Role of vitreoretinal surgery in maximizing treatment outcome following complications after proton therapy for uveal melanoma.

L'utilisation de faisceaux de protons accélérés dans le traitement des mélanomes de l'uvée a été utilisée pour la première fois en Suisse (et par ailleurs en Europe) en 1984. Depuis, la protonthérapie a constamment évolué avec des logiciels toujours plus performants et précis pour devenir à l'heure actuelle le traitement de référence pour ce type de tumeurs. Ainsi, jusqu'à ce jour, l'Institut Paul Scherrer à Villigen a traité plus de 7000 cas de tumeurs oculaires. Mais la protonthérapie, aussi efficace soit-elle avec un taux de guérison de plus de 98%, comporte malheureusement un certain nom bre d'effets secondaires et indésirables pouvant parfois mener le patient jusqu'à l'énucléation secondai re. De la simple dermatite actinique à l'hémorragie intravitréenne massive, les complications induites sont pour la plupart bien connues et documentées mais leurs prises en charge, notamment sur un organe préalablement irradié diffèrent. Alors que nous avons beaucoup de recul sur la protonthérapie, la gestion de ses complications reste propre à chaque centre de soin et n'est que très peu documentée. Les complications majeures de la protonthérapie qui ont nécessité une prise en charge par le chirurgien vitrorétinien représentent souvent un défi majeur. Bien que rares, puisqu'elles ne représentent que 2% de notre collectif, celles-ci peuvent avoir de lourdes conséquences. Pa r exemple, une hémorragie intravitréenne massive, complication la plus fréquente dans notre série, compromet l'observation de la tumeur au fond d'oeil et empêche le bon suivi oncologique. La chirurgie vitrorétinienne a alors pour mission, de restaurer la transparence des milieux, élément indispensable à l'ophtalmologue pour le suivi clinique, iconographique et radiologique des mélanomes de l'uvée. Secondairement, cette chirurgie permet parfois d'augmenter l'acuité visuelle de l'oeil malade. La chirurgie vitrorétinienne est un précieux atout pour l'oncologue et permet d'éviter une énucléation secondaire. Elle participe ainsi à la prise en charge globale du patient atteint de mélanome de l'uvée.

The loss of GLUT2 expression in the pancreatic beta-cells of diabetic db/db mice is associated with an impaired DNA-binding activity of islet-specific trans-acting factors.

GLUT2 expression is reduced in the pancreatic beta-cells of several diabetic animals. The transcriptional control of the gene in beta-cells involves at least two islet-specific DNA-binding proteins, GTIIa and PDX-1, which also transactivates the insulin, somatostatin and glucokinase genes. In this report, we assessed the DNA-binding activities of GTIIa and PDX-1 to their respective cis-elements of the GLUT2 promoter using nuclear extracts prepared from pancreatic islets of 12 week old db/db diabetic mice. We show that the decreased GLUT2 mRNA expression correlates with a decrease of the GTIIa DNA-binding activity, whereas the PDX-1 binding activity is increased. In these diabetic animals, insulin mRNA expression remains normal. The adjunction of dexamethasone to isolated pancreatic islets, a treatment previously shown to decrease PDX-1 expression in the insulin-secreting HIT-T15 cells, has no effect on the GTIIa and PDX-1 DNA-binding activities. These data suggest that the decreased activity of GTIIa, in contrast to PDX-1, may be a major initial step in the development of the beta-cell dysfunction in this model of diabetes.

Poly-N-Acetyl Glucosamine Fibers Induce Angiogenesis in ADP Inhibitor-Treated Diabetic Mice

Background: It has been previously demonstrated that short-fiber poly-N-acetyl-glucosamine (sNAG) nanofibers specifically interact with platelets, are hemostatic, and stimulate diabetic wound healing by activating angiogenesis, cell proliferation, and reepithelialization. Platelets play a significant physiologic role in wound healing. The influence of altered platelet function by treatment with the ADP inhibitor Clopidogrel (CL) on wound healing and the ability of sNAG to repair wounds in diabetic mice treated with CL were studied.Methods: Dorsal 1 cm2 skin wounds were excised on genetically diabetic 8-week to 12-week-old, Lep/r-db/db male mice, and wound healing kinetics were determined. Microscopic analysis was performed for angiogenesis (PECAM-1) and cell proliferation (Ki67). Mice were either treated with CL (P2Y12 ADP receptor antagonist, CL) or saline solution (NT). CL wounds were also treated with either a single application of topical sNAG (CL-sNAG) or were left untreated (CL-NT).Results: CL treatment did not alter wound healing kinetics, while sNAG induced faster wound closure in CL-treated mice compared with controls. CL treatment of diabetic mice caused an augmentation of cell proliferation and reduced angiogenesis compared with nontreated wounds. However, sNAG reversed the effects of CL on angiogenesis and partially reversed the effect on cell proliferation in the wound beds. The sNAG-treated wounds in CL-treated mice showed higher levels of cell proliferation and not did inhibit angiogenesis.Conclusions: CL treatment of diabetic mice decreased angiogenesis and increased cell proliferation in wounds but did not influence macroscopic wound healing kinetics. sNAG treatment did not inhibit angiogenesis in CL-treated mice and induced faster wound closure; sNAG technology is a promising strategy to facilitate the healing of complex bleeding wounds in CL-treated diabetic patients.

