High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes.
S E Bursell ,
A C Clermont ,
L P Aiello ,
L M Aiello ,
D K Schlossman ,
E ...P Feener ,
L Laffel and
G L King
Beetham Eye Institute, Joslin Diabetes Center, Boston, Massachusetts, USA.
Abstract
OBJECTIVE: To determine the effectiveness of vitamin E treatment in normalizing retinal blood flow and renal function in patients
with <10 years of type 1 diabetes. RESEARCH DESIGN AND METHODS: An 8-month randomized double-masked placebo-controlled crossover
trial evaluated 36 type 1 diabetic and 9 nondiabetic subjects. Subjects were randomly assigned to either 1,800 IU vitamin
E/day or placebo for 4 months and followed, after treatment crossover, for a further 4 months. Retinal blood flow was measured
using video fluorescein angiography, and renal function was assessed using normalized creatinine clearance from timed urine
collections. RESULTS: After vitamin E treatment, serum levels of vitamin E were significantly elevated (P<0.01) in both type
1 diabetic and control patients. Hemoglobin A1c was not affected by vitamin E treatment. Diabetic patient baseline retinal
blood flow (29.1+/-7.5 pixel2/s) was significantly (P = 0.030) decreased compared with that of nondiabetic subjects (35.2+/-7.2
pixel2/s). After vitamin E treatment, diabetic patient retinal blood flow (34.5+/-7.8 pixel2/s) was significantly increased
(P<0.001) and was comparable with that of nondiabetic subjects. Additionally, vitamin E treatment significantly (P = 0.039)
normalized elevated baseline creatinine clearance in diabetic patients. CONCLUSIONS: Oral vitamin E treatment appears to be
effective in normalizing retinal hemodynamic abnormalities and improving renal function in type 1 diabetic patients of short
disease duration without inducing a significant change in glycemic control. This suggests that vitamin E supplementation may
provide an additional benefit in reducing the risks for developing diabetic retinopathy or nephropathy.
Aim:To address the cellular components and the contractile mechanisms of the idiopathic epiretinal membrane (ERM).Methods:Ten surgically removed ERMs were fixed in 4% paraformaldehyde and analysed by ...whole-mount immunohistochemistry with anti-glial fibrillar acidic protein (GFAP) and alpha smooth-muscle actin (αSMA) antibodies. Type I collagen gel contraction assay, an established wound-healing assay in vitro, was performed using cultured bovine hyalocytes or normal human astrocytes (NHA) to evaluate the contractile property of the cells in the presence of tissue growth factor (TGF)-β2. The expression of αSMA was also analysed by western blot analysis to examine myofibroblastic transdifferentiation of the cells. Vitreous-induced collagen gel contraction was also evaluated.Results:All membranes were composed of αSMA immunopositive cells in contracted foci and GFAP immunopositive cells in the periphery. No apparent double positive cells were observed in any membranes examined. Cultured hyalocytes showed overexpression of αSMA and hypercontraction of collagen gels in response to TGF-β2, while glial cells showed marginal change. The vitreous from ERM patients also caused overexpression of αSMA and hypercontraction of the gels embedding hyalocytes, which were almost completely inhibited in the presence of anti-TGF-β2 neutralising antibody.Conclusions:Hyalocytes might be one of the critical components of ERM mediating its contractile property through the effect of TGF-β2 in the vitreous fluid.
We review the evolution of human bipedal locomotion with a particular emphasis on the evolution of the foot. We begin in the early twentieth century and focus particularly on hypotheses of an ...ape‐like ancestor for humans and human bipedal locomotion put forward by a succession of Gregory, Keith, Morton and Schultz. We give consideration to Morton's (1935) synthesis of foot evolution, in which he argues that the foot of the common ancestor of modern humans and the African apes would be intermediate between the foot of Pan and Hylobates whereas the foot of a hypothetical early hominin would be intermediate between that of a gorilla and a modern human. From this base rooted in comparative anatomy of living primates we trace changing ideas about the evolution of human bipedalism as increasing amounts of postcranial fossil material were discovered. Attention is given to the work of John Napier and John Robinson who were pioneers in the interpretation of Plio‐Pleistocene hominin skeletons in the 1960s. This is the period when the wealth of evidence from the southern African australopithecine sites was beginning to be appreciated and Olduvai Gorge was revealing its first evidence for Homo habilis. In more recent years, the discovery of the Laetoli footprint trail, the AL 288‐1 (A. afarensis) skeleton, the wealth of postcranial material from Koobi Fora, the Nariokotome Homo ergaster skeleton, Little Foot (Stw 573) from Sterkfontein in South Africa, and more recently tantalizing material assigned to the new and very early taxa Orrorin tugenensis, Ardipithecus ramidus and Sahelanthropus tchadensis has fuelled debate and speculation. The varying interpretations based on this material, together with changing theoretical insights and analytical approaches, is discussed and assessed in the context of new three‐dimensional morphometric analyses of australopithecine and Homo foot bones, suggesting that there may have been greater diversity in human bipedalism in the earlier phases of our evolutionary history than previously suspected.
