Proliferative diabetic retinopathy is associated with a low level of the natural ocular anti-angiogenic agent pigment epithelium-derived factor (PEDF) in aqueous humor. a pilot study.

Retinopathy is the most common microvascular diabetes complication and represents a major threat to the eyesight. The aim of this study was to address the role of pro- and anti-angiogenic molecules in diabetic retinopathy in the aqueous humor of the eye. Aqueous humor was collected at cataract surgery from 19 diabetic patients and from 13 age- and sex-matched normoglycemic controls. Levels of pro-angiogenic vascular endothelial growth factor (VEGF) and angiogenic inhibitor pigment epithelium-derived factor (PEDF) were determined. Angiogenic activity of the aqueous humor was quantified by measuring its effect on the migration of capillary endothelial cells. In the aqueous fluid, VEGF levels were increased in diabetics (mean values: 501 vs. 367 pg/ml; p = 0.05), compared to controls. PEDF was found to be decreased in diabetics (mean values: 2080 vs. 5780 ng/ml; p = 0.04) compared to controls. In seven diabetic patients with proliferative retinopathy, the most profound finding was a significant decrease of the PEDF level (mean value: 237 ng/ml), whereas VEGF levels were comparable to diabetic patients without proliferation (mean value: 3153; p = 0.003). Angiogenic activity in samples of patients from the control group was generally inhibitory due to PEDF, and inhibition was blocked by neutralizing antibodies to PEDF. Likewise, in diabetics without proliferation, angiogenic activity was also blocked by antibodies to PEDF. We will demonstrate here that the level of the natural ocular anti-angiogenic agent PEDF is inversely associated with proliferative retinopathy. PEDF is an important negative regulator of angiogenic activity of aqueous humor. Our data may have implications for the development of novel regimens for diabetic retinopathy.     

Low phospholipid arachidonic acid values in diabetic platelets.

Platelet aggregation is enhanced in diabetes mellitus, and platelets may be implicated in the pathogenesis of diabetic angiopathy. Increased platelet aggregation is probably mediated by the production of the proaggregatory prostaglandin thromboxane, which is synthesised from arachidonic acid (C20:4) by the action of the platelet enzymes cyclo-oxygenase and thromboxane synthetase. The fatty acid composition of platelet phospholipid was measured in 20 normal controls, 10 insulin-treated diabetics with no or minimal retinopathy, and 10 insulin-treated diabetics with proliferative retinopathy. The percentage of arachidonic acid was significantly higher in controls (mean 22.6%) than in the diabetics with no or minimal retinopathy (mean 18.5%; p less than 0.025) and the diabetics with proliferative retinopathy (mean 14.6%; p less than 0.001). The percentage of linoleic acid was lower in controls (mean 8.9%) than in the diabetics with no or minimal retinopathy (mean 12.6%; p less than 0.01) and diabetics with proliferative retinopathy (mean 13.1%; p less than 0.001). The mean percentage of linolenic acid was significantly lower in the diabetics with proliferative retinopathy (2.7%) than in the normal control group (4.4%; p less than 0.01). A significant negative correlation was found between the percentages of arachidonic acid and glycosylated haemoglobin (Rs = -0.58; p less than 0.001). A significant positive correlation was found between linoleic acid and the percentage of glycosylated haemoglobin (Rs = 0.51; p less than 0.01). The reciprocal correlation between percentages of arachidonic acid and glycosylated haemoglobin suggests that diabetic control may influence thromboxane release and platelet activity directly and that low percentages of arachidonic acid reflect the increased degree of in-vivo activation.     

