Afroditi A. Papathanasiou

Methylenetetrahydrofolate reductase gene polymorphism as a risk factor for diabetic nephropathy: a meta-analysis

AbstractInvestigations into the association between diabetic nephropathy (DN) and MTHFR C677T gene polymorphism in several case-control studies has yielded contradictory results. To shed light on these inconclusive findings, a meta-analysis of all available studies relating the C677T polymorphism to the risk of developing DN was conducted. The PubMed database was searched, and case-control studies investigating the association between MTHFR C677T gene polymorphism and DN were included in the meta-analysis. The meta-analysis included 15 studies, of which 8 involved Caucasians and 5 East Asians; 11 studies involved subjects with type 2 diabetes and 4 with type 1 diabetes. The main analysis (all studies) revealed significant heterogeneity between the studies (PQ < 0.01) and a marginal association between the 677T allele and the risk of developing DN; the random effects (RE) pooled odds ratio (OR) was 1.30 (1.03-1.64). However, the sensitivity analysis (exclusion of studies not in Hardy-Weinberg equilibrium) produced non-significant results. The recessive model derived significant results in main analysis [fixed effects (FE) OR = 1.32 (1.10-1.58), PQ = 0.27], and in type 2 diabetes [FE OR = 1.30 (1.06-1.60), PQ = 0.38]. The additive model produced significant association in main analysis [RE OR = 1.65 (1.13-2.42), PQ < 0.01] in Caucasians [FE OR = 1.48 (1.11-1.98), PQ = 0.17] and in type 2 diabetes [RE OR = 1.65 (1.03-2.67), PQ < 0.01]. However, sensitivity analysis diminished the significant results in type 2 diabetes. There is no differential magnitude of effect in large versus small studies. In conclusion, although there is some evidence of association between MTHFR C677T gene polymorphism and DN, the above findings reinforce the need for further and more rigorous association studies.

Randomized trials of dopamine agonists in restless legs syndrome: A systematic review, quality assessment, and meta-analysis

BACKGROUND The use of dopamine agonists (DAs) for the treatment of restless legs syndrome (RLS) has been assessed in numerous randomized clinical trials (RCTs). OBJECTIVES The aims of this study were to assess the reporting quality of published RCTs according to the Consolidated Standards of Reporting Trials (CONSORT) statement and to synthesize the study results in terms of efficacy and tolerability to inform the clinical management of RLS. METHODS PubMed and Cochrane Controlled Trials Register were searched for English-language RCTs that assessed the effects of DAs in RLS. Quality of reporting was measured using the proportion of 17 CONSORT checklist items included in each study. The 2 primary outcomes were pooled mean change from baseline in International RLS (IRLS) Study Group rating scale score (Deltamu) (95% CI) and relative risk (RR) (95% CI) of response based on the Clinical Global Impression-Improvement (CGI-I) scale score. The pooled proportions of adverse events (PAEs) (95% CI) were also estimated. RESULTS Eighteen RCTs (N = 2848 patients) were included. Two of the 17 CONSORT checklist items were reported in 7 studies (39%) and 9 of the 17 items were reported in all 18 studies (100%). The differences in the IRLS scores and RR for CGI-I were significantly greater with pramipexole, ropinirole, rotigotine, and cabergoline compared with placebo. Results for heterogeneity were nonsignificant. The difference in Deltamu (95% CI) was significant with pramipexole (-6.63 [-9.15 to -4.10]) versus ropinirole (-3.64 [-4.76 to 2.51]) (P = 0.04). The difference between pramipexole and rotigotine was nonsignificant. The pooled PAEs (95% CI) for pramipexole, ropinirole, and rotigotine were 4.8% (2.0% to 8.7%), 10.2% (2.6% to 22.1%), and 7.6% (1.3% to 18.5%), respectively. In the trial of sumanirole, the PAE value was 2% (0% to 5.4%). CONCLUSION Based on the findings from the meta-analysis, DAs were significantly more efficacious in the treatment of RLS compared with placebo.

