A J-shaped relationship between the atherogenic index of plasma and new-onset myocardial infarction in hypertensive patients with obstructive sleep apnea: a cohort study.

OBJECTIVE: This study aimed to investigate the relationship between baseline atherogenic index of plasma (AIP) and new-onset myocardial infarction (MI) in hypertensive patients with obstructive sleep apnoea (OSA). PATIENTS AND METHODS: 2,281 participants were included in this analysis after strict adherence to the inclusion and exclusion criteria. Hazard ratio (HR) and 95% confidence interval (CI) were estimated using multivariable Cox regression models. A generalized additive model was employed to determine nonlinear relationships. RESULTS: In multivariate-adjusted models, there was a positive association between AIP and new-onset MI (per SD increase; HR=1.42, 95% CI: 1.22-1.65). Smoothing curve fitting revealed a J-shaped association between AIP and new-onset MI, with a turning point of approximately -0.08. The addition of AIP to a model with established risk factors improved the C-index (p=0.007), integrated discrimination improvement (p=0.007), and continuous net reclassification improvement (p=0.027) for the new-onset MI. CONCLUSIONS: A J-shaped relationship was observed between AIP and new-onset MI.

Potential effects of age on screening for primary aldosteronism.

Aldosterone/renin ratio (ARR) is currently regarded as the most reliable and available screening test for primary aldosteronism (PA), however, the falling accuracy of ARR with increasing age has posed crucial challenge for PA screening among older-aged population. To clarify potential effects of age on screening for PA, 216 subjects with PA and 657 subjects with non-PA were recruited and subdivided into four age groups (⩽39, 40-49, 50-59 and ⩾60 years) and their biochemical parameters were compared. As expected, plasma renin activity (PRA) lowered more than plasma aldosterone concentration (PAC) and led to gradually elevated ARR with increasing age in the non-PA group (P<0.001), whereas this phenomenon was unconspicuous in the PA group. The best cut-off values of ARR for PA screening were elevated in subjects ⩾50 years, whereas the area under the receiver operating characteristic curves (AUCs), sensitivity, specificity and Youden's index (YI) of ARR were declined with increasing age, especially in patients ⩾60 years (AUC=0.863, sensitivity=95.2%, specificity=69.0%, YI=0.643). The AUCs of PAC increased with increasing age and even slightly surpassed that of ARR in patients ⩾60 years (AUCPAC=0.884). Our data suggest that the criteria of ARR for PA screening in patients ⩾50 years may need setting higher; the falling accuracy of ARR with increasing age, especially in patients ⩾60 years, could be improved by taking into account the absolute value of the PAC when applicable by the center.

Relationship between zinc finger protein 36 (ZFP36) gene polymorphisms and obstructive sleep apnea.

Recent data have indicated that inflammation may have an important correlation with obstructive sleep apnea (OSA). Studies have indicated a relationship between OSA and TNF-α gene polymorphisms. Zinc finger protein 36 (ZFP36) regulates TNF-α mRNAs. However, ZFP36 gene polymorphisms have not been investigated in OSA. Therefore, we conducted the present case-control study to assess whether variances in ZFP36 gene polymorphisms account for differences in TNF-α levels in patients with moderate-to-severe OSA. This case-control study aims to investigate the relationship between genetic variations in the ZFP36 gene and moderate-to-severe OSA. Three common single nucleotide polymorphisms of the ZFP36 gene (rs251864, rs3746083, and rs17879933) were evaluated in a group of patients with moderate-to-severe OSA (N = 408) and in a control group (N = 394) by using TaqMan polymerase chain reaction analysis. The moderate-to-severe OSA group and the control group exhibited significant differences in the distributions of rs251864 and rs17879933 genotypes and alleles (P < 0.05). TNF-α levels were significantly different not only among the three rs251864 genotypes but also between the II genotype and the DD + ID genotypes of rs17879933. However, no significant differences in sleep apnea parameters in the three ZFP36 gene polymorphisms were observed. Logistic regression analyses demonstrated that TNF-α and the three ZFP36 gene polymorphisms were not independently associated with OSA. ZFP36 might be involved in TNF-α regulation. However, ZFP36 gene variants were not independent risk factors for moderate-to-severe OSA.

Relationship between polymorphism of SOCS-3 and dyslipidemia in China Xinjiang Uygur.

