Barbara Esser

Effects of medical therapies on retinopathy progression in type 2 diabetes.

BACKGROUND We investigated whether intensive glycemic control, combination therapy for dyslipidemia, and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes. Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy. METHODS In a randomized trial, we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or standard treatment for glycemia (target glycated hemoglobin level, <6.0% or 7.0 to 7.9%, respectively) and also for dyslipidemia (160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin) or for systolic blood-pressure control (target, <120 or <140 mm Hg). A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale (as assessed from seven-field stereoscopic fundus photographs, with 17 possible steps and a higher number of steps indicating greater severity) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy. RESULTS At 4 years, the rates of progression of diabetic retinopathy were 7.3% with intensive glycemia treatment, versus 10.4% with standard therapy (adjusted odds ratio, 0.67; 95% confidence interval [CI], 0.51 to 0.87; P=0.003); 6.5% with fenofibrate for intensive dyslipidemia therapy, versus 10.2% with placebo (adjusted odds ratio, 0.60; 95% CI, 0.42 to 0.87; P=0.006); and 10.4% with intensive blood-pressure therapy, versus 8.8% with standard therapy (adjusted odds ratio, 1.23; 95% CI, 0.84 to 1.79; P=0.29). CONCLUSIONS Intensive glycemic control and intensive combination treatment of dyslipidemia, but not intensive blood-pressure control, reduced the rate of progression of diabetic retinopathy. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov numbers, NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study.)

The biologic activity of mast cell granules: VIII. In vivo and in vitro characterization of mast cell granule-derived inflammatory factors involved in rat late-phase reactions

Intradermal injections of isolated mast cell granules (MCGs), as well as solubilized high-molecular-weight (HMW) (greater than 10,000 daltons) and low-molecular-weight (LMW) (10,000 greater than MW greater than 500 daltons) fractionated granule constituents, can produce inflammatory responses termed late-phase reactions (LPRs). The identity and mechanism of action of various inflammatory factor(s) contained within these fractions is incompletely established. Since rat LPRs are neutrophil-dependent responses, we analyzed the inherent neutrophil chemoattractant potential of HMW and LMW granule fractions using a 48-well microchemotaxis chamber. Although both HMW and LMW fractions attracted rat neutrophils, the LMW fraction was less active at equivalent protein concentrations. Checkerboard analysis demonstrated that the HMW fraction enhanced random migration of neutrophils, indicating that the HMW fraction contains factors that are primarily chemokinetic. To analyze further the HMW fraction, solubilized MCGs were sequentially fractionated with XM300 (MW greater than 300,000 daltons), and YM100 (300,000 greater than MW greater than 100,000 daltons), XM50 (100,000 greater than MW greater than 50,000 daltons), and YM10 (50,000 greater than MW greater than 10,000 daltons) ultrafiltration membranes. This process revealed that most in vivo inflammation-provoking activity as well as the in vitro chemoattractant activity resided in the XM300 and YM100 retentate fractions. Two of the major constituents of the HMW fraction, heparin and chymase, were evaluated for their contribution to the chemoattraction. Purified MCG heparin did not evoke neutrophil migratory responses in vitro or in vivo. Sepharose 4B chromatography of solubilized MCG demonstrated a peak of inflammation-provoking activity beginning at the void volume and tapering off near the 400,000 MW range. This in vivo activity was clearly separable from the chymase activity and represents the HMW inflammatory factors. These results demonstrate that both HMW and LMW granule fractions contain inflammatory activities capable of producing LPR in vivo and suggest that enhancement of neutrophil migration at sites of mast cell degranulation is one mechanism of action.

Lack of Association Between Thiazolidinediones and Macular Edema in Type 2 Diabetes: The ACCORD Eye Substudy

OBJECTIVE To assess the cross-sectional association of thiazolidinediones with diabetic macular edema (DME). METHODS The cross-sectional association of DME and visual acuity with thiazolidinediones was examined by means of baseline fundus photographs and visual acuity measurements from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Visual acuity was assessed in 9690 participants in the ACCORD trial, and 3473 of these participants had fundus photographs that were centrally read in a standardized fashion by masked graders to assess DME and retinopathy from October 23, 2003, to March 10, 2006. RESULTS Among the subsample, 695 (20.0%) people had used thiazolidinediones, whereas 217 (6.2%) people had DME. Thiazolidinedione use was not associated with DME in unadjusted (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.71-1.44; P = .95) and adjusted (OR, 0.97; 95% CI, 0.67-1.40; P = .86) analyses. Significant associations with DME were found for retinopathy severity (P < .001) and age (OR, 0.97; 95% CI, 0.952-0.997; P = .03) but not for hemoglobin A(1c) (P = .06), duration of diabetes (P = .65), sex (P = .72), and ethnicity (P = .20). Thiazolidinedione use was associated with slightly greater visual acuity (0.79 letter; 95% CI, 0.20-1.38; P = .009) of uncertain clinical significance. CONCLUSIONS In a cross-sectional analysis of data from the largest study to date, no association was observed between thiazolidinedione exposure and DME in patients with type 2 diabetes; however, we cannot exclude a modest protective or harmful association. Trial Registration clinicaltrials.gov Identifier: NCT00542178.

