Kai von Dickhoff

Apolipoprotein E phenotype is related to macro- and microangiopathy in patients with non-insulin-dependent diabetes mellitus.

The role of apoliprotein E (apo E) in modulating the susceptibility of individuals with non-insulin-dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 143 male and 128 female patients with NIDDM. The data show that the apolipoprotein phenotype E2 somehow protects from macrovascular complications in NIDDM both in men and women. E2 also tends to protect from microvascular complications. In contrast, apo E phenotypes E4/4 and E4/3 tend to increase the risk for macroangiopathy in NIDDM patients. The lower prevalence of macroangiopathy in the subjects with E2 was associated with lower plasma total and LDL cholesterol concentrations and low plasma lipoprotein(a) levels. Overall, this study demonstrates the role of the apo E phenotype to modulate the risk for diabetic complications in patients with NIDDM. The confirmation of the association of apo E polymorphism with diabetic complications warrants, however, long-term follow-up studies.

Matrix metalloproteinase‐2 (MMP‐2) immunoreactive protein—a new prognostic marker in uveal melanoma?

Uveal melanoma is the most common primary intraocular tumour. Once haematogenous metastasis has occurred, there is no cure for the disease and there is an obvious need for new biological prognostic markers to estimate the risk of metastasis. In this study, the expression of matrix metalloproteinase‐2 (MMP‐2) was characterized immunohistochemically in 29 human uveal melanomas. Enzyme‐linked immunoassays and gelatin zymographies were assessed in order to quantify the expression of gelatinases A and B, as well as the tissue inhibitor of metalloproteinases (TIMPs), in the vitreous body. A total of 49 per cent of the uveal melanomas displayed a positive immunoreaction for MMP‐2 in melanoma cells, the epithelioid cells showing the most frequent staining. There was no correlation between the positivity of MMP‐2 staining and the size of the primary tumour, gender or age. The expression of MMP‐2 was associated with a dismal prognosis: the 5‐year overall survival rate for MMP‐2‐positive cases was significantly inferior to that of the MMP‐2 negative cases, 49 per cent vs. 86 per cent, respectively (p=0·02). A patient group at high risk of metastatic disease was identified; only 38 per cent of patients with a MMP‐2‐positive non‐spindle cell uveal melanoma survived for 5 years. The analyses of MMPs or TIMPs in the vitreous body had no prognostic value. Positive immunostaining for MMP‐2 was observed in the retinal pigment epithelium, corneal epithelium, and fibroblasts in the ciliary body and choroid. It is concluded that immunohistochemical analysis of MMP‐2 may help to predict a risk of metastasis in uveal melanoma. Copyright

Apolipoprotein B gene DNA polymorphisms are associated with macro‐ and microangiopathy in non‐insulin‐dependent diabetes mellitus

Ukkola O, Savolainen MJ, Salmela PI, von Dickhoff K, Kesäniemi YA. Apolipoprotein B gene DNA polymorphisms are associated with macro‐and microangiopathy in non‐insulin‐dependent diabetes mellitus.

DNA polymorphisms at the locus for human cholesteryl ester transfer protein (CETP) are associated with macro- and microangiopathy in non-insulin-dependent diabetes mellitus.

The effect of variation at the cholesteryl ester transfer protein (CETP) gene locus and in the apolipoprotein (apo) AI‐CIII‐AIV gene cluster on the susceptibility of individuals with non‐insulin‐dependent diabetes mellitus (NIDDM) to atherosclerotic vascular disease was studied in 136 male and 122 female patients with NIDDM. The prevalence of myocardial infarction was high (38%) in patients with the EcoNI genotype 2–2 of the CETP gene locus (= 2‐2; subjects homozygous for the absence of the restriction site) compared with patients with the genotype 1–1 (=1–1; subjects homozygous for the presence of the restriction site) (18%, p < 0.02). The prevalence of any evidence of coronary heart disease (CHD) (presence of ischaemic ECG changes or definite myocardial infarction) was high in 2–2 (73%) compared with the genotype 1–2 (= 1–2; heterozygous for the presence of the restriction site) (52%, p < 0.02) and genotype 1–1 (p = 0.06). CHD was more prevalent in men with 2–2 (70%) than in those with 1–1 (42%, p < 0.05), but in women no significant differences were found in the prevalences of CHD between the EcoNI genotypes. Neuropathy was more often present in the patients with 2–2 (31%) than in those with 1–1 (12%, p < 0.02) or 1–2 (14%, p < 0.01). Plasma total cholesterol and total‐ and VLDL‐triglycerides were higher in women with the EcoNI genotype 1–1 than in those with the genotype 1–2. In men no significant differences in plasma lipids were found. In addition, the prevalence of cerebrovascular disease was high (21%) in the patients with the genotype 1–1 of the TaqlB polymorphism compared with the genotype 2–2 (6%, p < 0.0–2). None of the alleles defined by four polymorphisms in the apo AI‐CIII‐AIV gene region were associated with an increased risk for macroangiopathy. The PstI polymorphism had an effect on plasma triglyceride levels. At the CETP locus one pair of loci (TaqlB and EcoNI) and three pairs of loci at the apo AI‐CIII‐AIV gene cluster (SacI and MspI, SapI and PvuII and MspI and PvuII) showed significant allelic association. In conclusion, the variation of CETP locus modulates the risk for diabetic complications in patients with NIDDM and the effect seems to be different between men and women. In contrast, the AI‐CIII‐AIV gene cluster polymorphisms seem not to be related to the risk of CHD in NIDDM. Long‐term follow‐up studies are needed to confirm the association of CETP gene polymorphism with diabetic complications.

