E65 K polymorphism in KCNMB1 gene is not associated with ischaemic heart disease in Spanish patients

Hypertension is a main risk factor for atherosclerosis through vascular wall hyperplasia. A recent study reported a new polymorphism (E65 K) in the ₁ subunit (KCNMB1) gene of the Ca²⁺-dependent potassium channel with a protective effect against the severity of diastolic hypertension, but further data have lead to conflicting results. In order to ascertain the involvement of the E65 K variant in cardiovascular system regulation, the potential association between this mutation and ischaemic heart disease was assessed through a family-based association study (n=302 individuals). Transmission disequilibrium analysis failed to detect any association between this polymorphism and ischaemic heart disease. Although a minor effect cannot be discarded, sample analytical power and negative results do not support a major role for E65 K polymorphism in atherogenic pathologies.     

Association between heart rate at rest and myocardial perfusion in patients with acute myocardial infarction undergoing cardiac rehabilitation – a pilot study

Introduction

This study was conducted to determine if there was a link among heart rate at rest (rHR), muscle volume changes, and single photon emission computed tomography (SPECT) parameters after 6-month cardiac rehabilitation in patients with acute myocardial infarction (AMI).

Material and methods

Twenty-nine consecutive AMI patients (mean age: 63.0 ±9.1 years) who received appropriate percutaneous coronary intervention on admission were enrolled. ^99mTc-Sestamibi myocardial SPECT images were obtained at the early (30 min) and delayed (4 h) phases after tracer injection at 2 weeks (0M) and 6 months (6M) after the onset of AMI. Within a few days of SPECT, all patients underwent cardiopulmonary exercise test for evaluation of cardiac rehabilitation effects. Before the initiation of exercise test, leg muscle volume was measured. All patients were stratified into the ≥ 70 beats per minute (bpm) (n = 15) or < 70 bpm (n = 14) group based on rHR at 6M.

Results

There were no significant differences in the recanalization time, peak cardiac enzyme, or initial left ventricular ejection fraction between the two groups. After the 6-month training, the muscle volume changes in the lower limbs (< 70 bpm, 0.23 ±0.22; ≥ 70 bpm, –0.07 ±0.26, p < 0.05) were significantly greater in the < 70 bpm group than the ≥ 70 bpm group. The decreased rate of rHR had a significant correlation with the improved global severity (r = 0.62, p = 0.001) and extent (r = 0.48, p = 0.017) of left ventricle evaluated by ^99mTc-Sestamibi myocardial SPECT delayed phase.

Conclusions

The result of this preliminary study demonstrated that improved myocardial perfusion was closely related to decreased rHR after cardiac rehabilitation.     

Brain metastases in patients under 50?years of age: retrospective analysis

Several previous publications suggested that younger patients with brain metastases have longer survival than older patients. However, detailed studies of younger patient groups are scarce. Therefore, a multi-institutional analysis of younger patients with brain metastases was performed (defined as adults with age <50?years). Prognostic factors for survival were examined by uni- and multivariate analyses and compared to those obtained in patients with age ??50?years. Multivariate analysis of 106 patients (median age 44?years, range 23?C49?years) revealed three independent prognostic factors for survival: performance status, extracranial metastases and primary tumor control. Survival was significantly better in patients treated after the year 2000 (median 9.4?months) as compared to those treated before the year 2000 (median 5.1?months, p?=?0.04). This improvement appeared to be related to an increased use of surgery or radiosurgery (SRS) and decreasing numbers of patients with uncontrolled primary tumor. Irrespective of management approach, survival beyond 5?years was uncommon (actuarial rate 6?%; 17?% in patients treated with upfront surgery or SRS). In conclusion, more intense multidisciplinary approaches aiming at control both in the brain, extracranial metastatic sites, and primary tumor site might have contributed to gradual survival improvements in recent years. Nevertheless, further efforts are necessary to improve long-term survival.     

