Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis.

BACKGROUND: Results of several studies have shown a possible beneficial effect of renin-angiotensin system (RAS) inhibitors on diabetic retinopathy, but the findings were contradictory. We did a systematic review and meta-analysis to assess the effect of RAS inhibitors on diabetic retinopathy. METHODS: We identified relevant publications in PubMed, Embase, Cochrane Library Central Register of Controlled Trials, and abstracts from main annual meetings. Only randomised controlled trials comparing angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) monotherapy with other antihypertensive drugs or placebo in type 1 or type 2 diabetes were eligible for inclusion in the analysis. The primary outcomes were progression and regression of diabetic retinopathy in all patients and several subgroups. Risk ratios (RRs) with corresponding 95% CIs were pooled. We also did a network meta-analysis to assess the effect of different antihypertensive drugs on diabetic retinopathy by ranking order. This study is registered with the International Prospective Register of Systematic Reviews (PROSPERO), number CRD42013004548. FINDINGS: 21 randomised clinical trials with 13,823 participants were included in the meta-analysis. RAS inhibitors were associated with reduced risk of progression (absolute risk difference -3%, 95% CI -5 to -1; pooled RR 0.87, 95% CI 0.80-0.95; p=0.002) and increased possibility of regression of diabetic retinopathy (8%, 1-16; RR 1.39, 95% CI 1.19-1.61; p=0.00002). In normotensive patients, RAS inhibitors decreased risk of diabetic retinopathy progression (0.81, 0.69-0.94; p=0.007) and increased possibility of regression (1.43, 1.14-1.79; p=0.002). In hypertensive patients, RAS inhibitors were not associated with difference in risk of progression of diabetic retinopathy (0.93, 0.79-1.10; p=0.42) or possibility of diabetic retinopathy regression (2.21, 0.92-5.31; p=0.08). ACE inhibitors were associated with reduced risk of diabetic retinopathy progression (0.84, 0.75-0.94; p=0.002) and higher possibility of disease regression (1.50, 1.20-1.86; p=0.0003). ARBs were associated with a higher possibility of diabetic retinopathy regression (1.32, 1.07-1.61; p=0.008), but had no effect on disease progression (0.92, 0.80-1.06; p=0.25). Network meta-analysis showed the association of antihypertensive drugs with risk of diabetic retinopathy progression was lowest for ACE inhibitors, followed by ARBs, ß blockers, calcium channel blockers, and placebo in rank order. The association of antihypertensive drugs with possibility of diabetic retinopathy regression was highest for ACE inhibitors, followed by ARBs, placebo, and calcium channel blockers in rank order. INTERPRETATION: In patients with diabetes, RAS inhibitors reduce the risk of diabetic retinopathy, and increase the possibility of diabetic retinopathy regression. ACE inhibitors might be better than ARBs for treating diabetic retinopathy, and might exert the most beneficial effect on diabetic retinopathy of all widely used antihypertensive drug classes.

[DUOX2 mutations in children with congenital hypothyroidism].

OBJECTIVE: To study the features of DUOX2 mutations and genotype-phenotype relationship in children with congenital hypothyroidism (CH), in order to provide evidence for gene diagnosis and gene treatment of CH. METHODS: Blood samples were collected from 10 CH children with thyromegaly. Genomic DNA was extracted from peripheral blood leukocytes. All exons of DUOX2 gene were analyzed using PCR and direct sequencing. RESULTS: G3632A mutation in the exon 28 of DUOX2 that may result in arginine to histidine substitution at codon 1211 was found in one patient. T2033C mutation in the exon 17 of DUOX2 that may result in histidine to arginine substitution at codon 678 was found in three patients. They were all heterozygous mutations. CONCLUSIONS: Heterozygous mutations in DUOX2 may affect protein function and cause CH. The relationship between DUOX2 genotypes and clinical phenotypes is unclear and needs further studies.

