Association of CVD Candidate Gene Polymorphisms with Ischemic Stroke and Cerebral Hemorrhage in Chinese Individuals

Background

Contribution of cardiovascular disease related genetic risk factors for stroke are not clearly defined. We performed a genetic association study to assess the association of 56 previously characterized gene variants in 34 candidate genes from cardiovascular disease related biological pathways with ischemic stroke and cerebral hemorrhage in a Chinese population.

Methods

There were 1280 stroke patients (1101 with ischemic stroke and 179 with cerebral hemorrhage) and 1380 controls in the study. The genotypes for 56 polymorphisms of 34 candidate genes were determined by the immobilized probe approach and the associations of gene polymorphisms with ischemic stroke and cerebral hemorrhage were performed by logistic regression under an allelic model.

Results

After adjusting for age, sex, BMI and hypertension status by logistic regression analysis, we found that NPPA rs5063 was significantly associated with both ischemic stroke (odds ratio [OR] 0.69; 95% confidence interval [CI], 0.52 to 0.90; P = 0.006) and cerebral hemorrhage(OR = 0.39; 95%CI, 0.19 to 0.78; P = 0.007). In addition, MTHFR rs1801133 also was associated with cerebral hemorrhage (OR = 1.48; 95%CI, 1.16 to1.89; P = 0.001) but not with ischemic stroke (OR = 1.08; 95%CI, 0.96 to1.22; P = 0.210). After false discovery rate (FDR) correction, the association of NPPA rs5063 and MTHFR rs1801133 with cerebral hemorrhage remained significant.

Conclusions

The NPPA rs5063 is associated with reduced risk for cerebral hemorrhage and MTHFR rs1801133 is associated with increased risk of cerebral hemorrhage in a Chinese population.     

The Common Variant rs11646213 Is Associated with Preeclampsia in Han Chinese Women

Background

Preeclampsia, characterized by hypertension and proteinuria, is a multifactorial disease caused by complex interactions between environmental and genetic factors. A recent genome-wide association study of blood pressure reported an association between hypertension and rs11646213. This study evaluated the association between preeclampsia and rs11646213.

Methods

A total of 454 cases and 460 controls were recruited to participate in this study. The single nucleotide polymorphism (SNP) rs11646213 was genotyped by polymerase chain reaction (PCR) and direct sequencing.

Results

The allele frequency of rs11646213 was significantly different between the preeclampsia and control groups (P = 0.017, OR = 1.36, 95% CI = 1.06–1.76). Differences were particularly significant in the severe preeclampsia subgroup (P = 0.002, OR = 1.54, 95% CI = 1.17–2.03) and the early-onset preeclampsia subgroup (P = 0.004, OR = 1.57, 95% CI = 1.16–2.13). Genotyping analysis showed that the T allele of rs11646213 could confer a risk for preeclampsia, severe preeclampsia and early-onset preeclampsia.

Conclusions

Rs11646213 upstream of the CDH13 gene is associated with preeclampsia in Han Chinese women.     

Optimal Proteinuria Target for Renoprotection in Patients with IgA Nephropathy

Background

Proteinuria is a target for renoprotection in kidney diseases. However, optimal level of proteinuria reduction in IgA nephropathy (IgAN) is unknown.

Methods

We conducted a retrospective observational study in 500 patients with biopsy-proven IgAN. Time-averaged proteinuria (TA-P) was calculated as the mean of every 6 month period of measurements of spot urine protein-to-creatinine ratio. The study endpoints were a 50% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease (ESRD), and slope of eGFR.

Results

During a median follow-up duration of 65 (12–154) months, a 50% decline in eGFR occurred in 1 (0.8%) patient with TA-P of <0.3 g/g compared to 6 (2.7%) patients with TA-P of 0.3–0.99 g/g (hazard ratio, 2.82; P = 0.35). Risk of reaching a 50% decline in eGFR markedly increased in patients with TA-P of 1.0–2.99 g/g (P = 0.002) and those with TA-P≥3.0 g/g (P<0.001). ESRD did not occur in patients with TA-P<1.0 g/g compared to 26 (20.0%) and 8 (57.1%) patients with TA-P of 1.0–2.99 and ≥3.0 g/g, respectively. Kidney function of these two groups deteriorated faster than those with TA-P<1.0 g/g (P<0.001). However, patients with TA-P of 0.3–0.99 g/g had a greater decline of eGFR than patients with TA-P<0.3 g/g (−0.41±1.68 vs. −0.73±2.82 ml/min/1.73 m²/year, P = 0.03).