Lymphotoxin-α and galectin-2 SNPs are not associated with myocardial infarction in two different German populations

Recent data provided strong evidence for the association of single nucleotide polymorphisms (SNPs) in the lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) genes with myocardial infarction (MI) in a Japanese population. For populations of other genetic background, the relevance of these polymorphisms in the pathogenesis of MI remains controversial. We aimed to define the role of LTA and LGALS2 SNPs in two German MI populations with markedly different ascertainment strategies. Two different MI populations were studied. In the first population, MI patients were ascertained by a strong family history of MI (n = 1214). Controls were unrelated disease-free participants of the study (n = 1080). The second population included patients suffering from sporadic (nonfamilial) MI from the German KORA register (n = 607). The control group consisted of participants of the WHO MONICA survey in Germany (n = 1492). TaqMan assays were used to determine the genotypes of 4 SNPs in the LTA genomic region and 1 SNP in the LGALS2 gene. Single SNPs in both genomic regions as well as haplotypes in the LTA genomic region were tested for association in various models of inheritance. No association with MI could be found for any of the examined SNPs in the LTA genomic region and LGALS2 gene, or for haplotypes spanning the LTA genomic region. In two MI populations of European descent with markedly different ascertainment strategies, we were not able to identify a significant association of SNPs in the LTA genomic region or the LGALS2 gene with MI. These variants are unlikely to play a significant role in populations of European origin.     

IFN-γ 874A>T genotype is associated with higher CCR5 expression in peripheral blood mononuclear cells from HIV+ patients

We previously showed that certain cytokines impact on the expression of drug transporters and chemokine receptors in peripheral blood mononuclear cells. Known single-nucleotide polymorphism genes in the genes encoding interferon γ (874A>T, rs62559044) and interleukin 2 (-330T>G, rs2069763) were genotyped in 66 HIV+ patients, and the impact of single-nucleotide polymorphisms on expression of ABCB1, ABCC1, ABCC2, CXCR4, and CCR5 in peripheral blood mononuclear cells from HIV+ patients was assessed. The IFN-γ 874A>T allele and viral load were independently associated with CCR5 expression in patients. These associations have potential implications for HIV disease progression and treatment response that now warrant further study.     

Maternal ABCA1 genotype is associated with severity of Smith–Lemli–Opitz syndrome and with viability of patients homozygous for null mutations

The Smith–Lemli–Opitz syndrome (SLOS [MIM 270400]) is an autosomal recessive malformation syndrome that shows a great variability with regard to severity. SLOS is caused by mutations in the Δ7sterol-reductase gene (DHCR7), which disrupt cholesterol biosynthesis. Phenotypic variability of the disease is already known to be associated with maternal apolipoprotein E (ApoE) genotype. The aim of this study was to detect additional modifiers of the SLOS phenotype. We examined the association of SLOS severity with variants in the genes for ApoC-III, lecithin-cholesterol acyltransferase, cholesteryl-ester transfer protein, ATP-binding cassette transporter A1 (ABCA1), and methylene tetrahydrofolate reductase. Our study group included 59 SLOS patients, their mothers, and 49 of their fathers. In addition, we investigated whether ApoE and ABCA1 genotypes are associated with the viability of severe SLOS cases (n=21) caused by two null mutations in the DHCR7 gene. Maternal ABCA1 genotypes show a highly significant correlation with clinical severity in SLOS patients (P=0.007). The rare maternal p.1587Lys allele in the ABCA1 gene was associated with milder phenotypes. ANOVA analysis demonstrated an association of maternal ABCA1 genotypes with severity scores (logarithmised) of SLOS patients of P=0.004. Maternal ABCA1 explains 15.4% (R²) of severity of SLOS patients. There was no association between maternal ApoE genotype and survival of the SLOS fetus carrying two null mutations. Regarding ABCA1 p.Arg1587Lys in mothers of latter SLOS cases, a significant deviation from Hardy–Weinberg equilibrium (HWE) was observed (P=0.005). ABCA1 is an additional genetic modifier in SLOS. Modifying placental cholesterol transfer pathways may be an approach for prenatal therapy of SLOS.     

Risk of new tumors in von Hippel–Lindau patients depends on age and genotype

PurposeThe von Hippel–Lindau (vHL) phenotype is variable, which complicates genetic counseling and surveillance. We describe how the rate of new tumor development varies through the lifetimes of vHL patients and how it is influenced by age and genotype.MethodsIn a national cohort study, we included 52 VHL mutation carriers who were retrospectively followed for a total of 799 person-years. From birth to current age, 581 manifestations were diagnosed during 2,583 examinations in the study subjects. Manifestation rates were analyzed using Poisson regression and compared in groups of different ages, tumor sites, and genotypes.ResultsThe rate of new tumor development varied significantly with age and was highest at 30–34 years (0.4 new tumors/year). Tumor location further influenced the rate. The risk of retinal tumors was highest in subjects during the teenage years but was highest for cerebellar tumors in subjects during their 30s. Truncating VHL mutation carriers had a significantly higher manifestation rate compared with missense mutation carriers (hazard ratio = 1.85, 95% confidence interval: 1.06–3.24, P value = 0.031).ConclusionThe rate of new manifestation development is not constant throughout the life span of vHL patients; instead, it varies significantly with age and genotype and depends on anatomical location. Retinal surveillance is crucial during the teenage years, whereas cerebellar surveillance is especially important in adulthood.     