贝伐单抗辅助的23G玻璃体切割术治疗严重增生性糖尿病视网膜病变的疗效观察

目的：2011年,我国糖尿病患者人数高达9240万。糖尿病视网膜病变（diabeticretinopathy,DR）作为糖尿病患者的常见并发症,在糖尿病人群中的患病率为37％,是导致成人获得性盲的最主要原因之一。严重增生性糖尿病视网膜病变以牵拉性视网膜脱离、玻璃体出血为特征,具有致盲率大,手术难度高等特点。针对与此,本文主要探讨术前注射贝伐单抗对23G玻璃体切割手术治疗严重增生性糖尿病视网膜病变患者效果的影响。方法：回顾性病例对照研究。共收集严重增生性糖尿病视网膜病变患者70例,药物辅助手术组（A组）21例,术前3—7天行玻璃体腔注射贝伐单抗（1．25mg／O．05mL）;单纯手术组（B组）49例,行23G玻璃体切割术。分析两组术前及术后视力、手术时间、医源性裂孔、电凝、术后出血的不同。结果：在术后3月,两组视力提高有统计学意义（P〈O．05）。A组平均手术时间为74分钟,而B组平均手术时间为85分钟（P〉0．05）。医源性裂孔在A组中有1例,而B组中有16例（P〈0．05）,在A组中有3例使用电凝,B组中有25例使用电凝（P〈0．05）。A组有1例出现术中及术后出血,B组为20例（P〈O．05）。结论：在这个回顾性研究中,我们发现对于严重增生性糖尿病视网膜病变的病人,术前玻璃体腔注射1．25mg／O．05ml贝伐单抗可以显著减少医源性裂孔的发生,减少术中电凝使用及术中术后出血的发生。     

Retinal photocoagulation does not influence intraocular levels of IGF-I, IGF-II and IGF-BP3 in proliferative diabetic retinopathy-evidence for combined treatment of PDR with somatostatin analogues and retinal photocoagulation?

Retinal photocoagulation reduces the incidence of severe visual loss in proliferative diabetic retinopathy (PDR). Reduced levels of VEGF/VPF might result in an improved function of the blood-retina barrier and cause a decrease of blood derived intraocular growth factors such as IGF-I. This study investigates whether retinal photocoagulation is able to normalize the concentrations of IGF-I, IGF-II and IGF-BP3 in the vitreous humor of patients undergoing vitrectomy. Levels of IGFs and the permeability marker, albumin, were measured in serum and vitreous of 52 patients. Three groups were compared: controls without proliferating eye disease (n = 19) and patients with PDR with (PDR+; n = 25) and without (PDR-; n = 8) previous retinal photocoagulation. IGF-I, IGF-II, IGF-BP3 and albumin were determined by immunological methods and were confirmed to be increased in patients with PDR compared to controls. Retinal photocoagulation influenced neither the intraocular concentration of the permeability marker albumin (PDR+: 253.2 +/- 46 mg/dl; PDR-: 256.4 +/- 66.5 mg/dl) nor the levels of IGFs (PDR+: IGF-I: 1.2 +/- 0.1 ng/ml; p = 0.38; IGF-II: 34.8 +/- 2.2 ng/ml; p = 0.1; IGF-BP3: 75.7 +/- 9.7 ng/ml; p = 0.27; PDR-: IGF-I: 1.1 +/- 0.2ng/ml; IGF-II: 29.3 +/- 5.2 ng/ml; IGF-BP3: 61.5 +/- 18.3 ng/ml). Systemic levels of albumin and IGFs were not changed significantly by retinal photocoagulation. These results demonstrate that previous retinal photocoagulation in patients undergoing vitrectomy does not functionally reestablish the blood-retina barrier despite decreases in VEGF/VPF. The lack of influence on intraocular concentrations of the serum-derived growth factors, IGF-I, IGF-II and IGF-BP3, might in part explain the failure of previous photocoagulation in the investigated patients. These results suggest that a combined treatment with retinal photocoagulation and growth hormone-lowering drugs, such as somatostatin analogues, could be a useful treatment, which may prevent further loss of visual acuity in patients with PDR.     