Appropriateness of colonoscopy in Europe (EPAGE II): presentation of methodology, general results, and analysis of complications.

BACKGROUND AND STUDY AIMS: Appropriate use of colonoscopy is a key component of quality management in gastrointestinal endoscopy. In an update of a 1998 publication, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy (EPAGE II) defined appropriateness criteria for various colonoscopy indications. This introductory paper therefore deals with methodology, general appropriateness, and a review of colonoscopy complications. METHODS:The RAND/UCLA Appropriateness Method was used to evaluate the appropriateness of various diagnostic colonoscopy indications, with 14 multidisciplinary experts using a scale from 1 (extremely inappropriate) to 9 (extremely appropriate). Evidence reported in a comprehensive updated literature review was used for these decisions. Consolidation of the ratings into three appropriateness categories (appropriate, uncertain, inappropriate) was based on the median and the heterogeneity of the votes. The experts then met to discuss areas of disagreement in the light of existing evidence, followed by a second rating round, with a subsequent third voting round on necessity criteria, using much more stringent criteria (i. e. colonoscopy is deemed mandatory). RESULTS: Overall, 463 indications were rated, with 55 %, 16 % and 29 % of them being judged appropriate, uncertain and inappropriate, respectively. Perforation and hemorrhage rates, as reported in 39 studies, were in general < 0.1 % and < 0.3 %, respectively CONCLUSIONS: The updated EPAGE II criteria constitute an aid to clinical decision-making but should in no way replace individual judgment. Detailed panel results are freely available on the internet (www.epage.ch) and will thus constitute a reference source of information for clinicians.

A comparative study of T-cell receptor V beta usage in non-obese diabetic (NOD) and I-E transgenic NOD mice.

The non-obese diabetic (NOD) mouse is a model for the study of insulin-dependent diabetes mellitus (IDDM). Recently transgenic NOD mice have been derived (NOD-E) that express the major histocompatibility complex (MHC) class II I-E molecule. NOD-E do not become diabetic and show negligible pancreatic insulitis. The possibility pertained that NOD-E mice are protected from disease by a process of T-cell deletion or anergy. This paper describes our attempts to discover whether this was so, by comparing NOD and NOD-E mouse T-cell receptor V beta usage. Splenocytes and lymph node cells were therefore tested for their ability to proliferate in response to monoclonal anti-V beta antibodies. We were unable to show any consistent differences between NOD and NOD-E responses to the panel of antibodies used. Previously proposed V beta were shown to be unlikely candidates for deletion or anergy. T cells present at low frequency (V beta 5+) in both NOD and NOD-E mice were shown to be as capable of expansion in response to antigenic stimulation as were more frequently expressed V beta. Our data therefore do not support deletion or anergy as mechanisms which could account for the observed disease protection in NOD-E mice.

SPECT myocardial perfusion imaging: long-term prognostic value in diabetic patients with and without coronary artery disease.

AIM: To determine the long-term prognostic value of SPECT myocardial perfusion imaging (MPI) for the occurrence of cardiovascular events in diabetic patients. PATIENTS, METHODS: SPECT MPI of 210 consecutive Caucasian diabetic patients were analysed using Kaplan-Meier event-free survival curves and independent predictors were determined by Cox multivariate analyses. RESULTS: Follow-up was complete in 200 (95%) patients with a median period of 3.0 years (0.8-5.0). The population was composed of 114 (57%) men, age 65 +/- 10 years, 181 (90.5%) type 2 diabetes mellitus, 50 (25%) with a history of coronary artery disease (CAD) and 98 (49%) presenting chest pain prior to MPI. The prevalence of abnormal MPI was 58%. Patients with a normal MPI had neither cardiac death, nor myocardial infarction, independently of a history of coronary artery disease or chest pain. Among the independent predictors of cardiac death and myocardial infarction, the strongest was abnormal MPI (p < 0.0001), followed by history of CAD (Hazard Ratio (HR) = 15.9; p = 0.0001), diabetic retinopathy (HR = 10.0; p = 0.001) and inability to exercise (HR = 7.7; p = 0.02). Patients with normal MPI had a low revascularisation rate of 2.4% during the follow-up period. Compared to normal MPI, cardiovascular events increased 5.2 fold for reversible defects, 8.5 fold for fixed defects and 20.1 fold for the association of both defects. CONCLUSION: Diabetic patients with normal MPI had an excellent prognosis independently of history of CAD. On the opposite, an abnormal MPI led to a >5-fold increase in cardiovascular events. This emphasizes the value of SPECT MPI in predicting and risk-stratifying cardiovascular events in diabetic patients.