Conclusion

In this study, patients with TA-P<1.0 g/g show favorable outcomes. However, given the faster eGFR decline in patients with TA-P of 0.3–0.99 g/g than in patients with TA-P<0.3 g/g, the ultimate optimal goal of proteinuria reduction can be lowered in the management of IgAN.     

High Homocysteine and Blood Pressure Related to Poor Outcome of Acute Ischemia Stroke in Chinese Population

Objectives

To assess the association between plasma homocysteine (Hcy), blood pressure (BP) and poor outcome at hospital discharge among acute ischemic stroke patients, and if high Hcy increases the risk of poor outcome based on high BP status in a northern Chinese population.

Methods

Between June 1, 2009 and May 31, 2013, a total of 3695 acute ischemic stroke patients were recruited from three hospitals in northern Chinese cities. Demographic characteristics, lifestyle risk factors, medical history, and other clinical characteristics were recorded for all subjects. Poor outcome was defined as a discharge modified Rankin Scale (mRS) score ≥3 or death. The association between homocysteine concentration, admission blood pressure, and risk of poor outcome following acute ischemic stroke was analyzed by using multivariate non-conditional logistic regression models.

Results

Compared with those in the lowest quartile of Hcy concentration in a multivariate-adjusted model, those in the highest quartile of Hcy concentration had increased risk of poor outcome after acute ischemic stroke, (OR = 1.33, P<0.05). The dose-response relationship between Hcy concentration and risk of poor outcome was statistically significant (p-value for trend  = 0.027). High BP was significantly associated with poor outcome following acute ischemic stroke (adjusted OR = 1.44, 95%CI, 1.19–1.74). Compared with non-high BP with nhHcy, in a multivariate-adjusted model, the ORs (95% CI) of non-high BP with hHcy, high BP with nhHcy, and high BP with hHcy to poor outcome were 1.14 (0.85–1.53), 1.37 (1.03–1.84) and 1.70 (1.29–2.34), respectively.

Conclusion

The present study suggested that high plasma Hcy and blood pressure were independent risk factors for prognosis of acute ischemic stroke, and hHcy may further increase the risk of poor outcome among patients with high blood pressure. Additionally, the results indicate that high Hcy with high BP may cause increased susceptibility to poor outcome among acute ischemic stroke patients in a northern Chinese population.     

Genetic Polymorphism in PDE4D Gene and Risk of Ischemic Stroke in Chinese Population: A Meta-Analysis

Background

Stroke is the second most common cause of death and major cause of disability worldwide. The SNP 83 in PDE4D gene has been suggested as a risk factor in ischemic stroke, but direct evidence from genetic association studies remains inconclusive even in Chinese population.

Methods

Meta-analysis of case-control studies on the relationship between SNP 83 in PDE4D gene and susceptibility to ischemic stroke in Chinese population published domestically and abroad from January 2003 to September 2012.

Results

9 case-control studies were selected. Meta-analysis results showed that the significant association between SNP 83 and ischemic stroke was found under the dominant model (OR = 1.34, 95% CI: 1.20–1.49) and recessive model (OR = 1.45, 95% CI: 1.19–1.76) in Chinese population. In subgroup meta-analysis, SNP 83 and atherothrombotic stroke, rather than lacunar stroke, showed the significant association under the dominant model (OR = 1.69, 95% CI: 1.41–2.01) and recessive model (OR = 1.47, 95% CI: 1.04–2.06).

Conclusions

The results suggest that SNP 83 in PDE4D gene is significantly associated with susceptibility to ischemic stroke in Chinese population.     

The PlA1/A2 Polymorphism of Glycoprotein IIIa as a Risk Factor for Stroke: A Systematic Review and Meta-Analysis

Background

The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been reported to be associated with risk of stroke in some studies, although other studies suggest no such association. This meta-analysis and systematic review was conducted to investigate the hypothesis that carriage of the PlA2 allele is a risk factor for stroke.

Methods

Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating carriage of the PlA2 allele and the incidence of stroke. Pooled odds ratios (ORs) were calculated using fixed-effect and random-effect models.