Elevated plasma CD105 and vitreous VEGF levels in diabetic retinopathy

Diabetic retinopathy is the leading cause of blindness in the industrialized world. Hyperglycaemia induces retinal hypoxia that upregulates a range of vasoactive factors which may lead to macular oedema and/or angiogenesis and hence potentially sight threatening retinopathy. In this study, we have focused on the association of CD105 and vascular endothelial growth factor (VEGF) with the development and progression of diabetic retinopathy by means of quantifying their expression in the plasma and vitreous of diabetic patients. CD105 levels were quantified in the plasma of 38 type I diabetic patients at various stages of retinopathy and 15 non-diabetic controls. In an additional cohort of 11 patients with advanced proliferative retinopathy and 23 control subjects, CD105 and VEGF were measured in the vitreous. The values were expressed as median (range) and statistical analysis was carried out using the non-parametric Mann-Whitney U test. Plasma CD105 levels were significantly increased in diabetic patients [1.8 (1.1-2.4) ng/ml] compared with non-diabetic controls [0.7 (0.3-1.8) ng/ml] (p<0.01). Plasma CD105 levels were elevated in diabetic patients with all stages of retinopathy, the highest level was observed in background retinopathy [2.3 (2.1-2.5) ng/ml] followed by proliferative retinopathy [2.1 (0.9-2.8) ng/ml] and advanced proliferative retinopathy [1.4 (0.6-1.8) ng/ml]. Vitreous contents of CD105 did not differ between controls and patients with advanced proliferative retinopathy, but vitreous levels of VEGF were elevated by approximately 3-fold in patients with advanced proliferative retinopathy [7.2 (1.90-15.60) ng/ml] compared with the control subjects [1.80 (1.10-2.210)] (p<0.01). These observations indicate that plasma levels of CD105 and vitreous levels of VEGF are associated with diabetic retinopathy, suggesting that CD105 and the angiogenic factor VEGF may play a critical role in the development and progression of diabetic retinopathy. Further studies are required to determine whether circulating CD105 levels could serve as a surrogate marker for early stage retinopathy and for monitoring disease progression.     

Pituitary Ablation for Diabetic Retinopathy

Pituitary ablation was performed on 26 patients with advanced diabetic retinopathy by pituitary stalk section (nine patients) or transphenoidal hypophysectomy (17 patients). After a latent period varying from six to 12 months, retinal hemorrhages disappeared, vitreous hemorrhages stopped and new vessels regressed. Eight of 10 patients followed up for more than a year had a complete remission, although in one of two patients whose ablation was incomplete the retinopathy remained active. Preoperative visual acuity levels were preserved in 47 of 50 eyes of patients followed up for a mean period of 12 months. Three patients have died, two from causes related to their operation. Twenty of the survivors have continued in their usual occupation. Pituitary ablation is effective in preventing the progressive visual deterioration usually associated with advanced diabetic retinopathy.     

Red blood cell deformability index in diabetic retinopathy

In order to investigate the relationship between haemorheological disturbances and diabetic microangiopathy we have studied the red blood cell deformability index (RBCD-index) by means of a filtration technique in 69 diabetics, aged 49-83 years, and in 40 non diabetic healthy controls (group A) of respective age and sex. The diabetics were classified into the following groups, according to the findings of a thorough clinical and laboratory investigation. Twenty patients (group B) were free of vascular complications, whereas 9 (group C) suffered from background retinopathy, 27 (group D) background retinopathy and ischaemic cardiopathy or peripheral arterial occlusive disease and 13 (group E) of proliferative retinopathy with diffuse micro- and macroangiopathy. The RBCD-index was significantly (P less than 0.001) decreased in diabetics with retinopathy compared to the diabetic and non diabetic controls. The lowest RBCD-index was observed in diabetics with proliferative retinopathy and in those with diffuse micro- and macrovascular complications (RBCD-index, means +/- SDM ml/min: A 0.68 +/- 0.15; B 0.64 +/- 0.08; C 0.60 +/- 0.08; D 0.49 +/- 0.09; E 0.48 +/- 0.09). These findings suggest that the RBCD is impaired in diabetics with retinopathy, especially in those with severe vascular complications, and that this abnormal rheological behavior of erythrocytes can be found even in the early stages of diabetic microangiopathy.     

Capillary electrophoretic assay for nitrate levels in the vitreous of proliferative diabetic retinopathy

The determination of nitric oxide (NO) in human vitreous samples is complicated by the relatively short half-life of the analyte and the viscous, high salt and protein biological matrix. In this work, we developed a fast (<5min) and useful CE method to determine the stable metabolite, nitrate, from vitreous samples. This proposed method has been successfully applied to determine the nitrate levels from the vitreous humor of patients undergoing vitrectomy for a variety of conditions. A statistically significant increase (P=0.000001) of the mean level of nitrate was observed in vitreous humor of patients with proliferative diabetic retinopathy (41.17+/-4.09microM, n=27) versus controls (15.22+/-0.86microM, n=35). The elevated levels of nitrate in the vitreous of patients known to have diabetic retinopathy suggests that NO is involved with the pathology of this disease.     

