls (13.5 +/- 3.6 ng/ml vs 7.1 +/- 1.1 ng/ml, p0.001), but also when compared with patients without complications (vs 9.1 +/- 1.8 ng/ml, p0.001) or with a predominant retinopathy (vs 8.7 +/- 1.9 ng/ml, p0.001).These preliminary data suggest that a dysregulation of the Fas system in peripheral neuronal cells may be involved in the increase of sFas observed in diabetic patients with neuropathy.

In type 2 diabetes, the primary and secondary prevention of long-term micro- and macrovascular complications requires a control of blood glucose levels 24 hours a day. The present study was undertaken to assess the effect of a new formulation of gliclazide administered once daily, gliclazide modified release, on plasma glucose levels over 24 hours.In 21 type 2 diabetic patients previously treated by diet alone or oral antidiabetic agents, glycemic profile (8 am, 10 am, 12 am, 2 pm, 5 pm, 8 pm, 10 pm, 3 am and 8 am), overall glycemic control, acceptability, and compliance with treatment were assessed before and after a 10-week treatment with gliclazide modified release, (30-60 mg), given once daily at breakfast.The results indicate a significant decrease in plasma glucose levels at all points of the cycle. Mean plasma glucose levels over 24 hours and mean plasma glucose levels during the fasting and the postprandial periods were significantly improved after treatment. In previous drug-naive patients, decrease in HbA1C was observed (1.0 +/- 1.1%, P=0.022). The acceptability was good, with no hypoglycemic events, and a high compliance with treatment was also observed.We can therefore conclude that gliclazide modified release, given once daily at breakfast, is effective over 24 hours in reducing plasma glucose levels in type 2 diabetes. This once-daily administration should lead to an optimal patient compliance with treatment.

Keywords Beta cell function.Cardiovascularcomplications.Glycaemic control.Guidelines.Nephropathy.Sulfonylureas.Treatment.Trials.Type 2 diabetesAbbreviationsADOPT A Diabetes Outcome Progression TrialADVANCE Action in Diabetes and Vascular Disease:Preterax and Diamicron-MR ControlledEvaluationUKPDS UK Prospective Diabetes StudyTo the Editor: InarecentissueofDiabetologia, Schernthanerand colleagues [1] state that the last consensus statementfrom the ADA and EASD released in October 2008 [2]wasnot based strongly enough on clinical evidence, and raisesome concerns about the role of sulfonylureas in treatingtype 2 diabetes.Trialsevaluatingdrugsforthetreatmentoftype2diabeteswiththehighestdegreeofevidencearesparse,andtothebestof my knowledge include only the UK Prospective DiabetesStudy (UKPDS) [3, 4], A Diabetes Outcome ProgressionTrial (ADOPT) [5], Action in Diabetes and VascularDisease: Preterax and Diamicron-MR Controlled Evaluation(ADVANCE) [6] and PROspective pioglitAzone ClinicalTrial In macroVascular Events (PROactive) [7]. The firstthree of these studies in which sulfonylureas were usedfound in favour of their beneficial effect in the long-term,either on glycaemic control, beta cell function or cardiovas-cular events.Concerning beta cell function, Schernthaner et al.advocate the positive results with rosiglitazone in ADOPT[5]. However, it is worth considering that after 5 years, betacell function was identical between the rosiglitazone- andglibenclamide (known as glyburide in the USA andCanada)-treated groups, and higher than in the metformin-treated group. UKPDS data also demonstrated a similareffect on beta cell function after 6 years, comparingmetformin vs sulfonylureas [8].Concerning cardiovascular events, in the most recenttrial, namely ADVANCE [6], based on modified-releasegliclazide (gliclazide MR) with normalisation of HbA

Thyroid medullary carcinoma is usually detected in the presence of an isolated thyroid nodule or in the context of a family disease: familial thyroid medullary carcinoma or multiple endocrine neoplasia type 2A.Here we report a third means of detection: an unexplained rise in carcinoembryonic antigen levels after cancer surgery. In each case, the carcinoembryonic antigen increase led to the assessment of the caicitonin plasma level and to a thyroid echography being performed. Thyroid medullary carcinoma was confirmed in every case after surgery.Even though the association of thyroid follicular carcinoma with familial adenomatous polyposis is common, the association of thyroid medullary carcinoma with breast or colonic carcinoma remains exceptional and probably accidental. Due to the seriousness of the thyroid medullary carcinoma, it is mandatory to look for it in the event of an unexplained rise in the carcinoembryonic antigen level, by assessing the calcitonin plasma level.