Diabetes mellitus and poorer prognosis in hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Previous studies suggested that diabetes mellitus was associated with cancer risk and prognosis, but studies investigating the relationship between diabetes mellitus and survival in patients with hepatocellular carcinoma (HCC) reported inconsistent findings. To derive a more precise estimate of the prognostic role of diabetes mellitus in HCC, we systematically reviewed published studies and carried out a meta-analysis. METHODS: Eligible articles were identified in electronic databases from their inception through September 16, 2013. To evaluate the correlation between diabetes mellitus and prognosis in HCC, the pooled hazard ratios (HR) and their 95% confidence intervals (95% CI) for poorer overall and disease-free survivals were calculated by standard meta-analysis techniques with fixed-effects or random-effects models. RESULTS: 21 studies with a total of 9,767 HCC patients stratifying overall survival and/or disease-free survival in HCC patients by diabetes mellitus status were eligible for meta-analysis. 20 studies with a total of 9,727 HCC cases investigated the overall survival, and 10 studies with a total of 2,412 HCC patients investigated the disease-free survival. The pooled HRs for overall survival and disease-free survival were 1.46 (95% CI, 1.29 to 1.66; P<0.001) and 1.57 (95% CI, 1.21 to 2.05; P = 0.001), respectively. The adjusted HRs for overall survival and disease-free survival were 1.55 (95% CI, 1.27 to 1.91; P<0.001) and 2.15 (95% CI, 1.75 to 2.63; P<0.001), respectively. In addition, for patients receiving hepatic resection, diabetes mellitus was associated with both poorer overall survival and poorer disease-free survival, and for patients receiving non-surgical treatment or patients receiving radiofrequency ablation, diabetes mellitus was associated with poorer overall survival. There was no evidence for publication bias. CONCLUSION: Diabetes mellitus is independently associated with both poorer overall survival and poorer disease-free survival in HCC patients.

Significant associations between X-ray repair cross-complementing group 3 genetic polymorphisms and thyroid cancer risk.

Polymorphisms in X-ray cross-complementing group 3 (XRCC3) are proposed to be associated with cancer susceptibility, but previous studies on the associations between XRCC3 polymorphisms and thyroid cancer are controversial. We performed a systemic review and meta-analysis to investigate the associations of XRCC3 polymorphisms with thyroid cancer risk. We used odds ratio (OR) with 95 % confidence interval (95%CI) to assess the associations. For XRCC3 C241T polymorphism, meta-analysis of total eligible studies showed that there was no association between XRCC3 C241T polymorphism and thyroid cancer risk, but subgroup analysis in Caucasians showed that there was a significant association between XRCC3 C241T polymorphism and thyroid cancer risk (T versus C: OR = 1.30, 95%CI 1.05-1.62, P = 0.01; TT versus CC: OR = 1.74, 95%CI 1.13-2.70, P = 0.01; TT versus CC/CT: OR = 1.74, 95%CI 1.16-2.60, P = 0.007). For XRCC3 A17893G polymorphism, meta-analysis of total eligible studies showed that there was an obvious association between XRCC3 A17893G polymorphism and thyroid cancer risk (GG versus AA/AG: OR = 0.57, 95%CI 0.35-0.93, P = 0.02), but subgroup analysis by ethnicity only identify the significant association in Asians. In summary, the meta-analysis suggests that there are significant associations of XRCC3 polymorphisms with thyroid cancer risk. Besides, more studies with large sample sizes are needed to further assess the associations above.

Association between TP53 Arg72Pro polymorphism and thyroid carcinoma risk.

TP53 Arg72Pro polymorphism has been proposed to have some effects on host's susceptibility to cancer. Several studies were published to assess the association between TP53 Arg72Pro polymorphism and thyroid carcinoma, but they reported controversial results. We performed a systemic review and meta-analysis to assess the association between TP53 Arg72Pro polymorphism and thyroid carcinoma. Odds ratio (OR) with 95% confidence interval (95% CI) was used to assess the association. Fourteen individual studies with 3,483 subjects were finally included into the meta-analysis. Overall, there was an obvious association between TP53 Arg72Pro polymorphism and thyroid carcinoma under the recessive model (ProPro vs. ArgArg/ArgPro, OR = 2.02, 95% CI 1.13 to 3.62, P = 0.02). Subgroup analysis by race showed that TP53 Arg72Pro polymorphism was associated with thyroid carcinoma in Caucasians (ProPro vs. ArgArg/ArgPro, OR = 2.31, 95% CI 1.08 to 4.93, P = 0.03). Subgroup analysis by histological type showed that TP53 Arg72Pro polymorphism was not associated with a risk of different types of thyroid carcinoma. In summary, the meta-analysis suggests that TP53 Arg72Pro polymorphism is associated with thyroid carcinoma risk in Caucasians. Besides, more studies with large sample size are needed to further assess the associations above.

NALP3 inflammasome functional polymorphisms and gout susceptibility.

Gout is the most common autoinflammatory arthritis characterized by elevated serum urate and recurrent attacks of intra-articular crystal deposition of monosodium urate (MSU). Although the pathogenesis of gout is still unclear, accumulated studies indicate that genetic factors trigger gout development, including some susceptibility genes that control the production and clearance of urate and lead to hyperuricemia. However, the epidemiological evidence suggests that only less than 10% of hyperuricemia patients develop gout, indicating that other genes unrelated to the urate metabolism may also contribute to the diseases susceptibility. Accumulated evidences have implied that MSU crystal-induced inflammation is a paradigm of innate immunity and that NALP3 inflammasome, an innate immune complex containing NALP3, ASC and CARD-8, is involved in gout development. Recent studies suggest that NALP3 and CARD-8 functional mutations contribute to the development of autoinflammatory diseases including hereditary periodic fever syndrome, arthritis as well as hypertension susceptibility. Taking into account these genetic findings, here we would like to propose a novel hypothesis that functional mutations in NALP3 inflammasome may make NALP3 inflammasome as attractive susceptibility candidates and genetic markers for gout. Further clinical genetic studies need to be performed to confirm the role of NALP3 inflammasome in the etiology of gout.