Treatment of renal failure from diabetic nephropathy with cadaveric homograft

We report two patients with terminal renal failure secondary to diabetic nephropathy treated with cadaveric kidney transplantation. Neither of these patients had peripheral vascular disease or peripheral neuropathy. There was a proliferative diabetic retinopathy with hemorrhages and exudates in one patient and only background diabetic changes in the ocular fundi of the other; there have been no significant changes in visual acuity or retinopathy in either patient following the transplantation. Both have good kidney function after 8 and 15 months and are completely rehabilitated.The requirement for insulin decreased in both patients during the period of renal insufficiency and increased following transplantation; this seemed to be related to the large dose of steroids given because now that a maintenance level of steroids has been established, both patients require the same dosage of insulin as they did before the onset of renal insufficiency.     

玻璃体腔注药联合微创玻璃体切除治疗糖尿病视网膜病变的临床疗效研究

目的:探讨玻璃体腔注药联合微创玻璃体切除治疗糖尿病视网膜病变的临床疗效。方法:选择2014年1月至2016年1月在我院确诊并治疗的增生性糖尿病视网膜病变患者80例,共83只患眼,随机分为A、B两组。A组共42例患眼,接受25 G玻璃体微创手术;B组共41例患眼,在A组治疗的基础上给予玻璃体腔注射康柏西普。比较两组患者的手术情况、治疗前后最佳视力的矫正(Best-corrected visual acuity,BCVA)情况、视网膜厚度以及术后1个月不良反应的发生情况。结果:B组患者的手术时间较A组显著缩短(P0.05),且术中使用电凝的患眼、术中出血以及术中发生医源性裂隙的患眼比例显著低于A组(P0.05),新生血管消失的患眼比例显著高于A组(P0.05)。B组患者术后1个月和3个月的BVCA显著高于A组(P0.05),且术后视网膜的厚度显著薄于A组(P0.05),术后发生玻璃体积血和前方出血的患眼比例显著低于A组(P0.05)。结论:玻璃体腔注射康柏西普联合25G玻璃体微创切除术治疗增生性糖尿病视网膜病变的临床疗效显著,有利于患者术后视力以及视网膜恢复。     

Phacoemulsification, vitrectomy and the implantation of an intraocular lens in diabetic patients

The purpose of this study was to evaluate results of combined phacoemulsification, intraocular lens implantation and pars plana vitrectomy in patients with advanced diabetic retinopathy. We retrospectively evaluated postoperative outcomes and complications in 102 eyes of 102 patients who underwent a combined procedure. All patients had a visually significant cataract. Forty two patients had vitreous hemorrhage and mild proliferative diabetic retinopathy. Sixty patients had a mild tractional retinal detachment. The median follow up was 14 months (range 6-36 months). 80% of patients had an increase of visual acuity of at least 2 Snellen lines. The most frequent early postoperative complication was elevated intraocular pressure, followed by mild fibrinous reaction. The most frequent late postoperative complication was the presence of posterior synechia, followed by glaucoma. Eleven patients required a repeated pars plana vitrectomy. Combined phacoemulsification, posterior chamber intraocular lens implantation and pars plana vitrectomy can be successfully performed in selected diabetic patients with favorable postoperative outcome.     

In-vitro venous prostacyclin production,plasma 6-keto-prostaglandin F1 alpha concentrations,and diabetic retinopathy.

Previous studies have shown that vessels from diabetics produce less prostacyclin in vitro than those from normal controls. To determine whether this decreased production is related to complications elective biopsy of a superficial forearm vein was performed on 12 insulin-dependent male diabetics, six with nil or minimal and six with proliferative retinopathy, and seven male controls. Vein segments from the diabetics and controls produced similar amounts of prostacyclin in vitro (medians 0.11 and 0.19 ng/mg tissue respectively), but the segments from the diabetics with nil or minimal retinopathy produced less than those from the diabetics with proliferative retinopathy (medians 0.09 and 0.18 ng/mg respectively). Preoperative plasma immunoreactive concentrations of 6-keto-prostaglandin F1 alpha were not significantly different between the controls and the diabetics (medians 101 and 116 pg/ml respectively). In a separate study, however, 11 diabetics with duration of disease of over 10 years and nil or minimal retinopathy had significantly lower concentrations than a matched group of 16 with background or proliferative retinopathy (medians 79 and 121 pg/ml respectively). These results do not support an association between reduced prostacyclin production and diabetic retinopathy.     

