Vasoactive mediators and retinopathy during type 1 diabetic pregnancy

PURPOSE: To evaluate the role of various vasoactive hormones in the evolution of diabetic retinopathy during pregnancy and postpartum. METHODS: Retinopathy was graded from fundus photographs of 45 pregnant women with type 1 diabetes and seven pregnant women without diabetes in a prospective study. Markers of renin-angiotensin-system (RAS), plasma renin activity (PRA), angiotensin II (AngII), aldosterone, natriuretic peptides (ANP, BNP, CNP) and adreonomedullin (AM) were measured during the first and third trimesters and at 3 months postpartum. The women with diabetes were grouped by progression of retinopathy during pregnancy and postpartum. RESULTS: Levels of PRA (p = 0.001) and ANP (p = 0.03) were significantly lower in diabetes than in non-diabetes subjects throughout pregnancy and postpartum. No significant differences appeared in levels of AngII, aldosterone, AM, BNP or CNP between the two groups. In multivariate logistic regression analyses with retinopathy progression by the third trimester as the dependent variable, only duration of diabetes qualified in the model (p = 0.027, R = 0.227, Exp(B) = 1.28). CONCLUSIONS: Diabetic pregnancy is associated with lower levels of PRA and ANP compared to non-diabetic pregnancy. Lowered RAS activity may contribute to the hyperdynamic blood flow and progression of DR during diabetic pregnancy. Within the power of this study no clear associations between the vasoactive hormones and progression of retinopathy could be detected.     

Fas costimulation of naive CD4 T cells is controlled by NF-kappaB signaling and caspase activity

Fas ligation induces apoptosis of activated T cells via the caspase cascade but can also mediate costimulatory signals to na?ve T cells at the time of activation. We have previously shown that Fas ligation of na?ve CD4 T cells activated by dendritic cells induces death or accelerates their proliferation and increases interferon-gamma (IFN-gamma) production. To understand this costimulation, we investigated the roles of caspases and nuclear factor (NF)-kappaB in survival and proliferation of responding T cells. Fas ligation increased caspase-3 and -8 activities during T cell activation, irrespective of cell fate. The accelerated proliferation induced by Fas ligation could be reduced by selective inhibition of both caspases. Inhibition of NF-kappaB simultaneously with Fas ligation inhibited the increased IFN-gamma production and caused uniform death of all responding T cells. Thus, Fas-mediated costimulation of na?ve CD4 T cells is driven by active caspases, and NF-kappaB acts as a dominant survival-supporting factor of Fas-costimulated cells containing high levels of activated caspase-8 and -3.     

Craniofacial structures and dental development in three patients with Nager syndrome

In Finland, 3 patients have been diagnosed with Nager syndrome (NS) during the last 17 years. Thus the incidence for NS in Finland is 3:1,000,000. The craniofacial structures and dental development of these patients were studied clinically and radiographically at the age of 3-4 years, and compared to age-matched controls and to the norms of the Finnish population. The striking structural finding was a severely short, retrognathic and posteriorly rotated mandible. Especially the ramus was deficient; its height was, on average, less than one-third of that of the control group. All children were tracheostomized neonatally. At the age of 3-4, the lower pharyngeal airway was still severely obstructed or completely closed. Nasopharyngeal airway was wide and the soft palate was missing in all patients. All patients had a complete deciduous dentition, but agenesis of permanent teeth (ranging from 2-10 missing teeth) was observed in each patient. Accelerated dental development was found in two subjects. Condylar ankylosis or severely limited mouth opening were observed.The present findings give new information and quantify earlier observations of craniofacial structures and dental development in NS. Analysis of facial structures suggests that if surgical intervention is needed to enable better breathing, the goal of the structural correction should be aimed at the most deficient structure, namely the ramus height. As a result of severe dentofacial deviation, a treatment process through the growth requires multidisciplinary teamwork of surgeons, pediatrists, orthodontists and prosthodontists.     

Antigen targeting to endosomal pathway in dendritic cell vaccination activates regulatory T cells and attenuates tumor immunity

Lymphoma cells are malignant cells of the T- or B-cell lineage that often express many surface markers inappropriately, yet are not recognized as abnormal by the immune system. We modeled this situation by inoculating ovalbumin-expressing E.G7-OVA lymphoma cells into mice that expressed ovalbumin as a self antigen in pancreatic islets, and investigated the efficacy of dendritic cell (DC) vaccination in these mice. Although vaccination with DC-expressing ovalbumin induced strong cytotoxic T-cell immunity, which led to clearance of E.G7-OVA lymphoma cells in naive C57BL/6 mice, DC vaccination was ineffective in mice expressing ovalbumin as a self antigen. Antigen modification to increase its processing via the endosomal processing pathway dramatically increased CD4 T-cell activation but paradoxically, impaired the protective effect of DC vaccination even in naive mice. Depletion of CD25⁺ T cells (regulatory T cells [Tregs]) prior to vaccination restored the efficacy of DC vaccination and allowed eradication of lymphoma also in mice expressing ovalbumin as a self antigen. We conclude that lymphoma cells may be eradicated using DC vaccination if activation of CD25⁺ Tregs is simultaneously inhibited, and that intentionally enhanced endosomal antigen processing in DC vaccines may shift the balance from CD4 T-cell help toward stimulation of Tregs.      

Elevated protein carbonyl and HIF‐1α levels in eyes with proliferative diabetic retinopathy

Purpose: To evaluate the role of protein carbonyls and hypoxia inducible factor‐1α (HIF‐1α) in diabetic eyes with proliferative diabetic retinopathy (PDR). Methods: Prospective consecutive controlled observational study was performed. Vitreous samples were collected at the start of the 3‐ppp vitrectomy. Protein carbonylation analysis was performed by Western blotting with antibody against 2,4‐Dinitrophenol (anti‐DNP), following derivatization of protein carbonyls with 2,4 Dinitrophenylhydrazine (DNHP). Protein carbonylation was quantified by scanning densitometry analysis and relativized to the total amount of protein into the ponceau staining of membranes. Vitreous HIF‐1 α was determined with ELISA in a subgroup of the samples. Thirty‐one eyes were operated due to PDR (study group). Of the 189 controls, 39 had nonproliferative diabetic retinopathy (non‐PDR), 111 retinal detachment (RD) and 39 macular hole/pucker (MH). Results: Comparison of eyes with PDR with controls revealed that the mean vitreous concentrations of protein carbonyls were significantly higher in the eyes affected with PDR being 242 ± 130 (SD) compared with non‐PDR controls 180 ± 142, nondiabetic eyes affected with RD 175 ± 131 and MH/pucker 140 ± 95 (p = 0.008, one‐way anova ). Mean HIF‐1α values were higher in eyes with PDR compared with controls (RD, MH/pucker); the values being 0.53 ± 0.34 (SEM; n = 4) and 0.13 ± 0.04 (SEM; n = 19), respectively (p = 0.009). Conclusions: Protein carbonyl and HIF‐1 α levels were significantly increased in the vitreous fluid of surgically treated eyes with PDR. Our findings suggest an association between increased intravitreal levels of protein carbonyls and the pathogenesis of PDR.