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

Candidate-gene association studies that examined the association between polymorphisms of endothelial nitric oxide synthase (NOS3) gene (G894T, 4b/a, and T786C) and diabetic nephropathy or diabetes leading to severe nephropathy produced inconclusive results. Thus, a meta-analysis of all candidate-gene association studies with endothelial nitric oxide synthase genotyping (7401 cases and 8046 controls) was conducted. Other study designs, such as family-based association studies and genome-wide linkage and association studies were also reviewed for supportive evidence of implication of endothelial nitric oxide synthase gene in diabetic nephropathy. The meta-analysis showed that G894T is significantly associated with diabetic nephropathy and diabetes leading to severe nephropathy in type 2 diabetics and in East Asians, respectively. Concerning the 4b/a polymorphism and its relationship to diabetes leading to severe nephropathy, a significant association was shown for East Asians. Heterogeneity between studies was in general high. There was no differential magnitude of effect in large versus small studies. One genome-wide linkage scan provided evidence of linkage nearby the endothelial nitric oxide synthase locus. Studies exploring gene and environment interactions with endothelial nitric oxide synthase polymorphisms may help understand better the genetics of diabetic nephropathy.

MTHFR gene polymorphisms and response to chemotherapy in colorectal cancer: a meta-analysis

AIMS Pharmacogenetic studies investigating the relationship between MTHFR gene polymorphisms and response to fluorouracil-based chemotherapy in patients with colorectal cancer have produced inconclusive results. In an attempt to interpret these results, a meta-analysis of all eligible studies published up until January 2009 was carried out. MATERIALS & METHODS A total of ten studies relating MTHFR C677T and six studies relating MTHFR A1298C to the response to chemotherapy in patients with colorectal cancer were included in the meta-analysis and random effects pooled odds ratios were estimated. The heterogeneity between studies, the sources of potential bias and the consistency of genetic effects across ethnicities were explored. Cumulative and recursive cumulative meta-analyses were also performed. RESULTS For both the C677T and A1298C polymorphisms, the main analysis revealed nonsignificant heterogeneity and a lack of association under the allele contrast, the recessive and dominant models. The subgroup analysis by ethnicity did not change this pattern of results. The lack of stability of the relative change of odds ratio in the recursive cumulative meta-analysis for both polymorphisms indicated the need for more evidence to support a definite lack of association. There was no differential magnitude of the effect in large versus small studies. CONCLUSION The available evidence indicates that MTHFR C677T and A1298C gene polymorphisms cannot be considered as reliable predictors of response to fluorouracil-based chemotherapy in patients with colorectal cancer.

Uric acid excretion in North American and Southeast European children with obstructive sleep apnea.

BACKGROUND AND OBJECTIVES Responses to nocturnal hypoxemia accompanying sleep-disordered breathing (SDB) may vary in different populations. Aims of this study were to (1) assess whether severity of SDB is related to uric acid excretion in North American and Southeast European children and (2) evaluate the interaction between nocturnal hypoxemia and country of childrens origin in uric acid excretion. METHODS Consecutive US and Greek children with snoring who were referred for polysomnography were recruited. Uric acid excretion expressed as uric acid-to-creatinine concentrations ratio in a morning urine specimen was the primary outcome measure. RESULTS One hundred and twenty-six US children (6.8+/-0.7years old) and 123 Greek children (6.4+/-2.5years old) were recruited. Forty-three US and 53 Greek participants had moderate-to-severe nocturnal hypoxemia (SpO(2) nadir <90%). Obstructive apnea-hypopnea index and SpO(2) nadir were related to uric acid excretion in Greek (but not US) children after adjustment by age, gender and body mass index z-score (p<0.05). There was a significant interaction between severity of hypoxemia and country of childrens origin in uric acid excretion after adjustment by age, gender and body mass index z-score (p=0.036). Greek children with moderate-to-severe hypoxemia had higher uric acid excretion (0.85+/-0.35) than those with mild/no hypoxemia (0.69+/-0.25) (p=0.005). US children with moderate-to-severe hypoxemia (0.41+/-0.20) did not differ in uric acid excretion from those with mild/no hypoxemia (0.42+/-0.22) (p=0.823). CONCLUSIONS Uric acid excretion differs in children with SDB and different ethnic backgrounds or environmental exposures.

Serum nitrite and nitrate levels in children with obstructive sleep-disordered breathing.