Comparison of Combined and Sequential Surgery for Proliferative Diabetic Retinopathy: A Single Surgeon Study

Purpose

To compare the results of combined and consecutive surgeries to treat proliferative diabetic retinopathy and cataract.

Methods

Retrospective comparative study. Forty-one patients with proliferative diabetic retinopathy (PDR) were enrolled. Twenty-nine eyes for the combined surgery group and twelve eyes for the sequential group were included. All surgeries were performed by one surgeon. Phacoemulsification was performed using a clear cornea incision. The vitrectomy was performed using a 20-gauge vitreous cutter.

Results

The best corrected visual acuity (BCVA) and intra- and post-operative complications were the main outcome measures. In the combined surgery group, the BCVA increased in 18 (62.1%) eyes, while eight (27.6%) eyes remained stable and three (10.3%) eyes decreased. Postoperative complications included fibrinous exudation in nine eyes, macular edema in three eyes and vitreous hemorrhage in three eyes. In the sequential surgery group, the BCVA increased in seven (58.3%) eyes, remained the same in four (33.3%) eyes and was reduced in one (8.3%) eye. Postoperative complications included macular edema in two eyes, neovascular glaucoma in two eyes and vitreous hemorrhage in one eye.

Conclusions

Both combined and sequential surgeries are safe and effective for treating PDR and cataracts. The combined surgery had a higher incidence of fibrinous exudation.     

Chemokines in proliferative diabetic retinopathy and proliferative vitreoretinopathy

PURPOSE: To determine levels of the chemokines CCL1/I-309, CCL2/MCP-1, CCL3/MIP-1alpha, CCL4/MIP-1beta, CCL7/MCP-3, CCL8/MCP-2, CXCL5/ENA-78, CXCL6/GCP-2, CXCL10/IP-10, and CXCL11/I-TAC in the vitreous humor and serum, from patients with proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and rhegmatogenous retinal detachment with no PVR (RD), and to investigate the expression of MCP-1, CXCL12/SDF-1, and the chemokine receptor CXCR3 in epiretinal membranes. METHODS: Paired vitreous humor and serum samples were obtained from patients undergoing vitrectomy for the treatment of RD (57 specimens), PVR (32 specimens), and PDR (88 specimens). The levels of chemokines were measured by enzyme-linked immunosorbent assays. Eighteen PDR and 5 PVR membranes were studied by immunohistochemical techniques. RESULTS: Of all the chemokines studied, only MCP-1 and IP-10 were detected in vitreous humor samples. MCP-1 levels in vitreous humor samples were significantly higher than in serum samples (p < 0.001). MCP-1 levels were significantly higher in vitreous humor samples from patients with PVR and PDR compared with RD (p = 0.0002). MCP-1 levels in vitreous humor samples from patients with active PDR were significantly higher than in inactive PDR cases (p = 0.0224). IP-10 levels in vitreous humor samples were significantly higher than in serum samples (p = 0.0035). IP-10 levels were significantly higher in vitreous humor samples from patients with PVR and PDR compared with RD (p = 0.0083). The incidence of IP-10 detection in vitreous humor samples was significantly higher in active PDR cases compared with inactive cases (p = 0.0214). There was a significant association between the incidence of IP-10 detection and increased levels of MCP-1 in vitreous humor samples from all patients, and patients with RD and PDR (p < 0.001 for all comparisons). MCP-1, and SDF-1 were localized in myofibroblasts in PVR and PDR membranes and in vascular endothelial cells in PDR membranes. CXCR3 was expressed by vascular endothelial cells in PDR membranes. CONCLUSION: MCP-1, IP-10 and SDF-1 may participate in pathogenesis of PVR and PDR. Myofibroblasts and vascular endothelial cells are the major cell types expressing MCP-1, SDF-1, and CXCR3 in epiretinal membranes.     