Much of the morbidity and mortality associated with diabetes is primarily attributable to sequelae of microvascular and macrovascular disease. Over the past decade, dramatic progress has been ...achieved in elucidating the fundamental processes underlying the pathogenesis of these complications. Angiogenic factors in particular now appear to play a pivotal role in the development of microvascular complications as well as the response to macrovascular disease. Hyperglycemia, other growth factors, advanced glycation end products, oxidative stress, and ischemia can increase growth factor expression. In some microvascular tissues, the result is pathologic neovascularization and increased vascular permeability. These responses account for much of the visual loss associated with diabetic retinopathy and may, in addition, serve a significant role in nephropathy and neuropathy. In contrast, recent data suggest that vascular collateralization resulting from ischemia-induced growth factor release in tissues compromised by macrovascular disease may be important in reducing clinical symptoms and tissue damage. This angiogenic response, which may be beneficial in coronary artery and peripheral limb disease, appears to be reduced in patients with diabetes. Thus, two apparently diametrically opposed therapeutic paradigms are arising for the treatment of vascular complications in diabetes. Indeed, growth factor antagonists have been used successfully in diabetes-related animal models to block angiogenic and permeability complications in the retina and kidney. Conversely, growth factor agonists have been successfully used to stimulate collateral vessel formation and reduce ischemic symptoms from macrovascular disease in the coronary arteries and peripheral limbs. Both of these approaches are currently being evaluated in clinical trials for their respective indications. Thus, as these divergent therapeutic modalities begin to enter the clinical arena, this apparent paradox necessitates careful consideration of the potential risks, benefits, and interactions of the opposing regimens. Using vascular endothelial growth factor as a classic example of growth factor involvement, we discuss the current preclinical and clinical data supporting these approaches and the implications arising from the probable coexistence of these two therapeutic modalities.
Intraocular neovascularization occurs in numerous ischemic retinal disorders, including diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity
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. This ...proliferation often results in vitreous hemorrhage, retinal detachment, and neovascular glaucoma, with subsequent visual loss. Although numerous growth factors stimulate angiogenesis in vivo,
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these factors are not consistently increased in proliferative retinopathies
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or secreted, as would be expected if they caused intraocular neovascularization at sites distant from those of retinal ischemia.
In neovascular retinopathies such as proliferative diabetic retinopathy, there is initially extensive active proliferation of new vessels
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. Visual loss at this time results from . . .
To evaluate the ability to determine clinical levels of diabetic retinopathy, timing of next appropriate retinal evaluation, and necessity of referral to ophthalmology specialists using stereoscopic ...nonmydriatic digital-video color retinal images as compared with Early Treatment Diabetic Retinopathy Study (ETDRS) seven standard field 35-mm stereoscopic color fundus photographs.
Prospective, clinic-based, comparative instrument validation study.
Fifty-four patients (108 eyes) with type 1 or type 2 diabetes mellitus selected after chart review from a single center to include the full spectrum of diabetic retinopathy.
Nonsimultaneous 45°-field stereoscopic digital-video color images (JVN images) were obtained from three fields with the Joslin Vision Network (JVN) system before pupil dilation. Following pupil dilation, ETDRS seven standard field 35-mm stereoscopic color 30° fundus photographs (ETDRS photos) were obtained. Joslin Vision Network images and ETDRS photos were graded on a lesion-by-lesion basis by two independent, masked readers to assess ETDRS clinical level of diabetic retinopathy. An independent ophthalmology retina specialist adjudicated interreader disagreements in a masked fashion.
Determination of ETDRS clinical level of diabetic retinopathy, timing of next ophthalmic evaluation of diabetic retinopathy, and need for prompt referral to ophthalmology specialist.
There was substantial agreement (κ = 0.65) between the clinical level of diabetic retinopathy assessed from the undilated JVN images and the dilated ETDRS photos. Agreement was excellent (κ = 0.87) for suggested referral to ophthalmology specialists for eye examinations. Comparison of individual lesions between the JVN images and the ETDRS photos and for interreader comparisons were comparable to the prior ETDRS study.
Undilated digital-video images using the JVN system were comparable photographs for the determination of diabetic retinopathy level. The results validate the agreement between nonmydriatic JVN images and dilated ETDRS photographs and suggest that this digital technique may be an effective telemedicine tool for remotely determining the level of diabetic retinopathy, suggesting timing of next retinal evaluation and identifying the need for prompt referral to ophthalmology specialists. Thus, the JVN system would be an appropriate tool for facilitating increased access of diabetic patients into recommended eye evaluations, but should not be construed as a paradigm that would replace the need for comprehensive eye examinations.
Role of vascular endothelial growth factor in diabetic vascular complications
Much of the morbidity and mortality associated with diabetes mellitus predominantly reflects its deleterious effects on ...microcirculation and macrocirculation. During the past few years, rapid advancement has been made in our understanding of the mechanisms and molecules involved in the pathogenesis of diabetic microvasculopathy. This is particularly true with regard to retinal vascular disease and the role of the angiogenesis- and vasopermeability-inducing molecule, vascular endothelial growth factor (VEGF).
Biochemical studies in many relevant cell types have been performed. Effects of VEGF action and inhibition have been evaluated in animals. Interventions that block the biochemical pathways initiated by VEGF have been tested both in culture and in animals. Human clinical trials have begun.
VEGF induces vascular endothelial cell proliferation, migration and vasopermeability in many cells and tissues. In vivo, VEGF has been identified as a primary initiator of proliferative diabetic retinopathy, and as a potential mediator of nonproliferative retinopathy. In addition, VEGF has been implicated in the development of neuropathy and nephropathy in the patient with diabetes. In patients with diabetes and coronary artery or peripheral vascular disease, VEGF may induce development of cardiac and limb vascular collateralization, respectively. Many biochemical processes mediating these actions have now been elucidated.
VEGF appears to play a central role in mediating diabetic vasculopathy in many organs. Improved understanding of the molecular mechanisms underlying these processes has permitted development of novel therapeutic interventions, several of which are now in human clinical trials. These scientific advances and various implications for the future care of vasculopathy associated with diabetes will be discussed.
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