Ocular complications in young adults with insulin-dependent diabetes mellitus since childhood.

A cross‐sectional study in 80 insulin‐dependent diabetic patients born 1963–1968 who experienced the onset of diabetes before 15 years of age showed that at a mean age of 21.6 (range 17–25) years and after a mean duration of diabetes of 13.3 (range 6–24) years, 80% of the patients had retinopathy: 70% had background and 10% proliferative changes. Retinopathy correlated with the duration of the diabetes and poor glucose control at 15 years of age but not with the actual level of glycated haemoglobin. The severity of retinopathy was worse in women than in men. One patient (1.2%) was blind. Two patients had had cataract operations and 66% had myopic refraction in one or both eyes. In 61 patients a further period of ophthalmological follow‐up of 3–4 years was included. After 20 years of diabetes, all had retinopathy and 29% had proliferative changes: 33% had received laser treatment after 8–27 (mean 16.1) years of diabetes. Altogether, 2 patients (2.5% of the original series) were blind. For prevention of diabetic retinopathy and blindness, good glucose control from puberty and careful ophthalmological follow‐up after transfer of the patient from paediatric to adult diabetes care play major roles.

A study of the mechanism of ocular irritation following YAG laser capsulotomy in rabbits.

The irritative response to Nd:YAG laser capsulotomy was studied in unanaesthetized rabbits. Posterior lens capsulotomy with a total energy of 100 mJ had no effect on the pupil size but increased the intraocular pressure by 5-10 mmHg and caused a breakdown of the blood-aqueous barrier. Anterior lens capsulotomy with a total energy of 20, 60 or 100 mJ caused constriction of the pupil, and an increase in intraocular pressure in a dose-dependent manner, and a breakdown of the blood-aqueous barrier. Indomethacin attenuated all the component parts of the irritative response and (D-arg1, D-pro2, D-trp7,9, leu11)-SP attenuated the miotic response. A combination of indomethacin and the substance P antagonist almost completely abolished the irritative response. This indicates that the acute YAG-laser-induced irritation in the rabbit eye is dependent both on a release of prostaglandins and on substance P, the former probably releasing the latter from sensory nerves.

Contrast sensitivity after resolution of central serous retinopathy

The contrast sensitivity of 21 patients was measured using TV equipment (Wavetek 143 function generator and Sony PVM90CE video monitor) and the Vistech test 6–15 years after the acute stage of central serous retinopathy. In the majority of cases contrast sensitivity was lower in the affected eye. The difference between the affected and the fellow eye was statistically significant at 1 and 6 cycles/degree (c/d) but not at 19 c/d. In 13/21 cases (62%) the results of the Vistech test were consistent with those of the TV test. Contrast sensitivity did not correlate with the duration of the disease or with the ultimate clinical picture of the macula. At 6 c/d there was a statistically significant correlation between visual acuity and contrast sensitivity. If the visual acuity was less than 1.0, contrast sensitivity was decreased, but decreased contrast sensitivity was also observed in four eyes with normal visual acuity, indicating that the level of visual deficit may not be established by measurement of visual acuity alone.

Ocular irritative response to YAG laser capsulotomy in rabbits: Release of calcitonin gene-related peptide and effects of methysergide

The Neodymium (Nd):YAG laser is commonly used in ophthalmology mainly for the posterior capsulotomy in patients with secondary cataract after extracapsular cataract extraction. A frequent side-effect following different kinds of YAG laser treatments is an acute increase in the intraocular pressure (IOP). The present study addresses the role of calcitonin gene-related peptide (CGRP) in the ocular irritative response following YAG laser anterior capsulotomy in rabbits. The YAG laser anterior capsulotomy caused an irritative response in the eye, which consisted of an increase in the IOP, miosis and breakdown of the blood-aqueous barrier. Following YAG laser capsulotomy, CGRP-immunoreactivity was found in the aqueous humour in different molecular weight forms as revealed by gel-permeation chromatography. One of the peaks coeluted with synthetic human CGRP. Methysergide attenuated the increase in the IOP and disruption of the blood-aqueous barrier, but not the miosis, following YAG laser anterior capsulotomy. The present study demonstrates the release of CGRP into the aqueous humour following YAG laser capsulotomy, and suggests that CGRP is partly causing the increase in IOP and disruption of the blood-aqueous barrier in this irritative response.