Detection of Serum Antibodies Cross-Reacting with Mycobacterium avium Subspecies paratuberculosis and Beta-Cell Antigen Zinc Transporter 8 Homologous Peptides in Patients with High-Risk Proliferative Diabetic Retinopathy

Purpose

MAP3865c, a Mycobacterium avium subspecies paratuberculosis (MAP) cell membrane protein, has a relevant sequence homology with zinc transporter 8 (ZnT8), a beta-cell membrane protein involved in Zn++ transportation. Recently, antibodies recognizing MAP3865c epitopes have been shown to cross-react with ZnT8 in type 1 diabetes patients. The purpose of this study was to detect antibodies against MAP3865c peptides in patients with high-risk proliferative diabetic retinopathy and speculate on whether they may somehow be involved in the pathogenesis of this severe retinal disorder.

Methods

Blood samples were obtained from 62 type 1 and 80 type 2 diabetes patients with high-risk proliferative diabetic retinopathy and 81 healthy controls. Antibodies against 6 highly immunogenic MAP3865c peptides were detected by indirect ELISA.

Results

Type 1 diabetes patients had significantly higher rates of positive antibodies than controls. Conversely, no statistically significant differences were found between type 2 diabetes patients and controls. After categorization of type 1 diabetes patients into two groups, one with positive, the other with negative antibodies, we found that they had similar mean visual acuity (∼0.6) and identical rates of vitreous hemorrhage (28.6%). Conversely, Hashimoto''s thyroiditis prevalence was 4/13 (30.7%) in the positive antibody group and 1/49 (2%) in the negative antibody group, a statistically significant difference (P = 0.016).

Conclusions

This study confirmed that type 1 diabetes patients have significantly higher rates of positive antibodies against MAP/ZnT8 peptides, but failed to find a correlation between the presence of these antibodies and the severity degree of high-risk proliferative diabetic retinopathy. The significantly higher prevalence of Hashimoto''s disease among type 1 diabetes patients with positive antibodies might suggest a possible common environmental trigger for these conditions.     

Prolactin response to sulpiride in non insulin dependent diabetes mellitus

Blood glucose, insulin and prolactin concentrations were determined before and after sulpiride injection (50 mg i.m.) in 20 non-insulin-dependent diabetic patients (10 with retinopathy and 10 without evidence of retinal damage) and 10 subjects with normal glucose tolerance. Prolactin response to sulpiride was significantly higher in diabetics than in controls (at 20 min., p less than 0.01; at 30 and 60 min., p less than 0.005; at 90 min., p less than 0.01; at 120 min., p less than 0.05). The sulpiride induced hyperprolactinemia did not influence blood glucose and plasma insulin levels in controls as well as in diabetic patients. Prolactin response to sulpiride was the same in diabetics with and in those without retinal changes. We conclude that acute hyperprolactinemia seems to have no influence on glucose homeostasis in normal and non insulin-dependent diabetic subjects.     

Relationship between Vitreous Levels of Matrix Metalloproteinases and Vascular Endothelial Growth Factor in Proliferative Diabetic Retinopathy

To investigate which matrix metalloproteinases (MMPs) are more likely to be involved in the angiogenic process in proliferative diabetic retinopathy (PDR), we measured the levels of MMPs in the vitreous fluid from patients with PDR and controls and correlated these levels with the levels of vascular endothelial growth factor (VEGF). Vitreous samples from 32 PDR and 24 nondiabetic patients were studied by mosaic multiplex MMPs enzyme-linked immunosorbent assay (ELISA), single ELISA, Western blot and zymography analysis. Epiretinal membranes from 11 patients with PDR were studied by immunohistochemistry. MMP-8 and MMP-13 were not detected. ELISA, Western blot and gelatin ymography assays revealed significant increases in the expression levels of MMP-1, MMP-7, MMP-9 and VEGF in vitreous samples from PDR patients compared to nondiabetic controls, whereas MMP-2 and MMP-3 were not upregulated in vitreous samples from PDR patients. Significant correlations existed between ELISA and zymography assays for the quantitation of MMP-2 (r=0.407; p=0.039) and MMP-9 (r=0.711; p<0.001). Significant correlations were observed between levels of VEGF and levels of MMP-1 (r=0.845; P<0.001) and MMP-9 (r=0.775; p<0.001), and between levels of MMP-1 and MMP-9 (r=0.857; p<0.001). In epiretinal membranes, cytoplasmic immunoreactivity for MMP-9 was present in vascular endothelial cells and stromal monocytes/macrophages and neutrophils. Our findings suggest that among the MMPs measured, MMP-1 and MMP-9 may contribute to the angiogenic switch in PDR.     