Findings

A total of 35 articles were eligible for inclusion, of which 25 studies were suitable for statistical analysis. For carriage of the PlA2 allele, OR 1.12 (n = 11,873; 95% CI = 1.03–1.22; p = 0.011) was observed for the incidence of stroke in adults, with subgroup analyses identifying the association driven by stroke of an ischaemic (n = 10,494; OR = 1.15, 95% CI = 1.05–1.27; p = 0.003) but not haemorrhagic aetiology (n = 2,470; OR = 0.90, 95% CI = 0.71–1.14; p = 0.398). This association with ischaemic stroke was strongest in individuals homozygous for the PlA2 allele compared to those homozygous for wild-type PlA1 (n = 5,906; OR = 1.74, 95% CI = 1.34–2.26; p<0.001). Subgroup analysis of ischaemic stroke subtypes revealed an increased association with stroke of cardioembolic (n = 1,271; OR 1.56, 95% CI 1.14–2.12; p = 0.005) and large vessel (n = 1,394; OR = 1.76, 95% CI 1.34–2.31; p<0.001) aetiology, but not those of small vessel origin (n = 1,356; OR = 0.99, 95% CI 0.74–1.33; p = 0.950). Egger''s regression test suggested a low probability of publication bias for all analyses (p>0.05).

Conclusions

The totality of published data supports the hypothesis that carriage of the PlA2 polymorphism of GPIIIa is a risk factor for ischaemic strokes, and specifically those of cardioembolic and large vessel origin.     

Urinary Uromodulin Excretion Predicts Progression of Chronic Kidney Disease Resulting from IgA Nephropathy

Background

Uromodulin, or Tamm-Horsfall protein, is the most abundant urinary protein in healthy individuals. Recent studies have suggested that uromodulin may play a role in chronic kidney diseases. We examined an IgA nephropathy cohort to determine whether uromodulin plays a role in the progression of IgA nephropathy.

Methods

A total of 344 IgA nephropathy patients were involved in this study. Morphological changes were evaluated with the Oxford classification of IgA nephropathy. Enzyme Linked Immunosorbent Assay (ELISA) measured the urinary uromodulin level on the renal biopsy day. Follow up was done regularly on 185 patients. Time-average blood pressure, time-average proteinuria, estimated glomerular filtration rate (eGFR) and eGFR decline rate were caculated. Association between the urinary uromodulin level and the eGFR decline rate was analyzed with SPSS 13.0.

Results

We found that lower baseline urinary uromodulin levels (P = 0.03) and higher time-average proteinuria (P = 0.04) were risk factors for rapid eGFR decline in a follow-up subgroup of the IgA nephropathy cohort. Urinary uromodulin level was correlated with tubulointerstitial lesions (P = 0.016). Patients that had more tubular atrophy/interstitial fibrosis on the surface had lower urinary uromodulin levels (P = 0.02).

Conclusions

Urinary uromodulin level is associated with interstitial fibrosis/tubular atrophy and contributes to eGFR decline in IgA nephropathy.     

The Outcome of Patients with Mild Stroke Improves after Treatment with Systemic Thrombolysis

Introduction

In up to one third of patients with mild stroke suitable to receive systemic thrombolysis the treatment is not administered because the treating physicians estimate a good spontaneous recovery. However, it is not settled whether the fate of these patients is equivalent to those who are thrombolysed.

Methods

We analyzed 203 consecutive patients (134 men and 69 women, mean age 69±14 years) without premorbid disability and a NIHSS score ≤5 at admission [median 3 (IQR 2–4)]. Intravenous thrombolysis was administered within 4.5 hours from stroke onset (n = 119), or it was withheld (n = 84) whenever the treating physician predicted a spontaneous recovery. The baseline risk factors, clinical course, infarction volume, bleeding complications, and functional outcome at 3 months were analyzed and declared to a Web-based registry which was accessible to the local Health Authorities.

Results

Expectedly, not thrombolysed patients had the mildest strokes at admission [median 2 (IQR 1–3.75)]. At day 2 to 5, the infarct volume on DWI-MRI was similar in both groups. There were no symptomatic cerebral bleedings in the study. An ordinal regression model adjusted for baseline stroke severity showed that thrombolysis was associated with a greater proportion of patients who shifted down on the modified Rankin Scale score at 3 months (OR 2.66; 95% CI 1.49–4.74, p = 0.001).

Conclusions

Intravenous thrombolysis seems to be safe in patients with mild stroke and may be associated with improved outcome compared with untreated patients. These results support the evaluation of the efficacy of intravenous thrombolysis in mild stroke patients in randomized clinical trials.     