Hypoglycemia is a clinical and biological syndrome, caused by an abnormal decrease in plasma glucose levels to below 0.55 g/l (3.0 mmol/l). Hypoglycemia is responsible for non-specific signs and symptoms which should be noted in a particular pathological context, and for secretion of counterregulatory hormones (mainly glucagon and catecholamines). Difficulty in identifying the etiology is variable, based upon history and physical examination, and hormonal investigations or imaging procedures, according to the results. Drug-related hypoglycemia is the most frequent observed cause (mainly in insulin-treated diabetic patients, but many drugs may be involved), followed par toxicity (alcohol mainly). Tumor-induced hypoglycemia is secondary to inappropriate insulin secretion by a beta-cell pancreatic tumor (insulinoma), and, rarely to an extrapancreatic mesenchymal large tumor secreting IGF-II. Hypoglycemia is present in other diseases, such as hormonal deficiencies, hepatic, or renal failure, or acute cardiac insufficiency. Multifactorial hypoglycemia seems to be underdiagnosed, mainly in hospitalized, underfed older patients with severe disease or sepsis. Autoimmune hypoglycemia is rare, due to insulin or insulin-receptor autoantibodies. Reactive hypoglycemia is observed after gastrectomy, but true primitive hypoglycemia appears to be rare, with false excess diagnosis in the majority of the cases.

We report the case of a Caucasian patient with insulin autoimmune syndrome (IAS), defined as the association of hypoglycaemic attacks with insulin autoantibodies in individuals not previously treated with exogenous insulin. This rare syndrome (more than 200 published cases) has been reported mainly in Japan. Most affected patients present with other autoimmune disorders, most often Graves' disease. In most cases, insulin autoantibodies appear a few weeks after the beginning of treatment with a drug containing a sulphyldryl group. A significant increase in insulin and C-peptide plasma concentrations and the presence of other antiorgan antibodies are observed. The susceptibility haplotype is present in the Japanese population, which may account for the high frequency of IAS. Spontaneous remission is observed in 80% of cases, with cessation of hypoglycaemic attacks and disappearance of insulin autoantibodies some months after withdrawal of the drug. This rare cause of hypoglycaemia in Caucasian subjects should be considered in aetiologic investigation of spontaneous hypoglycaemia.

To investigate the capability of the learning vector quantizer (LVQ) in the discrimination of benign from malignant thyroid lesions.The study was performed on May-Grünwald-Giemsa-stained smears taken by fine needle aspiration (FNA). Using a custom image analysis system, 25 features that describe the size, shape and texture of approximately 100 nuclei were measured from each case. Statistical features were extracted from each case, and a linear regression analysis was performed to detect the statistically significant features. The cases were distributed by category, as follows: 100 cases of goiter and follicular adenomas, 11 cases of follicular carcinoma, 35 cases of papillary carcinoma, 24 cases of oncocytic adenoma, 8 cases of oncocytic carcinoma and 20 cases of Hashimoto thyroiditis. About 30% of the cases from each class were used for training two LVQ classifiers. The remaining 139 cases, out of a total of 198, were used as the test set. A classifier was used to discriminate into four classes and a second into two classes.The application of LVQ neural networks allows good discrimination between benign and malignant lesions (O.A. = 97.8). However, reliable discrimination of the cytologic types of the lesions was not obtained.These results indicate that the use of neural networks combined with image morphometry may offer useful information on the potential for malignancy of thyroid lesions and may improve the diagnostic accuracy of FNA of the thyroid gland, especially in cases of follicular neoplasms classified as suspicious for malignancy and in cases of oncocytic tumors.

To evaluate the prevalence of macular pattern dystrophy (MPD) in maternally inherited diabetes and deafness (MIDD), a new subtype of diabetes mellitus that cosegregates with a mutation of mitochondrial DNA (i.e., the substitution of guanine for adenine at position 3243 of leucine transfer RNA) and to report the clinical characteristics of MPD.Prospective cohort study.Forty-six patients from 29 families with an adenine-to-guanine mutation of mitochondrial DNA were recruited from a French collaborative multicenter study. Thirty-five patients had MIDD, 8 were asymptomatic children of MIDD patients, and 3 had MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes). The 33 MIDD patients with diabetes were matched for diabetes duration and gender with 33 patients with "common" type-2 diabetes to compare the prevalence of diabetic retinopathy (DR) in both series.All patients had a full ophthalmologic examination and fundus photographs.The presence and severity of MPD and DR were assessed in each patient.Thirty MIDD patients (85.7%) of 35 exhibited bilateral MPD characterized by linear pigmentation surrounding the macula and optic disc. In 24 of these 30 patients, visual acuity was 20/25 or more in both eyes. The prevalence of DR was 6% in MIDD patients with diabetes versus 15% for patients with common type-2 diabetes (a difference that was not significant, P = 0.23). The fundus of each of the eight asymptomatic children was normal. MPD was present in one of the three cases of MELAS.The prevalence of MPD in MIDD is high. Its detection may be helpful for the diagnosis of this new subtype of diabetes, for which specific treatments may be proposed.