Evidence of early retinal microvascular changes in patients with type 2 diabetes and depression

Objective: To examine retinal vascular caliber, an indicator of early microvascular disease and depression in patients with Type 2 diabetes. Methods: We conducted a clinic-based study, comparing participants with Type 2 diabetes with major depression (n = 43), without depression (n = 49), and healthy controls without diabetes or depression (n = 54). Retinal vascular caliber was measured from digital photographs. Depression status was determined, using standardized clinical assessment. Results: After adjusting for age and gender, participants with diabetes and depression had larger arteriolar and venular calibers (147.7 &mgr;m for arteriolar and 215.7 &mgr;m for venular calibers) than participants with diabetes but without depression (143.3 &mgr;m and 213.9 &mgr;m) and healthy controls (135.8 &mgr;m and 202.5 &mgr;m, p for trend = .002 for arteriolar and p = .02 for venular caliber). In multivariate models adjusting for duration of diabetes, systolic blood pressure, cigarette smoking, serum glucose, Cerebrovascular Risk Factor Scale, Cumulative Illness Rating Scale, and retinopathy levels, this relationship remained significant for retinal arterioles (p = .02) but not for retinal venules (p = .10). Conclusions: These data show that patients with Type 2 diabetes with major depression have wider retinal arterioles, supporting the concept that depression is associated with early microvascular changes in Type 2 diabetes. CIRS = Cumulative Illness Rating Scale; CRFS = Cerebrovascular Risk Factor Scales; MRI = magnetic resonance imaging; SBP = systolic blood pressure.

Comparison of standardized clinical classification with fundus photograph grading for the assessment of diabetic retinopathy and diabetic macular edema severity.

Purpose: To compare evaluation by clinical examination with image grading at a reading center for the classification of diabetic retinopathy and diabetic macular edema. Methods: Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Family Investigations of Nephropathy in Diabetes (FIND) had similar methods of clinical and fundus photograph evaluation. For analysis purposes, the photographic grading scales were condensed to correspond to the clinical scales, and agreement between clinicians and reading center classification were compared. Results: Six thousand nine hundred and two eyes of ACCORD participants and 3,638 eyes of FIND participants were analyzed for agreement (percent, kappa) on diabetic retinopathy on a 5-level scale. Exact agreement between clinicians and reading center on diabetic retinopathy severity category was 69% in ACCORD and 74% in FIND (kappa 0.42 and 0.65). Sensitivities of the clinical grading to identify the presence of mild nonproliferative retinopathy or worse were 0.53 in ACCORD and 0.84 in FIND. Specificities were 0.97 and 0.96, respectively. Diabetic macular edema agreement in 6,649 eyes of ACCORD participants and 3,366 eyes of FIND participants was similar (kappa 0.35 and 0.41). Sensitivities of the clinical grading to identify diabetic macular edema were 0.44 and 0.53 and specificities were 0.99 and 0.94, respectively. Conclusion: The results support the use of clinical information for defining broad severity categories but not for documenting small-to-moderate changes in diabetic retinopathy over time.

In vivo and in vitro assessment of the role of leukotriene B4 as a mediator of rat cutaneous late-phase reactions

Mast cell-dependent late-phase reactions (LPR) occur in rat skin and are characterized histologically by an early (1 to 8 hours) neutrophil-rich infiltrate, which is essential to a later (24 hours) infiltration by mononuclear cells. Although the ability of preformed mast cell-granule constituents alone to elicit LPR is clearly established, the relative pathogenetic contributions of newly generated lipid mediators to rat LPR are unknown. Leukotriene B4 (LTB4) may be generated by stimulated mast cells in a number of species and might potentially contribute to the neutrophil ingress. In order to examine this possibility in a well-characterized animal model of LPR, the capacity of LTB4 to influence rat cutaneous inflammation was studied. LTB4 (0.1 to 100 ng) alone did not induce vasopermeability in rat skin nor potentiate the blueing response to histamine. Intracutaneous LTB4 (0.1 to 100 ng) did not cause significant infiltration of neutrophils 3 to 4, 6 to 8, or 24 hours after injection; increased numbers of mononuclear leukocytes were not appreciated through 24 hours. In the same animals intracutaneous anti-IgE and intact mast cell granules both produced intense biphasic infiltration characteristic of rat LPR. In order to examine if rat polymorphonuclear leukocytes were capable of responding to LTB4, several in vitro studies were performed. Rat peritoneal and peripheral blood neutrophils migrated toward formyl-methionyl-leucyl-phenyl-alanine in vitro but not to purified human or synthetic LTB4. Rat peripheral blood and elicited peritoneal neutrophils bound only 32% and 27%, respectively, of the quantity of [3H]LTB4 bound by human neutrophils.(ABSTRACT TRUNCATED AT 250 WORDS)

Is depression associated with microvascular disease in patients with type 2 diabetes

We hypothesize that late‐life depression is a manifestation of microvascular disease in patients with type 2 diabetes. We conducted a clinic‐based cross‐sectional study, comparing retinal vascular caliber, a marker of microvascular disease, in participants with type 2 diabetes with major depression (n=34), without depression (n=27) and healthy non‐diabetic controls (n=38). Retinal vascular caliber was measured from digital retinal photographs using a validated computer‐assisted method. After adjusting for age and gender, there was a trend of increasing retinal arteriolar caliber from healthy controls (132.6 μm), to diabetic patients without depression (139.2 μm), and diabetic patients with major depression (145.3 μm, P=0.008). The trend in retinal arteriolar caliber remains significant after adjusting for duration of diabetes, but not after further adjusting for vascular risk factors. Our findings suggest that there is variation in the retinal vascular caliber between type 2 diabetic patients with and without major depression and non‐diabetic controls. This variation was largely related to poorer diabetes control and a higher frequency of vascular risk factors in diabetic patients, particularly those with depression. Studies with larger sample size may provide further insights into this association. Depression and Anxiety, 2008. Published 2007 Wiley‐Liss, Inc.