Stroke Code Improves Intravenous Thrombolysis Administration in Acute Ischemic Stroke

Background and Purpose

Timely intravenous (IV) thrombolysis for acute ischemic stroke is associated with better clinical outcomes. Acute stroke care implemented with “Stroke Code” (SC) may increase IV tissue plasminogen activator (tPA) administration. The present study aimed to investigate the impact of SC on thrombolysis.

Methods

The study period was divided into the “pre-SC era” (January 2006 to July 2010) and “SC era” (August 2010 to July 2013). Demographics, critical times (stroke symptom onset, presentation to the emergency department, neuroimaging, thrombolysis), stroke severity, and clinical outcomes were recorded and compared between the two eras.

Results

During the study period, 5957 patients with acute ischemic stroke were admitted; of these, 1301 (21.8%) arrived at the emergency department within 3 h of stroke onset and 307 (5.2%) received IV-tPA. The number and frequency of IV-tPA treatments for patients with an onset-to-door time of <3 h increased from the pre-SC era (n = 91, 13.9%) to the SC era (n = 216, 33.3%) (P<0.001). SC also improved the efficiency of IV-tPA administration; the median door-to-needle time decreased (88 to 51 min, P<0.001) and the percentage of door-to-needle times ≤60 min increased (14.3% to 71.3%, P<0.001). The SC era group tended to have more patients with good outcome (modified Rankin Scale ≤2) at discharge (49.5 vs. 39.6%, P = 0.11), with no difference in symptomatic hemorrhage events or in-hospital mortality.

Conclusion

The SC protocol increases the percentage of acute ischemic stroke patients receiving IV-tPA and decreases door-to-needle time.     

Dual-Phase CT Collateral Score: A Predictor of Clinical Outcome in Patients with Acute Ischemic Stroke

Background and Purpose

The presence of good collaterals on CT angiography (CTA) is a well-known predictor for favorable outcome in acute ischemic stroke. Recently, multiphase CT has been introduced as a more accurate method in assessing collaterals. The aim of this study was to assess the ability of dual-phase CT to evaluate collateral status and predict clinical outcome.

Methods

Forty-three patients who underwent both dual-phase CT and transfemoral cerebral angiography (TFCA) for occluded intracranial internal carotid artery (ICA) and/or middle cerebral artery (M1 segment) were recruited from a prospectively collected database. The collateral status on dual-phase CT was graded by using a 4-point scale: grade 0 = no collaterals; 1 = some collaterals with persistence of some defects; 2 = slow but complete collaterals; and 3 = fast and complete collaterals. Univariate and multivariate analysis were performed to define the independent predictors for favorable outcome at 3 months.

Results

Dual-phase CT collateral status (ρ = 0.744) showed higher correlation with TFCA collateral status than CTA collateral status (ρ = 0.596) and substantial interobserver agreement (weighted κ = 0.776). In the univariate analysis, age, history of hypertension, collateral scores on CTA, dual-phase CT, and TFCA, occlusion in intracranial ICA, final infarct volume, and symptomatic hemorrhage were significantly associated with outcome. Among them, only the dual-phase CT collateral score was an independent predictor for favorable outcome (OR = 26.342 (2.788–248.864); P = 0.004) in the multivariate analysis.

Conclusions

The collateral status on dual-phase CT can be a useful predictor for clinical outcome in acute stroke patients, especially when advanced CT techniques are not available in emergent situations.     

Role of Key TYMS Polymorphisms on Methotrexate Therapeutic Outcome in Portuguese Rheumatoid Arthritis Patients

Background

Therapeutic outcome of rheumatoid arthritis (RA) patients treated with methotrexate (MTX) can be modulated by thymidylate synthase (TS) levels, which may be altered by genetic polymorphisms in TS gene (TYMS). This study aims to elucidate the influence of TYMS polymorphisms in MTX therapeutic outcome (regarding both clinical response and toxicity) in Portuguese RA patients.

Methods

Clinicopathological data from 233 Caucasian RA patients treated with MTX were collected, outcomes were defined and patients were genotyped for the following TYMS polymorphisms: 1) 28 base pairs (bp) variable number tandem repeat (rs34743033); 2) single nucleotide polymorphism C>G (rs2853542); and 3) 6 bp sequence deletion (1494del6, rs34489327). Chi-square and binary logistic regression analyses were performed, using genotype and haplotype-based approaches.

