Toke Bek

The oxygen saturation in retinal vessels from diabetic patients depends on the severity and type of vision-threatening retinopathy.

Diabetic retinopathy is characterized by morphological lesions in the retina secondary to disturbances in retinal blood flow which may influence the supply of oxygen to the retinal metabolism. Using retinal oximetry, it has been shown that the oxygen saturation is increased in retinal arterioles and venules from diabetic patients with retinopathy, but oxygenation before the development of retinopathy and possible differences in retinal oxygenation between diabetic maculopathy and proliferative diabetic retinopathy patients have not been evaluated.

24-h ambulatory blood pressure and retinopathy in normoalbuminuric IDDM patients.

Summary The role of blood pressure elevation in the incidence and progression of diabetic retinopathy is not clearly established and results have been conflicting. Blood pressure and urinary albumin excretion (UAE) are closely related. In order to evaluate the independent relationship between retinopathy and blood pressure elevation, precise information on UAE is essential, as confounding by renal disease (incipient or overt), cannot otherwise be excluded.The aim of the present study was to evaluate the association between diabetic retinopathy and 24-h ambulatory blood pressure (AMBP) in a group of well-characterized normoalbuminuric IDDM patients. In 65 normoalbuminuric (UAE < 20 μg/min) IDDM patients we performed 24-h AMBP (Spacelabs 90 207) with readings at 20-min intervals. Fundus photographs were graded independently by two experienced ophthalmologists. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. HbA1 c was determined by HPLC. Tobacco use and level of physical activity were assessed by questionnaire. Fifteen patients had no detectable retinal changes [grade 1], 35 had grade 2 retinopathy; and 15 had more advanced retinopathy [grade 3–6]. Diastolic night blood pressure was significantly higher in patients with diabetic retinopathy compared to patients without retinopathy (68 ± 8 mmHg [grade 3–6] and 65 ± 6 mmHg [grade 2], compared to 61 ± 4 mmHg [grade 1], p = 0.02). Diurnal blood pressure variation was significantly blunted in the patients with retinopathy as indicated by a higher night/day ratio of diastolic blood pressure (84.6 % ± 4 [grade 3–6], and 81.2 % ± 6 [grade 2] compared to 79.1 % ± 4 [grade 1], p = 0.01). Heart rate tended to be higher in patients in group 2 and 3–6 compared to patients without retinopathy with p values of 0.07 and 0.11 for day-time and 24 h values, respectively. Mean HbA1 c increased significantly with increasing levels of retinopathy (p < 0.01). Patients were similar regarding sex, age, tobacco use, and level of physical activity. Notably, UAE was almost identical in the three groups (5.0 × /÷1.7 [grade 1], 3.9 × /÷1.8 [grade 2], and 5.1 × /÷1.6 μg/min [grade 3–6]). In conclusion, night blood pressure is higher and circadian blood pressure variation blunted in patients with retinopathy compared to patients without retinopathy despite strict normoalbuminuria and similar UAE levels in the groups compared. Our data suggest that the association between blood pressure and diabetic retinopathy is present also when coexisting renal disease is excluded. Disturbed diurnal variation of blood pressure is a pathophysiological feature related to the development of both retinopathy and nephropathy in IDDM patients. [Diabetologia (1998) 41: 105–110]

Mutation analysis of the WFS1 gene in seven Danish Wolfram syndrome families; four new mutations identified.

Wolfram syndrome (WS) is a neuro-degenerative autosomal recessive (AR) disorder (OMIM #222300) caused by mutations in the WFS1 gene on 4p16.1. More than 120 mutations have been identified in WFS1 associated with AR WS, as well as autosomal dominant nonsyndromic low-frequency sensorineural hearing loss (LFSNHL). WFS1 variants were identified in eight subjects from seven families with WS, leading to the identification of four novel mutations, Q194X (nonsense), H313Y (missense), L313fsX360 (duplication frame shift) and F883fsX951 (deletion frame shift), and four previously reported mutations, A133T and L543R (missense), V415del (in frame triple deletion) and F883fsX950 (deletion frame shift). A mutation was found in 11/14 disease chromosomes, two subjects were homozygous for one mutation, one subject was compound heterozygous for two nucleotide substitutions (missense), one subject was compound heterozygous for a duplication and a deletion (frame shift), and in three families only one mutation was detected (Q194X and H313Y). All affected individuals shared clinically early-onset diabetes mellitus and progressive optic atrophy with onset in the first and second decades, respectively. In contrast, diabetes insipidus was present in two subjects only. Various degrees and types of hearing impairment were diagnosed in six individuals and cataract was observed in five subjects.

Diabetic retinopathy in pregnancy during tight metabolic control

Background. The relation between retinopathy and the parameters: 24‐h blood pressure, glucose control, albuminuria, and outcome of pregnancy was studied before, during, and after pregnancy in women with insulin‐dependent diabetes mellitus on tight metabolic control during pregnancy.