Improve the quality of care for diabetic patients in the hospital. [Améliorer la qualité de la prise en charge des patients diabétiques à l'hôpital.]

Objectif : La prise en charge des patients avec hyperglycémie en soins aigus estdifficile et les erreurs de prescription d'insuline sont fréquentes. Notre objectifest de promouvoir l'évolution des pratiques vers une gestion efficace et sécuritairede l'hyperglycémie.Matériels et méthodes : Création d'un programme de formation structuré pourla gestion de l'hyperglycémie en soins aigus. Ce programme est le produit dumétissage entre le modèle de l'accompagnement thérapeutique et la systémiquedu management. Il vise l'acquisition d'une métacognition pour une réflexiontransversale face à l'hyperglycémie. Les objectifs spécifiques sont : comprendreles particularités de l'hyperglycémie en aigu ; gérer le basal/bolus ; argumenterle choix thérapeutique ; s'approprier l'outil sécuritaire d'aide à l'insulinothérapie ;anticiper la sortie du patient. Une analyse mixte a été effectuée : quantitative,glycémies, hypoglycémies, durée de séjour et qualitative, évolution de la réflexionautour de l'hyperglycémie.Résultats : Nov. 2009-2010, dans le Service de Médecine du CHUV, nous avonsdispensé 3 sessions de formation (15 cours), suivies d'une période de coaching,pour 78 internes. Évaluation quantitative : 85 patients (56,4 % H), âge moyen72,7 ± 9,6 ans, glycémies à J3 dans la cible (4-8,5 mmol/l) 44,6 %, glycémiemoyenne 8,5 ± 1,8 mmol/l, hypoglycémies 0,9 %, durée moyenne de séjour9,7 ± 5,4 J. Évaluation qualitative : choix du schéma thérapeutique pertinentdans la majorité des cas, environ 90 % des internes ont intégré les éléments depondération de l'insulinothérapie, estiment que cette formation a eu un impactpositif sur leur gestion, sont plus confiants dans leurs capacités et ont unmeilleur sentiment d'auto-efficacité. Les modalités pédagogiques adoptées ontfavorisé le transfert des compétences et le niveau de satisfaction globale atteint90 %.Conclusion : Le développement d'un programme de formation des soignants,basé sur l'approche réflexive et participative, permet une amélioration importantede la gestion de l'hyperglycémie. Notre projet s'inscrit dans une démarcheglobale visant à doter les bénéficiaires d'une vision systémique du diabète.

Managing hypertension in high-risk patients: lessons and promises from the STRATHE and ADVANCE trials.

Pharmacological treatment of hypertension represents a cost-effective way of preventing cardiovascular and renal complications. To benefit maximally from antihypertensive treatment, blood pressure should be brought to below 140/90 mmHg in every hypertensive patient, and even lower (< 130/80 mmHg) if diabetes or renal disease co-exists. Such targets cannot usually be reached using monotherapies. This is especially true in patients who present with a high cardiovascular risk. The co-administration of two agents acting by different mechanisms considerably increases the blood pressure control rate. Such combinations are not only efficacious, but are also well tolerated, and some fixed low-dose combinations even have a placebo-like tolerability. This is the case for the preparation containing the angiotensin-converting enzyme inhibitor perindopril (2 mg) and the diuretic indapamide (0.625 mg), a fixed low-dose combination that has been shown in controlled trials to be more effective than monotherapies in reducing albuminuria, regressing cardiac hypertrophy and improving the stiffness of large arteries. Using this combination to initiate antihypertensive therapy has been shown in a double-blind trial (Strategies of Treatment in Hypertension: Evaluation; STRATHE) to normalize blood pressure (< 140/90 mmHg) in significantly more patients (62%) than a sequential monotherapy approach based on atenolol, losartan and amlodipine (49%) and a stepped-care strategy based on valsartan and hydrochlorothiazide (47%), with no difference between the three arm groups in terms of tolerability. An ongoing randomized trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; ADVANCE) is a study with a 2 x 2 factorial design assessing the effects of the fixed-dose perindopril-indapamide combination and of the intensive gliclazide modified release-based glucose control regimen in type 2 diabetic patients, with or without hypertension. A total of 11 140 patients were randomly selected. Within the first 6 weeks of treatment (run-in phase), the perindopril-indapamide combination lowered blood pressure from 145/81 +/- 22/11 mmHg (mean +/- SD) to 137/78 +/- 20/10 mmHg. Fixed-dose combinations are becoming more and more popular for the management of hypertension, and are even proposed by hypertension guidelines as a first-line option to treat hypertensive patients.