Results

Considering TYMS genotypes, 3R3R (p = 0.005, OR = 2.34), 3RC3RG (p = 0.016, OR = 3.52) and 6bp− carriers (p = 0.011, OR = 1.96) were associated with non-response to MTX. Multivariate analysis confirmed the increased risk for non-response to MTX in 6bp− carriers (p = 0.016, OR = 2.74). Data demonstrated that TYMS polymorphisms were in linkage disequilibrium (p<0.00001). Haplotype multivariate analysis revealed that haplotypes harboring both 3R and 6bp− alleles were associated with non-response to MTX. Regarding MTX-related toxicity, no statistically significant differences were observed in relation to TYMS genotypes and haplotypes.

Conclusion

Our study reveals that TYMS polymorphisms could be important to help predicting clinical response to MTX in RA patients. Despite the potential of these findings, translation into clinical practice needs larger studies to confirm these evidences.     

Predictors of Seizure Outcomes in Children with Tuberous Sclerosis Complex and Intractable Epilepsy Undergoing Resective Epilepsy Surgery: An Individual Participant Data Meta-Analysis

Objective

To perform a systematic review and individual participant data meta-analysis to identify preoperative factors associated with a good seizure outcome in children with Tuberous Sclerosis Complex undergoing resective epilepsy surgery.

Data Sources

Electronic databases (MEDLINE, EMBASE, CINAHL and Web of Science), archives of major epilepsy and neurosurgery meetings, and bibliographies of relevant articles, with no language or date restrictions.

Study Selection

We included case-control or cohort studies of consecutive participants undergoing resective epilepsy surgery that reported seizure outcomes. We performed title and abstract and full text screening independently and in duplicate. We resolved disagreements through discussion.

Data Extraction

One author performed data extraction which was verified by a second author using predefined data fields including study quality assessment using a risk of bias instrument we developed. We recorded all preoperative factors that may plausibly predict seizure outcomes.

Data Synthesis

To identify predictors of a good seizure outcome (i.e. Engel Class I or II) we used logistic regression adjusting for length of follow-up for each preoperative variable.

Results

Of 9863 citations, 20 articles reporting on 181 participants were eligible. Good seizure outcomes were observed in 126 (69%) participants (Engel Class I: 102(56%); Engel class II: 24(13%)). In univariable analyses, absence of generalized seizure semiology (OR = 3.1, 95%CI = 1.2–8.2, p = 0.022), no or mild developmental delay (OR = 7.3, 95%CI = 2.1–24.7, p = 0.001), unifocal ictal scalp electroencephalographic (EEG) abnormality (OR = 3.2, 95%CI = 1.4–7.6, p = 0.008) and EEG/Magnetic resonance imaging concordance (OR = 4.9, 95%CI = 1.8–13.5, p = 0.002) were associated with a good postoperative seizure outcome.

Conclusions

Small retrospective cohort studies are inherently prone to bias, some of which are overcome using individual participant data. The best available evidence suggests four preoperative factors predictive of good seizure outcomes following resective epilepsy surgery. Large long-term prospective multicenter observational studies are required to further evaluate the risk factors identified in this review.     

The C825T Polymorphism of the G-Protein β3 Subunit Gene and Its Association with Hypertension and Stroke: An Updated Meta-Analysis

Objective

Several epidemiological studies have evaluated the association between the GNB3 C825T polymorphism and hypertension or stroke. The results of these studies were inconsistent; therefore, we performed a meta-analysis to clarify these discrepancies.

Methods

We systematically searched the PubMed, Embase, Web of Science, CNKI, and CBM databases, and manually searched reference lists of relevant papers, meeting abstracts, and relevant journals. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for dominant, recessive, and allelic models. A fixed or random effects model was separately adopted depending on study heterogeneity. Subgroup and sensitivity analyses were performed to detect study heterogeneity and examine result stability, respectively. Publication bias was tested using funnel plots, the Egger''s regression test, and Begg''s test.

Results

We screened 66 studies regarding hypertension and eight concerning stroke. A combined analysis showed that only the allelic model found a marginal association with hypertension (OR = 1.07, 95% CI = 1.01–1.13) and female gender (OR = 1.11, 95% CI = 0.99–1.24). However, no comparison models found an association with stroke (allelic model: OR = 1.11, 95% CI = 0.94–1.32; dominant model: OR = 1.16, 95% CI = 0.92–1.48; and recessive model: OR = 1.05, 95% CI = 0.97–1.14). Sensitivity analysis suggested that all models did not yield a relationship to hypertension or stroke among Asians. Besides, there was a lack of statistical association with hypertension in Caucasians, which maybe due to a small sample size. When we restricted the included studies to normal populations according to the Hardy–Weinberg equilibrium, no association was found.