Regional morphology and pathophysiology of retinal vascular disease

Disturbances in the retinal vascular supply are involved in the pathophysiology of the most frequent diseases causing visual impairment and blindness in the Western World. These diseases are diagnosed by noting how morphological lesions in the retina vary in shape, size, location and dynamics, and subsequently concluding the presence of a specific disease entity. This diagnostic approach can be used to identify the site of a retinal vascular occlusion, to assess whether retinal diseases are primarily due to changes in the larger retinal vessels or the microcirculation, and to differentiate the relative involvement of the choroidal and the retinal vascular systems. However, a number of morphological manifestations of retinal vascular disease cannot presently be related to the underlying pathophysiology. The review concludes that there is a need for developing new methods for assessing vascular structure and function in the ciliary vascular system supplying the choroid and the optic nerve head. Presently, the study of these structures relies on imaging techniques with limited penetration and resolution into the tissue. Secondly, there is a need for studying oscillations in retinal vascular function occurring within days to weeks, and for studying regional manifestations of retinal vascular disease. This may constitute the basis for future research in retinal vascular pathophysiology and for the development of new treatment modalities to reduce blindness secondary to retinal vascular disease.

Openers of small conductance calcium-activated potassium channels selectively enhance NO-mediated bradykinin vasodilatation in porcine retinal arterioles

Background and purpose:  Small (SKCa or KCa2) and intermediate (IKCa or KCa3.1) conductance calcium‐activated potassium channels are involved in regulation of vascular tone and blood pressure. The present study investigated whether NS309 (6,7‐dichloro‐1H‐indole‐2,3‐dione 3‐oxime) and CyPPA (cyclohexyl‐[2‐(3,5‐dimethyl‐pyrazol‐1‐yl)‐6‐methyl‐pyrimidin‐4‐yl]‐amine), which are selective openers of SKCa and IKCa channels and of SKCa2 and SKCa3 channels, respectively, enhance endothelium‐dependent vasodilatation in porcine retinal arterioles.

Reduction of choroidal neovascularization in mice by adeno-associated virus-delivered anti-vascular endothelial growth factor short hairpin RNA

Strategies leading to the long‐term suppression of inappropriate ocular angiogenesis are required to avoid the need for repetitive monthly injections for treatment of diseases of the eye, such as age‐related macular degeneration (AMD). The present study aimed to develop a strategy for the sustained repression of vascular endothelial growth factor (VEGF), which is identified as the key player in exudative AMD.

Role of calcium-activated potassium channels with small conductance in bradykinin-induced vasodilation of porcine retinal arterioles.

PURPOSE Endothelial dysfunction and impaired vasodilation may be involved in the pathogenesis of retinal vascular diseases. In the present study, the mechanisms underlying bradykinin vasodilation were examined and whether calcium-activated potassium channels of small (SK(Ca)) and intermediate (IK(Ca)) conductance are involved in regulation of endothelium-dependent vasodilation in retinal arterioles was investigated. METHODS Porcine retinal arterioles (diameter approximately 112 microm, N = 119) were mounted in microvascular myographs for isometric tension recordings. The arterioles were contracted with the thromboxane analogue, U46619, and concentration-response curves were constructed for bradykinin and a novel opener of SK(Ca) and IK(Ca) channels, NS309. RESULTS In U46619-contracted arterioles, bradykinin and NS309 induced concentration-dependent relaxations. In vessels without endothelium, bradykinin relaxation was abolished and NS309 relaxation was attenuated. Inhibition of NO synthase with asymmetric dimethylarginine and/or cyclooxygenase with indomethacin markedly reduced bradykinin and NS309 relaxation. NO synthase and cyclooxygenase inhibition together with oxyhemoglobin abolished bradykinin relaxation and attenuated NS309 relaxation. Blocking of SK(Ca) and IK(Ca) channels with apamin plus charybdotoxin or blocking of SK(Ca) channels alone in the absence and the presence of indomethacin markedly reduced bradykinin and NS309 relaxation, whereas blocking of IK(Ca) channels had no significant effect. In vessels without endothelium, blocking of SK(Ca) channels alone had no effect on sodium nitroprusside-induced relaxation. CONCLUSIONS In porcine retinal arterioles, NO and prostaglandins mediate endothelium-dependent relaxation to bradykinin and NS309. Moreover, these findings suggest that SK(Ca) channels contribute to NO-mediated relaxation induced by bradykinin and NS309 and, hence, may play an important role in retinal arterial endothelial function.

Adeno-associated virus-delivered polycistronic microRNA-clusters for knockdown of vascular endothelial growth factor in vivo.

Vascular endothelial growth factor (VEGF) is an angiogenic growth factor that plays a critical role in several diseases, including cancer, rheumatoid arthritis and diseases of the eye. Persistent regulation of VEGF by expression of small interfering RNAs targeting VEGF represents a potential future strategy for treatment of such diseases. As a step toward this goal, the present study combines the potency of VEGF‐targeted miRNA mimics, produced from a miRNA cluster, with delivery by adeno‐associated virus (AAV)‐based vectors.

Individualized optimization of the screening interval for diabetic retinopathy: a new model

Introduction:  Screening programmes for diabetic retinopathy follow guidelines that ensure that vision‐threatening complications are detected even when the disease progression is fast. This implies that patients with slow disease progression will be recommended examinations more often than needed.