We investigated the relationship between the polymorphism of SOCS-3 and dyslipidemia of people from Uygur in Xinjiang, China. This cross-sectional study included 1379 participants in a Hetian Xinjiang Uygur population who were 30-70 years of age and were not from interracial marriages of 3 generations; all subjects were genotyped (909 dyslipidemia subjects, 470 healthy subjects). Allele (P = 0.002) and genotype (P = 0.003) frequencies of the distribution of rs12953258 was significantly different between dyslipidemia and control groups. Between the total cholesterol abnormal and control groups, high-density lipoprotein cholesterol abnormal and control groups, triglycerides abnormal and control groups, the frequencies of genotype in rs12953258 were significantly different (P = 0.007, 0.012, 0.0004, respectively). Based on the logistic regression analysis, genotype CA and AA of rs12953258 were independent and risk factors for dyslipidemia in Uygur (CC vs CA; odds ratio = 1.48, 95% confidence interval = 1.11-1.98, P = 0.008), (CC vs AA; odds ratio = 2.48, 95% confidence interval1.07-5.79, P = 0.035). Genotype AA of rs12953258 merged with subjects whose waist-to-hip ratio was abnormal, indicating the presence of dyslipidemia. The frequency of haplotype 4(H4) A-G-C in the dyslipidemia group was higher than in the control group (8.44 vs 5.37%, P = 0.003). rs12953258 site of the SOCS-3 gene showed a close relationship with dyslipidemia in Uygur. Combining genotype AA with subjects whose waist-to-hip ratios were abnormal will increase prevalence of dyslipidemia obviously.

Gender flip-flop association between genetic variations of NEDD4L and metabolic syndrome in the Kazakh general population.

Genetic variation is thought to contribute to etiology of metabolic syndrome (MS). Neural precursor cell expressed developmentally downregulated 4-like gene (NEDD4L) is a candidate gene for MS. This study investigated the relationship between variations of NEDD4L and MS in the Kazakh, which is an ideal population to study the genetic mechanisms of complex diseases such as MS. We screened the promoter and exons of NEDD4L in 48 Kazakh individuals with MS to identify representative variations. By genotyping the representative variations [271420T>C (rs2288774), 271454A>G (rs2288775), and 296921-296923delTTG] in the Kazakh general population, we conducted a case-control study. In female subjects, the distribution of genotypes and alleles of rs2288775 and 296921-296923delTTG differed significantly between the MS pacients and controls. In male subjects, the genotype distributions of 296921-296923delTTG were significantly different between the MS pacients and controls in the dominant model (P = 0.047). After adjustment for age, smoking, and drinking, multivariate logistic regression analysis showed that rs2288775 was significantly associated with MS [for the A/A genotype, odds ratio (OR) = 3.296, P = 0.011] in female subjects. For 296921-296923delTTG, the I/D+D/D genotype was the high-risk genotype for MS in female subjects (OR = 2.791, P = 0.035) and was a protective factor for MS in male subjects (OR = 0.580, P = 0.045). The 296921-296923delTTG variation of NEDD4L is a gender flip-flop associated with MS in Kazakh individuals. The A allele of rs2288775 may be an independent risk factor for MS in Kazakh women. The results suggest that the genetic variations of NEDD4L might be involved in the pathogenesis of MS.

Ezrin interacts with cortactin to form podosomal rosettes in pancreatic cancer cells.