[Effect of lipid-bound apoA-I cysteine mutants upon lipopolysaccharide-induced endotoxemia in mice].

OBJECTIVE: To determine the anti-inflammatory functions of different cysteine mutants of apolipoprotein A-I recombinant HDLs. METHODS: The authors reconstituted recombinant HDLs (namely rHDL74, rHDL129, rHDL195 and rHDL228) by mixing wild type or those mutants with dipalmitoyl phosphatidylcholine and examined their in vivo effects upon LPS-induced endotoxemia in mice. RESULTS: At 24 h post-injection, mice receiving rHDL74 [TNF-alpha: (24 +/- 3) pg/ml; IL-1beta: (45 +/- 5) pg/ml] had a significant decrease of plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta) as compared with control mice receiving either saline or rHDLwt [TNF-alpha: (135 +/- 12) pg/ml; IL-1beta: (82 +/- 8) pg/ml, P < 0.05]. Administration of rHDL74 to mice injected with LPS also led to a protection of lung against acute injury and attenuation of endotoxin-induced clinical symptoms in mice as compared with controls injected with LPS only. CONCLUSION: Compared with rHDLwt, rHDL74 exhibits higher anti-inflammation capabilities. And it may be a potential clinical candidate for therapy for endotoxin-induced septic shock.

Disordered osteoclast formation in RAGE-deficient mouse establishes an essential role for RAGE in diabetes related bone loss.

The mechanisms underlying diabetes-mediated bone loss are not well defined. It has been reported that the advanced glycation endproducts (AGEs) and receptor for AGEs (RAGEs) are involved in diabetic complications. Here, mice deficient in RAGE were used as a model for investigating the effects of RAGE on bone mass. We found that RAGE-/- mice have a significantly increased bone mass and bone biomechanical strength and a decreased number of osteoclasts compared to wild-type mice. The serum levels of IL-6 and bone breakdown marker pyridinoline were significantly decreased in RAGE-/- mice. RAGE-/- mice maintain bone mass following ovariectomy, whereas wild-type mice lose bone mass. Furthermore, osteoclast-like cells do express RAGE mRNA. Our data therefore indicate that RAGE serves as a positive factor to regulate the osteoclast formation, directly implicates a role for RAGE in diabetes-promoted bone destruction, and documents that the AGE-RAGE interaction may account for diabetes associated bone loss.

[The relevance of tumor necrosis factor-alpha gene-863C/A polymorphism with thyroid-associated ophthalmopathy].

OBJECTIVE: To investigate the relevance of tumor necrosis factor-alpha (TNF-alpha) gene -863C/A polymorphism with thyroid-associated ophthalmopathy (TAO). METHODS: TNF-alpha gene polymorphism at position -863 was determined by PCR-RFLP in 76 normal people, 54 patients with TAO and 60 patients with autoimmune thyroid disease (AITD) who had no ophthalmopathy. All the subjects were collected from July 2002 to December 2003 in out-patient department of endocrinology in the hospital. The difference of genotype and the variation of allele frequencies were analyzed by Chi-square test. RESULTS: (1) Frequencies distribution of CA + AA genotype in TAO, non-ophthalmopathy and control groups were 46.3%, 30.0%, 25.0% respectively, and allele A were 27.8%, 15.0%, 12.5% for those three groups respectively. (2) Frequencies of allele A in TAO group were significantly higher than those in non-ophthalmopathy and control groups (P = 0.018 and 0.002 respectively). (3) When the three groups were stratified according to sex, frequencies of -863 CA + AA genotype and allele A in male TAO patients were significantly higher than those in control group (OR = 4.31, P = 0.019; OR = 4.81, P = 0.003) and non-ophthalmopathy group (OR = 4.87, P = 0.027; OR = 5.38, P = 0.008). No significant difference was found in female patients (P > 0.05). (4) Frequencies of CA + AA genotype and allele A in TAO patients with 5 + 6 grade were significantly higher than those in non-ophthalmopathy group (CA + AA genotype: OR = 20.68, P = 0.021; allele A: OR = 39.67, P < 0.001). CONCLUSION: Allele A of TNF-alpha gene at position -863 may be associated with TAO especially in male patients.