Conclusions

There was no evidence indicating that the 825T allele or TT genotype was associated with hypertension or stroke in Asians or hypertension in Caucasians. However, further studies regarding Africans and other ethnicities are needed to identify further correlations.     

Filaggrin Gene Mutation c.3321delA Is Associated with Various Clinical Features of Atopic Dermatitis in the Chinese Han Population

Background

We confirmed that the filaggrin gene mutation c.3321delA is associated with atopic dermatitis in our previous genome wide association study of the Chinese Han population. c.3321delA is the most common filaggrin gene mutation in Chinese atopic dermatitis patients but is not present in European populations.

Objective

To investigate the genetic model for the c.3321delA mutation and to determine the correlation between c.3321delA and atopic dermatitis clinical phenotypes in the Chinese Han population.

Method

The filaggrin gene mutation c.3321delA was sequenced in 1,080 atopic dermatitis patients and 908 controls from the Chinese population. The χ² test, ANOVA,nonparametric tests and logistic regression were used to investigate the relationship between the c.3321delA genotype and atopic dermatitis clinical phenotypes in the Chinese Han population.

Results

Analyses of the genetic model revealed that the additive model best described the c.3321delA mutation (P = 3.09E-11, OR = 3.43, 95%CI = 2.38–4.96). Stratified analyses showed that the c.3321delA allele frequency distribution is significantly associated with concomitant skin xerosis (P = 1.68E-03, OR = 2.13,95%CI = 1.32–3.46), palmar hyperlinearity (P = 3.64E-17, OR = 4.0,95%CI = 2.86–5.70), white dermatographism (P = 4.25E-03, OR = 1.82,95%CI = 1.22–2.71), food intolerance (P = 1.51E-03, OR = 1.76,95%CI = 1.23–2.50) and disease severity ( P = 9.67E-05).

Conclusion

Our study indicates that the filaggrin gene mutation c.3321delA is associated with clinical phenotypes of atopic dermatitis in the Chinese Han population, which might help us gain a better understanding on the pathogenesis of atopic dermatitis.     

Predictors of Two Months Culture Conversion in Multidrug-Resistant Tuberculosis: Findings from a Retrospective Cohort Study

Background

Various studies have reported culture conversion at two months as a predictor of successful treatment outcome in multidrug-resistant tuberculosis (MDR-TB).

Objectives

The present study was conducted with the aim to evaluate the rate and predictors of culture conversion at two months in MDR-TB patients.

Methods

All confirmed pulmonary MDR-TB patients enrolled for treatment at Lady Reading Hospital Peshawar, Pakistan from 1 January to 31 December 2012 and met the inclusion criteria were reviewed retrospectively. Rate and predictors of culture conversion at two months were evaluated.

Results

Eighty seven (53.4%) out of 163 patients achieved culture conversion at two months. In a multivariate analysis lung cavitation at baseline chest X-ray (P = 0.006, OR = 0.349), resistance to ofloxacin (P = 0.041, OR = 0.193) and streptomycin (P = 0.017, OR = 0.295) had statistically significant (P<0.05) negative association with culture conversion at two months.

Conclusion

A reasonable proportion of patients achieved culture conversion at two months. Factors negatively associated with culture conversion at two months can be easily identified either before diagnosis or early in the course of MDR-TB treatment. This may help in better care of individual patients by identifying them early and treating them vigorously.     

Association between Methylenetetrahydrofolate Reductase C677T Polymorphism and Susceptibility to Cervical Cancer: A Meta-Analysis

Background

To assess the association between MTHFR polymorphism and cervical cancer risk, a meta-analysis was performed.

Methods

Based on comprehensive searches of the PubMed, Embase, and Web of Science databases, we identified outcome data from all articles estimating the association between MTHFR polymorphism and cervical cancer risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated.