Impaired musculoskeletal response to age and exercise in PPARβ(-/-) diabetic mice.

Fragility fractures are recognized complication of diabetes, but yet the underlying mechanisms remain poorly understood. This is particularly pronounced in type 2 diabetes in which the propensity to fall is increased but bone mass is not necessarily low. Thus, whether factors implicated in the development of insulin resistance and diabetes directly impact on the musculoskeletal system remains to be investigated. PPARβ(-/-) mice have reduced metabolic activity and are glucose intolerant. We examined changes in bone and muscle in PPARβ(-/-) mice and investigated both the mechanism behind those changes with age as well as their response to exercise. Compared with their wild type, PPARβ(-/-) mice had an accelerated and parallel decline in both muscle and bone strength with age. These changes were accompanied by increased myostatin expression, low bone formation, and increased resorption. In addition, mesenchymal cells from PPARβ(-/-) had a reduced proliferation capacity and appeared to differentiate into more of an adipogenic phenotype. Concomitantly we observed an increased expression of PPARγ, characteristic of adipocytes. The anabolic responses of muscle and bone to exercise were also diminished in PPARβ(-/-) mice. The periosteal bone formation response to direct bone compression was, however, maintained, indicating that PPARβ controls periosteal bone formation through muscle contraction and/or metabolism. Taken together, these data indicate that PPARβ deficiency leads to glucose intolerance, decreased muscle function, and reduced bone strength. On a molecular level, PPARβ appears to regulate myostatin and PPARγ expression in muscle and bone, thereby providing potential new targets to reverse bone fragility in patients with metabolic disturbances.

Nonsurgical options for treatment of diabetic macular edema

In the new book series 'ESASO Course Series', the essentials of the courses of the European School for Advanced Studies in Ophthalmology (ESASO) are made available to interested ophthalmologists, optometrists, technicians and residents all over the world. In this volume, the seminars on surgical retina presented by renowned experts during ESASO's activities are collected. Many specialists have contributed their knowledge to make this volume a device to give practical support. The topics range from prevention to state-of-the-art diagnostic techniques and the latest surgical treatment options for many eye conditions such as diabetic retinopathy and rhegmatogenous retinal detachment. This publication provides the ophthalmologist with the main aspects of surgical retina in a simple and practical update.

Complications of shoulder arthroplasty for osteoarthritis with posterior glenoid wear.

BACKGROUND: Anatomical total shoulder arthroplasty (TSA) for glenohumeral osteoarthritis (OA) and severe posterior glenoid wear may entail early postoperative complications (recurrence of posterior subluxation, glenoid loosening). To avoid these mechanical problems, reverse shoulder arthroplasty (RSA) has recently been proposed, mainly for its intrinsic stability. Our purpose was to present the results of TSA and RSA in glenohumeral OA with posterior glenoid wear of at least 20°. HYPOTHESIS: By virtue of its constrained design, RSA could prevent recurrence of posterior subluxation and limit the occurrence of mechanical complications. MATERIALS AND METHODS: A consecutive series of 23 patients (27 shoulders) were treated for glenohumeral OA with total shoulder prostheses: 19 TSAs and 8 RSAs. Mean age was 70years (range, 47-85years), mean retroversion angle 28° (20°-50°) and mean subluxation index 74% (57-89%). Constant Score, Subjective Shoulder Value (SSV), QuickDASH and Simple Shoulder Test (SST) were measured, and radiological examinations were performed at a mean follow-up of 52months (24-95months). RESULTS: TSA and RSA patients respectively displayed Constant Scores of 65 and 65, SSV of 79% and 74%, QuickDASH of 16 and 27, and SST of 88 and 78. Two patients underwent surgical revision of TSA because of glenoid loosening; 52% of TSA patients presented complete radiolucent lines and 11% recurrence of posterior subluxation. CONCLUSION: Complications are frequently observed after shoulder arthroplasty for OA with severe glenoid retroversion. RSA could be an alternative to TSA for selected patients, independently of rotator cuff status. Studies on RSA in this specific indication with longer follow-up are now needed. LEVEL OF EVIDENCE: Level IV; retrospective case series.