PinX1 is up-regulated and associated with poor patients’ survival in gliomas

PinX1, a conserved nuclear protein, could maintain telomere integrity and plays an important role in regulating telomerase activity. It has been reported that the expression of PinX1 is down-regulated in some cancer and associated with cancer prognosis. However, the value of PinX1 in gliomas has not been studied. In this study, two independent retrospective gliomas cohorts with the corresponding gliomas tissue microarrays (TMAs) were established to detect the expression level of PinX1 and the correlation of PinX1 expression with the clinicopathological features and the patients’ survival. Compared with non-cancerous brain tissues, PinX1 protein levels were remarkably up-regulated in gliomas (P = 0.001), and further increased from benign gliomas tissues to malignant gliomas tissues (P = 0.090). Moreover, high PinX1 expression was significantly positively associated with gliomas WHO grade in the training set (P = 0.019) and the validation set (P = 0.037). High PinX1 expression significantly correlated with a worse 5-year overall (P = 0.016) and disease-specific survival (P = 0.026). Simultaneously, the multivariate COX regression analysis showed that PinX1 was an independent unfavorable prognostic factor for 5-year overall survival (hazard ratio (HR) = 2.078, P = 0.015) and disease-specific survival (HR = 2.429, P = 0.012) after adjusting with age, sex and WHO grade in gliomas. In conclusion, PinX1 expression may serve as a prognostic and predictive biomarker for gliomas.     

Effect of atorvastatin in patients with chronic heart failure – insights from randomized clinical trials

Introduction

Recent large clinical trials have yielded disappointing results of rosuvastatin in the chronic heart failure (CHF) population. The question that remains is whether these results of rosuvastatin studies could be extended to other statins. Therefore, we performed a meta-analysis based on all currently available randomized controlled trials (RCTs) to evaluate the clinical efficacy of atorvastatin in CHF patients.

Material and methods

The published literature was scanned by formal searches of electronic databases up to January 2010. RCTs were eligible for inclusion if they compared atorvastatin versus placebo treatment in patients with CHF and reported the clinical outcomes.

Results

Pre-specified criteria were met by 7 trials involving 540 patients. The primary endpoint, all-cause mortality, was significantly reduced with atorvastatin therapy compared with placebo in CHF patients (odds ratio [OR] 0.39, P = 0.002), with similar results in cardiovascular mortality (OR 0.28, P = 0.002) and sudden cardiac death (OR 0.24, P = 0.01). There was also a significant decrease in hospitalization for worsening CHF with atorvastatin therapy compared with placebo (OR 0.30, P < 0.001).

Conclusions

This meta-analysis suggests the effectiveness of atorvastatin treatment in reducing the risks of all-cause mortality and worsening CHF hospitalization in patients with CHF. Further large, well-conducted randomized trials are needed to confirm the benefits of atorvastatin or other statins for CHF relative to placebo or rosuvastatin.     

Altered expression of estrogen receptor β2 is associated with different biological markers and clinicopathological factors in papillary thyroid cancer

Estrogen and estrogen receptor (ER)-α and -β play a role in the development and progression of thyroid cancer. ERβ2 is one major splicing variant of ERβ. In this study, we investigated the clinical significance of ERβ2 protein expression in the papillary thyroid carcinoma (PTC) lesion. ERβ2 expression was immunohisto-chemically examined in formalin-fixed, paraffin-embedded thyroid tissues from 106 patients with PTC by Elivision™ plus two-step system as previously described. The relationships between ERβ2 expression and clinicopathological/biological factors were then analyzed. ERβ2 protein was expressed in all the PTC patients studied. It was positively associated with Ki-67 expression in female PTC patients with advanced reproductive age (>45 years, in low-estrogen status) and with VEGF expression in male PTC patients with reproductive age (18~45 years, in low-estrogen status) (P=0.005 and P=0.044, respectively). There was no association between ERβ2 expression and tumor size, extrathyroidal extension and tumor-node-metastasis stage in PTC patients. In addition, ERβ2 expression was lower in female patients of reproductive age (18~45 years, in relatively high-estrogen status) with lymph node metastasis than that in those patients without lymph node metastasis (P=0.035). The present results suggest that the expression of ERβ2 in PTC is associated with the progression of the disease. Its potential effect may vary with different estrogen status. Further study will assess the underlying molecular mechanisms of ERβ2 in PTC.     