Thyrotropin-releasing hormone (TRH) does not suppress growth hormone response to L-dopa in insulin-dependent diabetes mellitus.

Thyrotropin-releasing hormone (TRH) blunts growth hormone (GH) response to various stimuli in normal subjects. We were interested if similar inhibitory effect of TRH could be demonstrated in diabetes mellitus where GH is abnormally regulated. In this study we compared the effect of TRH on GH response to L-dopa in normal and diabetic subjects. TRH 0.2 mg iv blunted GH response to L-dopa 0.5 g p.o. in normal subjects with peak GH values 13.1 and 7.3 micrograms/l, p < 0.05. In the diabetics no inhibitory effect of TRH was demonstrated and GH was even paradoxically increased after TRH: 14.9 and 21.9 micrograms/l, p = NS. Lack of inhibitory effect of TRH was more pronounced in patients with proliferative retinopathy. It is concluded that TRH has no inhibitory effect on L-dopa-induced GH response in diabetic subjects. This finding provides further evidence for disturbed GH regulation in diabetes mellitus.     

细菌脂多糖(LPS)在糖尿病视网膜微血管病变中的作用

本研究旨在通过Akita小鼠糖尿病模型及糖尿病人群血浆样本,探讨病原体相关性分子细菌脂多糖(lipopolysaccharide,LPS)在糖尿病视网膜病变中的重要作用。本研究选择6个月糖尿病病程的Akita小鼠(Ins2+/Akita)及其同年龄组野生型(wild type,WT)小鼠(C57BL/6J)尾静脉内注射脂多糖(LPS)或生理盐水对照共7 d,从影像学、电生理及病理学水平评估糖尿病视网膜眼病进展。最后收集糖尿病视网膜眼病患者及对照人群血标本,通过ELISA测定血浆LPS表达水平。通过光学相干断层扫描技术分析,发现Akita小鼠的视网膜层间厚度较WT小鼠组相比明显变薄(p=0.000 2),LPS处理进一步加重糖尿病小鼠视网膜结构损害(p=0.000 7)。视网膜电图检测发现LPS处理Akita小鼠组的视网膜细胞幅值较生理盐水处理Akita小鼠显著减慢,有统计学意义(p<0.05)。胰酶消化法分离及PAS染色小鼠眼球视网膜微血管网后,计数测得LPS处理显著增加了Akita小鼠视网膜中无细胞毛细血管数量(p=0.002 6),提示LPS在糖尿病微血管损伤中的重要作用。为保证该研究的临床转化性,我们进一步检测了糖尿病视网膜病变患者(n=19)、糖尿病患者(无微血管并发症)(n=23)及健康对照组(n=20)的血浆LPS水平,发现糖尿病患者血浆LPS水平较健康对照组显著升高(p=0.002 3),其中糖尿病视网膜病变患者LPS升高最为显著(p<0.000 1)。本研究表明,循环中细菌脂多糖增加在糖尿病视网膜病变进展中起到重要作用。     

Substance P and secretoneurin in vitreous aspirates of patients with various vitreoretinal diseases

By means of highly sensitive radioimmunoassays, the levels of substance P (SP) and secretoneurin (SN) were detected in vitreous aspirates of patients with macular holes which served as controls, in patients with nonproliferative diabetic retinopathy (DR), active proliferative diabetic retinopathy (active PDR), inactive PDR, rhegmatogenous retinal detachment and proliferative vitreoretinopathy (PVR). Furthermore, SN-like immunoreactivities were characterized by reversed phase-HPLC. The concentration of SN was more than 20-fold higher in macular holes when compared with SP and reversed phase HPLC revealed evidence that the vitreous levels of SN represent authentic SN. SN was significantly decreased in patients with nonproliferative DR, active PDR and inactive PDR by more than 70% which seems to result from a reduced expression and/or secretion from the cilary epithelium and a reduced release from the retina both due to diabetes mellitus. By contrast SP was increased in rhegmatogenous retinal detachment most obviously due to an enhanced outflow of the peptide through retinal breaks. Despite their proangiogenic activities, SP and SN are unlikely to be involved in the pathogenesis of neovascularizations in DR because of their unchanged and reduced levels, respectively, but the low levels of both peptides may facilitate the regression of vasoproliferations following laser photocoagulation.