BACKGROUND Diminished nitric oxide (NO) levels have been reported in adults with obstructive sleep apnea but no data are available for children with obstructive sleep-disordered breathing (SDB). OBJECTIVES To assess levels of serum NO metabolites in children with SDB and to explore the effects of NO metabolites, SDB and their interaction on blood pressure. METHODS Morning nitrite, the sum of nitrite and nitrate (NO(x)), and the average of evening and morning blood pressure were assessed in children with SDB referred for polysomnography and in controls without SDB. RESULTS Forty-three children with SDB (age: 5.8+/-2.1 years) had moderate-to-severe nocturnal hypoxemia (SpO(2) nadir: 85.6+/-4%), 54 subjects (6.6+/-2.7 years) had mild hypoxemia (SpO(2) nadir: 91.4+/-1.3%) and 20 subjects were controls free of SDB (6.7+/-3.7 years). Subjects with moderate-to-severe hypoxemia had significantly lower ln-transformed NO metabolites (1.4+/-0.7, nitrites; 2.6+/-0.5, NO(x)) compared to those with mild hypoxemia (1.9+/-0.8, nitrites; 3+/-0.6, NO(x)) and controls (2.2+/-0.7, nitrite; 3+/-0.6, NO(x); p<0.05). The effects of NO metabolites and SDB or their interaction on blood pressure were not significant (p>0.05). CONCLUSIONS Moderate-to-severe hypoxemia accompanying SDB is associated with reduced concentrations of morning serum NO metabolites, but NO levels do not seem to affect blood pressure.

XbaI GLUT1 Gene Polymorphism and the Risk of Type 2 Diabetes with Nephropathy

Altered expression of the facilitated glucose transporter GLUT1 affects pathways implicated in the pathogenesis of diabetic nephropathy. There is indication that variation of GLUT1 gene (SLC2A1) contributes to development of microangiopathy in diabetes mellitus type 2 (DM) patients. A genetic association study involving Caucasians was carried out to investigate the role of XbαI polymorphism in the GLUT1 gene in diabetic nephropathy (DN). Study population (n = 240) consisted of 148 unrelated patients with DM (92 cases with diabetic nephropathy (DN)), and of 92 matched healthy control subjects. Diabetic nephropathy was defined as persistent albuminuria (> 300 mg/24 h) and/or renal failure, in the absence of non-diabetes induced renal disease. The analysis showed that the risk of developing DM and DN in XbaI(−) carriers, when healthy individuals were considered as controls, was two-fold: odds ratio (OR) 2.08 [95% confidence interval (1.14–3.79)]. However, there was no evidence of association between XbaI(−) and DN when patients with DM and without DN were considered as controls: OR = 1.12 (0.55–2.26). Thus, the GLUT1 XbaI(−) allele is associated with DM, and possibly with a more severe form of the disease that can lead to development of DN.

The reporting quality of studies investigating the diagnostic accuracy of anti-CCP antibody in rheumatoid arthritis and its impact on diagnostic estimates

BackgroundRecently anti-CCP testing has become popular in the diagnosis of rheumatoid arthritis (RA). However, the inadequate reporting of the relevant diagnostic studies may overestimate and bias the results, directing scientists into making false decisions. The aim of the present study was to evaluate the reporting quality of studies used anti-CCP2 for the diagnosis of RA and to explore the impact of reporting quality on pooled estimates of diagnostic measures.MethodsPubMed was searched for clinical studies investigated the diagnostic accuracy of anti-CCP. The studies were evaluated for their reporting quality according to STARD statement. The overall reporting quality and the differences between high and low quality studies were explored. The effect of reporting quality on pooled estimates of diagnostic accuracy was also examined.ResultsThe overall reporting quality was relatively good but there are some essential methodological aspects of the studies that are seldom reported making the assessment of study validity difficult. Comparing the quality of reporting in high versus low quality articles, significant differences were seen in a relatively large number of methodological items. Overall, the STARD score (high/low) has no effect on the pooled sensitivities and specificities. However, the reporting of specific STARD items (e.g. reporting sufficiently the methods used in calculating the measures of diagnostic accuracy and reporting of demographic and clinical characteristics/features of the study population) has an effect on sensitivity and specificity.ConclusionsThe reporting quality of the diagnostic studies needs further improvement since the study quality may bias the estimates of diagnostic accuracy.

Supratentorial Multiple Sclerosis Lesions Affect the Blink Reflex Test

Introduction The Blink Reflex Test (BRT) is a neurophysiological examination used for evaluation of brainstem reflex circuits. MRI is the most precise modality for evaluation of MS lesion anatomy. Our study objective was to investigate how the functional results of the neurophysiological BRT relate to the anatomy of MS lesions in routine MRI studies. Methods 65 MS patients underwent the BRT within 2 months of a brain MRI showing demyelinating lesions. Results The overall sensitivity of the BRT was 90.8%, while in patients with at least one brainstem lesion and no brainstem lesions it was 91.4% and 90%, respectively. Discussion The presence of brainstem lesions does not significantly affect BRT sensitivity. This points to the influence of supratentorial MS lesions on the BRT. Gender, age, disease duration, type of MS, acuteness of an MS event and whether MS diagnosis was recent or not were not variables affecting the results.