Previous studies have failed to predict somatostatin analog response with somatostatin receptor scintigraphy in pituitary adenomas. In vitro studies have shown that the density of somatostatin receptors in pituitary tumors might be critical for octreotide response.The density of somatostatin receptors was calculated in vivo combining the uptake index obtained from somatostatin receptor scintigraphy and the tumor volume obtained by MRI. The ratio of these two values, called density index (DI), was established in 32 of 37 consecutive patients with pituitary adenomas (11 had growth hormone-secreting adenomas, 4 thyroid-stimulating hormone-secreting and 17 nonfunctioning). It was compared with hormonal response, assessed in 15 secreting adenomas on growth hormone or thyroid stimulating hormone suppression (which was considered significant when it reached at least 50% of basal level), and with tumor shrinkage (which was considered significant whenor =20% of pretherapeutic value) in 12 secreting and 14 nonfunctioning adenomas.In agreement with previous reports, uptake index is not predictive of octreotide response. In contrast, DI predicts both hormonal suppression and tumor shrinkage (P = 0.009 and P = 0.0002, respectively) obtained with octreotide therapy. DI sensitivity, specificity and accuracy were 92% each, and a positive correlation was found between DI and the percentage of tumor shrinkage (r = 0.54, P = 0.004).The combination of scintigraphic and MRI data allows the computation of a DI for somatostatin receptors that points out patients who can profit from somatostatin analog treatment.

Hereditary pancreatitis (HP) is a rare inherited disorder, characterised by recurrent episodes of pancreatitis often beginning in early childhood. The mode of inheritance suggests an autosomal dominant trait with incomplete penetrance. The gene, or at least one of the genes, responsible for hereditary pancreatitis has been mapped to the long arm of chromosome 7 and a missense mutation, an arginine to histidine substitution at residue 117 in the trypsinogen cationic gene (try4) has been shown to segregate with the HP phenotype. The aim of this work was to investigate the molecular basis of hereditary pancreatitis. This study was performed on 14 HP families. The five exons of the trypsinogen cationic gene were studied using a specific gene amplification assay combined with denaturing gradient gel electrophoresis (DGGE). The present paper describes three novel mutations, namely K23R and N29I and a deletion -28delTCC in the promoter region. We also found a polymorphism in exon 4, D162D. In eight of these families we found a mutation which segregates with the disease. A segregation analysis using microsatellite markers carried out on the other families suggests genetic heterogeneity in at least one of them. Our findings confirm the implication of the cationic trypsinogen gene in HP and highlight allelic diversity associated with this phenotype. We also show that the pattern of inheritance of HP is probably complex and that other genes may be involved in this genetic disease. Keywords: hereditary pancreatitis; mutation analysis; cationic trypsinogen

Relationships between glycaemic control, hypertension, and development of microangiopathy have been well documented in Type 1 (insulin-dependent) but not in Type 2 (non-insulin-dependent) diabetes mellitus. Therefore, we have investigated these relationships in a cohort of 64 Type 2 patients free of retinopathy (by angiofluorography), who were regularly followed until development of retinopathy or for at least 7 years as outpatients. Glycaemic control was assessed by 1 to 4 HbA1 determinations per year. Retinal status was monitored by annual angiofluorography. Nonproliferative retinopathy developed in 14 patients (cumulative incidence at 13 years: 29.8%) after a mean diabetes duration of 14.3+/-8.9 years (range 2-27). In multivariate analysis (Cox model), mean HbA1 during follow-up (p0.001), and hypertension at first examination (p = 0.09) were associated with the development of retinopathy, but age, sex, BMI, diabetes duration, smoking, and fasting blood glucose were not. The relative risk for developing retinopathy (RR) was 7.2 (IC 95%: 1.61-32.4) in patients with a mean HbA1 during follow-up above the median value of the cohort (8.3%) compared with patients with HbA1 during follow-up below this value. RR was 2.5 (IC 0.8-8) in patients with HbA1 at first examination above compared to below the median value (8.4%). RR was 3.0 (IC 0.9-10) in patients treated for hypertension at baseline compared to those without treatment. A sixfold increase in retinopathy prevalence was observed between patients with mean HbA1 in the highest or lowest quartile of mean HbA1 distribution during follow-up. This longitudinal study indicates a strong association between long-term glycaemic control and the development of diabetic retinopathy in Type 2 diabetes.

Germline mutations of the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2, including multiple endocrine type 2A (MEN 2A), type 2B (MEN 2B), and familial medullary thyroid carcinoma. The relationship between specific mutations and syndromic features has been established. In particular, the risk for pheochromocytoma and hyperparathyroidism (HPT) in MEN 2A patients is clearly associated with the presence of the RET mutation at a specific position, i.e. at codon 634. Also, a correlation between a specific mutation, C634R, and the development of HPT has been suggested but is still controversial. To further investigate the relationship between specific mutations of codon 634 and the development of HPT, we studied a population of 188 individuals, carrying mutations at codon 634, namely C634R (65 patients belonging to 10 families), C634Y (80 patients belonging to 11 families), or the less frequent codon 634 mutations [i.e. C634S, C634F, C634G, or C634W (43 patients belonging to 9 families)]. In this series of patients, we defined an overall HPT prevalence of 19.1% and found that this prevalence did not vary significantly, with respect to the nature of the mutation. However, irrespective of the particular mutation, the prevalence of HPT showed a high interfamilial variability. The statistical model that best fitted with the observed data was in favor of the heterogeneity of the risk for HPT, with 40% of the families showing an HPT risk of 34% and 60% of the families showing an HPT risk of 9%. In addition, our study clearly demonstrated that HPT could be an early component of the disease and provided the first estimate of age-specific and mutation-specific HPT penetrance in individuals with mutations of codon 634 of the RET proto-oncogene.