Molecular epidemiology of noroviruses in children under 5 years of age with acute gastroenteritis in Yaoundé, Cameroon

Norovirus is a common cause of acute gastroenteritis (AGE) among children in developing countries. Limited data on the prevalence and genetic variability of norovirus are available in Cameroon, where early childhood mortality due to AGE is common. We tested 902 fecal specimens from children younger than 5 years of age hospitalized with AGE between January 2010 and December 2013. Overall, 76 (8.4%) samples tested positive for norovirus, of which 83% (63/76) were among children below 12 months old. Most of the noroviruses detected were in children infected between July and December of each year. All norovirus-positive specimens were genotyped, with 80% (61/76) being GII.4 (three variants detected). Genotypes GI.2, GI.6, GII.1, GII.2, GII.3, GII.6, GII.16, GII.17, and GII.21 were also detected. Interestingly, GII.4 Sydney and GII.17 Kawasaki viruses were found as early as 2010, years before their emergence globally. This study suggests norovirus is a significant cause of moderate to severe gastroenteritis among young children in Cameroon. The results are important to highlight appropriate prevention and control strategies for reducing the burden of norovirus disease.     

Evolution of drug-resistant mutations in HBV genomes in patients with treatment failure during the past seven years (2010–2016)

The objective of this study was to analyze the prevalence of drug-resistant HBV mutants in patients with treatment failure during the past seven years (2010–2016). 4055 HBV-infected patients who underwent HBV polymerase gene mutation test from 2010 to 2016 were enrolled. The nucleos(t)ide analogues (NAs) resistance mutation positions, including rtL180, rtA181, rtT184, rtS202, rtM204, rtI233, rtN236, rtI169, rtV173, and rtM250 were analyzed. Genotypic resistance mutations were detected in 30.8% (1248/4055) of the patients with treatment failure. Rates of drug-resistant mutations associated with LAM, ADV, ETV, and multidrug were 27.23% (1104/4055), 9.67% (392/4055), 3.69% (150/4055), and 0.79% (32/4055). Among the primary NA-resistant mutations, rtM204I (13.44%, 545/4055) occurred more frequently, followed by rtM204V, rtN236T, rtA181T, and rtA181V. For single-base mutations, rtL180M and rtA181V increased gradually during the past seven years, while rtM204I/V and rtN236T decreased after 2015. The development of drug-resistant mutations positively correlated with the consumption of ETV (r = 0.964, P = 0.002), and weakly correlated with that of LAM (r = 0.679, P = 0.109) and ADV (r = 0.429, P = 0.354). Moreover, single-base mutation rtA181V and multi-base mutations (rtL180M + M204I and rtL180M + M204V + M204I) were more common in HBV genotype C than those in genotype B (1.94% vs. 0.66%, 1.84% vs. 0.16%, 1.02% vs. 0.16%, respectively). NA-related mutations in HBV RT region increased in the past seven years, especially for LAM. Frequencies of rtL180M and rtA181T/V increased gradually in the past seven years, to which we should pay more attention.     

Association of vitamin D deficiency with severe pneumonia in hospitalized children under 5 years

Pneumonia is the leading cause of childhood mortality accounting for 19 % of the 10.6 million deaths that occur each year. Vitamin D influences antimicrobial activity by acting on lymphocytes, neutrophils, macrophages, and respiratory epithelial cells. In addition, the immunomodulatory properties of vitamin D may influence the severity of infection. The objective of this study was to investigate whether vitamin D deficiency is a risk factor for severe pneumonia in children under 5 years. This case–control study was conducted in Cairo University Children Hospital, Egypt, from the first of February 2012 to the end of July 2012. It enrolled 81 patients hospitalized with severe pneumonia and 89 age- and sex-matched apparently healthy controls. Both cases and controls were subjected to questionnaire for pneumonia risk factors and were assessed for vitamin D status by measuring serum 25-hydroxyvitamin D [25(OH)D] concentrations using radioimmunoassay. This study included 170 subjects; the median age of the cases was 7 months and that of the controls was 9 months. The median serum concentration of 25(OH)D in cases [median (range) 32.4 (0–192.1)?nmol/L] was significantly lower than that in controls [median (range) 52.4 (0–244.6)?nmol/L] (P value 0.005). Breastfeeding provides significant protective effect against severe pneumonia compared to bottlefeeding (P value 0.04). Also, vitamin D deficiency was significantly related to breastfeeding compared to bottlefeeding (P value 0.04). There was a significant association between vitamin D deficiency and severe pneumonia in children below 5 years.