Results

A total of 12 studies with 2,924 cases (331 cervical intraepithelial neoplasia (CIN) I, 742 CIN II/III, 1851 invasive cervical cancer) and 2,581 controls were identified. There was no significant association between MTHFR C677T polymorphism and CIN I risk (T vs. C, OR = 1.10, 95% CI = 0.92–1.31; TT vs. CC, OR = 1.14, 95% CI = 0.78–1.68; TT+CT vs. CC, OR = 1.22, 95% CI = 0.94–1.58; TT vs. CT+CC, OR = 0.99, 95% CI = 0.70–1.40). For the CIN II/III, lack of an association was also found (T vs. C, OR = 1.08, 95% CI = 0.95–1.23; TT vs. CC, OR = 1.15, 95% CI = 0.87–1.52; TT+CT vs. CC, OR = 1.13, 95% CI = 0.94–1.35; TT vs. CT+CC, OR = 1.07, 95% CI = 0.83–1.38). The T allele had significant association to susceptibility of invasive cervical cancer in recessive model (TT vs. CT+CC, OR = 1.23, 95% CI = 1.02–1.49). On subgroup analysis by ethnicity, similarly significant differences in T vs. C, TT vs. CC, and recessive model were found in Asians.

Conclusion

The present meta-analysis suggested that MTHFR C677T polymorphism were to substantially contribute to invasive cervical cancer in recessive model.     

Reconstructive Treatment of Ruptured Intracranial Spontaneous Vertebral Artery Dissection Aneurysms: Long-Term Results and Predictors of Unfavorable Outcomes

Introduction

Few studies focused on predictors of unfavorable outcomes (modified Rankin Scale, 2–6) after reconstructive treatment of the ruptured intracranial spontaneous vertebral artery dissection aneurysms (ris-VADAs), which was evaluated based on 57 reconstructed lesions in this study.

Methods

Results of 57 consecutive patients (M:F = 29∶28; median age, 48 years; range, 27 to 69 years) harboring 57 ris-VADAs, which were treated with coils combined with single stent(n = 32), double overlapping stents (n = 16), and triple overlapping stents (n = 9) between October 2000 to March 2011, were retrospectively reviewed and analyzed.

Results

The available (n = 54) mean durations of angiographic and clinical follow-ups were 27 months (range, 12 to 78) and 62 months (range, 12 to 132), respectively. The involvement of PICA (p = 0.004), size of lesions (p = 0.000), quantity of stent (p = 0.001), and coil type (p = 0.002) affected the immediate obliteration grade, which was only risk factor for angiographic recurrences (p = 0.031). Although the post-treatment outcomes did not differ between single stent and multiple stents (p = 0.434), 5 angiographic recurrences, 1 rebleeding and 1 suspected rebleeding, all occurred in partial obliteration after single-stent-assisted coiling. Progressive thrombosis and in-stent obliteration were not detected on follow-up angiograms. Older age (odds ratio [OR] = 1.090; 95% confidence interval [CI], 1.004–1.184; p = 0.040) and unfavorable Hunt-Hess scale (OR = 4.289; 95%CI, 1.232–14.933; p = 0.022) were independent predictors of unfavorable outcomes in the reconstructed ris-VADAs.

Conclusions

Immediate obliteration grade was only risk factor for angiographic recurrence after reconstructive treatment. Unfavorable Hunt-Hess grade and older age were independent predictors of unfavorable outcomes in ris-VADAs.     

Lack of an Association between CYP11B2 C-344T Gene Polymorphism and Ischemic Stroke: A Meta-Analysis of 7,710 Subjects

Background

The association between aldosterone synthase (CYP11B2) C-344T gene polymorphism and ischemic stroke remains controversial and ambiguous. To better explain the association between CYP11B2 polymorphism and ischemic stroke risk, a meta-analysis was performed.

Methods

Based on comprehensive searches of Medline, Embase, Web of Science, CNKI and CBM databases, we identified and abstracted outcome data from all articles to evaluate the association between CYP11B2 polymorphism and ischemic stroke. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were performed in all genetic models. Fixed or random effects model was separately used depending on the heterogeneity between studies. Publication bias was tested by Begg''s funnel plot and Egger''s regression test.

Results

A total of 12 studies including 3,620 ischemic stroke cases and 4,090 controls were identified. There was no statistical evidence of association between CYP11B2 C-344T polymorphism and ischemic stroke in all genetic models (allelic model: OR = 1.19, 95% CI = 0.95–1.49; additive model: OR = 1.43, 95% CI = 0.91–2.27; dominant model: OR = 1.30, 95% CI = 0.89–1.89; and recessive model: OR = 1.24, 95% CI = 0.96–1.60). On subgroup analysis by ethnicity, similarly results were found in both Asians and non-Asians. For Asians, the combined ORs and 95% CIs were (allelic model: OR = 1.07, 95% CI = 0.87–1.32; additive model: OR = 1.15, 95% CI = 0.77–1.71; dominant model: OR = 1.13, 95% CI = 0.92–1.38; and recessive model: OR = 1.09, 95% CI = 0.84–1.40). For none-Asians, the combined ORs and 95% CIs were (allelic model: OR = 1.58, 95% CI = 0.90–2.76; additive model: OR = 2.37, 95% CI = 0.79–7.05; dominant model: OR = 1.79, 95% CI = 0.77–4.19; and recessive model: OR = 1.80, 95% CI = 0.96–3.36).