BACKGROUND AND AIMS: Pancreatic cancer is a highly invasive malignancy. Ezrin, a plasma membrane-cytoskeletal linker protein, is associated with the invasive behaviour of cancers. The purpose of this study was to elucidate a possible molecular mechanism for the invasive phenotype. METHODS: Using a combination of techniques, such as western blotting, co-immunoprecipitation, confocal and light microscopy, invasion and adhesion assays, organotypic cultures and human samples as well as RNA interference (RNAi) and expression of various mutant ezrin constructs, the dynamic molecular nature of podosomes in pancreatic cancer was dissected out. RESULTS: Podosome and podosomal rosette formation in pancreatic carcinoma (PaCa3) cells is ezrin dependent and associated with adhesion to fibronectin with subsequent digestion of this substrate. Ezrin binds to increasing amounts of cortactin during formation of the podosomal rosette, with the C-terminal region, specifically the actin-binding domain, mediating this molecular linkage. Further, it is shown that phosphorylation of Tyr353 and Thr567 sites on ezrin (conventionally shown to translocate ezrin to the plasma membrane) is not required for podosome formation. The podosomal rosette is revealed to be a highly dynamic and transient structure, which can metamorphose into other cellular processes, such as filopodia or lamellipodia, and thereby enable epithelial cancer cells to "palpate" the underlying substrate and modify their cytoskeletal behaviour accordingly. In human tumour tissues and organotypic cultures, specific subcellular expression of ezrin (basal membranous; cellular processes invading stroma) in pancreatic cancer cells can be correlated with tumour progression and disease-free survival (log-rank test (Mantel-Cox), p = 0.019). CONCLUSION: Podosomes and their rosettes are driven by ezrin-cortactin interaction and this plays a role in pancreatic cancer invasion.

A novel function of colony-stimulating factor 1 receptor in hTERT immortalization of human epithelial cells.

The receptor for macrophage colony-stimulating factor 1 receptor (CSF1R) is a product of the proto-oncogene c-fms and a member of the class III transmembrane tyrosine kinase receptor family. Earlier, we described increased mRNA expression of CSF1R in human telomerase reverse transcriptase (hTERT) immortalized human ovarian surface epithelial (IOSE) cell lines derived from a single donor. Here, we further describe that CSF1R is upregulated at both the mRNA and protein level in hTERT immortalized human normal OSE cells from two different donors and in hTERT immortalized human pancreatic ductal epithelial cells. CSF1R was not upregulated in hTERT immortalized epithelial clones that subsequently underwent senescence or in immortalized fibroblasts. Upon stimulation by the CSF1R ligand CSF1, the immortalized epithelial cell lines showed rapid internalization of CSF1R with concomitant down-modulation and colocalization of phosphorylated NFkappaBp65 with hTERT protein, hTERT translocation into the nucleus and the binding of c-Myc to the hTERT promoter region. Reducing the expression of CSF1R using short hairpin interfering RNA abolished these effects and also decreased cell survival and the number of population doublings under suboptimal culture conditions. The telomerase inhibitor GRN163L confirmed a role for telomerase in the cleavage of the intracellular domain of CSF1R. On the basis of these findings, we suggest that CSF1R may be a critical factor facilitating hTERT immortalization of epithelial cells.

Human ovarian surface epithelial cells immortalized with hTERT maintain functional pRb and p53 expression.

OBJECTIVE: Cell immortalization is considered to be a prerequisite status for carcinogenesis. Normal human ovarian surface epithelial (OSE) cells, which are thought to be the origin of most of human ovarian carcinomas, have a very limited lifespan in culture. Establishment of immortalized OSE cell lines has, in the past, required inactivation of pRb and p53 functions. However, this often leads to increased chromosome instability during prolonged culture. MATERIALS AND METHODS: In this study, we have used a retroviral infection method to overexpress human telomerase reverse transcriptase (hTERT) gene, in primary normal OSE cells, under optimized culture conditions. RESULTS: In vitro and in vivo analysis of hTERT-immortalized cell lines confirmed their normal epithelial characteristics. Gene expression profiles and functional analysis of p16(INK4A), p15(INK4B), pRb and p53 confirmed the presence of their intact functions. Our study suggests that inactivation of pRb and p53 is not necessary for OSE immortalization. Furthermore, down-regulation of p15(INK4B) in the immortalized cells may indicate a functional role for this protein in them. CONCLUSION: These immortal OSE cell lines are likely to be an important tool for studying human OSE biology and carcinogenesis.

[Surgical treatment of trilogy of Fallot in 42 adults].

From 1984 to 1989 corrective operation circulation was performed under extracorporeal in 42 adults with trilogy of Fallot (6.2% of total intracardial operations under direct vision in patients with congenital heart disease in our hospital). The obstruction was relieved by resection of the hypertrophial and sclerotic muscle trabeculae of the Rt. ventricular outflow tract and pulmonary valvotomy and patching with a piece of artificial blood vessel lined internally by auto-pericardium so that a bougie (more than 1.6cm) could be passed through. The Rt. ventricular pressure was reduced satisfactorily (PRV/PLV < 0.75). There was one operative death.