Conclusion

The present meta-analysis suggested that CYP11B2 C-344T polymorphism was unlikely contribute to ischemic stroke susceptibility.     

Association between MLH1 -93G>A Polymorphism and Risk of Colorectal Cancer

Background

The -93G>A (rs1800734) polymorphism located in the promoter of mismatch repair gene, MLH1, has been identified as a low-penetrance variant for cancer risk. Many published studies have evaluated the association between the MLH1 -93G>A polymorphism and colorectal cancer (CRC) risk. However, the results remain conflicting rather than conclusive.

Objective

The aim of this study was to assess the association between the MLH1 -93G>A polymorphism and the risk of CRC.

Methods

To derive a more precise estimation of the association, a meta-analysis of six studies (17,791 cases and 13,782 controls) was performed. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of the association. Four of these published studies were performed on subjects of known microsatellite instability (MSI) status. An additional analysis including 742 cases and 10,895 controls was used to assess the association between the MLH1 -93G>A polymorphism and the risk of MSI-CRC.

Results

The overall results indicated that the variant genotypes were associated with a significantly increased risk of CRC (AG versus GG: OR = 1.06, 95% CI = 1.01–1.11; AA/AG versus GG: OR = 1.06, 95% CI = 1.01–1.11). This increased risk was also found during stratified analysis of MSI status (AA versus GG: OR = 2.52, 95% CI = 1.94–3.28; AG versus GG: OR = 1.29, 95% CI = 1.10–1.52; AA/AG versus GG: OR = 1.45, 95% CI = 1.24–1.68; AA versus AG/GG: OR = 2.29, 95% CI = 1.78–2.96). Egger’s test did not show any evidence of publication bias.

Conclusion

Our results suggest that the MLH1 -93G>A polymorphism may contribute to individual susceptibility to CRC and act as a risk factor for MSI-CRC.     

Prognostic Value of Carbonic Anhydrase IX Immunohistochemical Expression in Renal Cell Carcinoma: A Meta-Analysis of the Literature

Background

Carbonic anhydrase IX (CAIX) protein has been correlated with progression and survival in patients with renal cell carcinoma (RCC). The prognostic value of CAIX in RCC however, remains inconclusive according to published works. This study aimed to analyze CAIX as a biological marker to predict RCC patient prognosis.

Methods

A literature search of the PubMed and Web of Knowledge databases was performed to retrieve original studies from their inception to December of 2013. Fifteen studies, collectively including a total of 2611 patients with renal cell carcinoma, were carefully reviewed. Standard meta-analysis methods were applied to evaluate the prognostic impact of CAIX expression on patient prognosis. The hazard ratio (HR) and its 95% confidence interval (CI) were recorded for the relationship between CAIX expression and survival, and the data were analyzed using Review Manager 5.2 software and Stata software 11.0.

Results

In patients with RCC, low CAIX expression was associated with poor disease-specific survival (HR = 1.89, 95% CI: 1.20–2.98, P = 0.006), unfavorable progression-free survival (HR = 2.62, 95% CI: 1.14–6.05, P = 0.02) and worse overall survival (HR = 2.03, 95% CI: 1.28–3.21, P = 0.002). Furthermore, low CAIX expression was significantly associated with the presence of lymph node metastases (odds ratio (OR) = 0.31, 95% CI = 0.15–0.62, P = 0.0009) and distant metastases (OR = 0.66, 95% CI = 0.46–0.96, P = 0.03) and predicted a higher tumor grade (OR = 0.41, 95% CI = 0.31–0.54, P<0.00001).

Conclusions

Low CAIX expression most likely indicates poor prognosis in RCC patients. Moreover, low CAIX expression was significantly associated with unfavorable clinicopathological factors. To strengthen our findings, further well-designed prospective studies should be conducted to investigate the role of CAIX expression in RCC.