Triglyceride-Glukose Index Predicts Adverse Events in Patients with Acute Coronary Syndrome: A Meta-Analysis of Cohort Studies.

The triglyceride-glucose (TyG) index, a recently proposed indicator for insulin resistance, has been related with cardiovascular risks. We aimed to summarize the association between TyG index and incidence of major adverse cardiovascular events (MACEs) in patients with acute coronary syndrome (ACS). Cohort studies demonstrating the association between TyG index and incidence of MACEs in ACS patients with multivariate adjusted analyses were identified by search of PubMed, Embase, and Web of Science databases. A random-effekt model incorporating the heterogeneity was applied to pool the results. Eight cohort studies with 19 611 participants were included. Results showed that compared to those with the lowest category of TyG index, ACS patients with the highest category of TyG index were independently associated with higher risk of MACEs [risk ratio (RR): 1.94, 95% confidence interval (CI): 1.47-2.56, I2=85%, p <0.001). Subgroup analyses showed consistent results in patients with ST-segment elevated myocardial infarction or non-ST segment elevated ACS, in patients with or without diabetes, and in patients after percutaneous coronary intervention. Results were consistent in studies with TyG index analyzed as continuous variable (RR for per standard deviation increment of TyG index: 1.59, 95% CI: 1.38-1.83, I2=24%, p <0.001). In conclusion, higher TyG index may be independently associated with higher incidence of MACEs in patients with ACS.

Calcium-sensing receptor gene (CASR) polymorphisms and CASR transcript level concerning dyslipidemia in hemodialysis patients: a cross-sectional study.

BACKGROUND: There is scarce data on CASR associations with dyslipidemia. We investigated in hemodialysis (HD) patients whether CASR single nucleotide polymorphisms (SNPs) rs7652589 and rs1801725 have associations with dyslipidemia and show epistatic interactions with SNPs of the energy homeostasis-associated gene (ENHO), retinoid X receptor α gene (RXRA), and liver X receptor α gene (LXRA). METHODS: The study included 1208 HD subjects. For diagnosis of dyslipidemia, both K/DOQI criteria and atherogenic index ≥3.8 were used. CASR rs1801725 was genotyped by TaqMan SNP Genotyping Assay, other SNPs - by high-resolution melting curve analysis or polymerase chain reaction-restriction fragment length polymorphism, as appropriate. Relative transcript levels of CASR, ENHO, RXRA, and LXRA were measured in peripheral blood mononuclear cells. The occurrence of dyslipidemic phenotypes concerning tested polymorphisms was compared using models of inheritance. Haplotypes were estimated using the Haploview 4.2 software. Epistatic interactions between tested SNPs were analyzed using the logistic regression and epistasis option in the PLINK software. RESULTS: Rs7652589 indicated a greater probability of atherogenic dyslipidemia in the dominant inheritance model (OR 1.4, 95%CI 1.0-2.0, P = 0.026), principally because of increased triglyceride (TG) levels. The rs1801725 variant allele was associated with a decreased probability of dyslipidemia characterized by non-HDL-cholesterol ≥130 mg/dL and TG ≥200 mg/dL (OR 0.6, 0.4-0.9, P = 0.012). There were no epistatic interactions between CASR and RXRA, LXRA, and ENHO regarding dyslipidemia. Both rs7652589 and rs1801725 SNPs were not in linkage disequilibrium (D' = 0.091, r2 = 0.003 for the entire HD group) and their haplotypes did not correlate with dyslipidemia. Relative CASR transcript was lower at a borderline significance level in patients harboring the rs1801725 variant allele compared with homozygotes of the major allele (0.20, 0.06-7.80 vs. 0.43, 0.04-5.06, P = 0.058). CASR transcript correlated positively with RXRA transcript (adjusted P = 0.001), LXRA transcript (adjusted P = 0.0009), ENHO transcript (borderline significance, adjusted P = 0.055), dry body weight (adjusted P = 0.035), and renal replacement therapy duration (adjusted P = 0.013). CONCLUSIONS: CASR polymorphisms (rs7652589, rs1801725) are associated with dyslipidemia in HD patients. CASR correlates with RXRA, LXRA, and ENHO at the transcript level. Further investigations may elucidate whether other CASR SNPs contribute to associations shown in this study.

Long-Term Antipsychotic Use and Major Cardiovascular Events: A Retrospective Cohort Study.

OBJECTIVE: Chronic treatment with antipsychotics may result in both metabolic side effects and cardiovascular disease. Our aim was to evaluate the effect of antipsychotic medications categorized by their metabolic side effect profiles as low, intermediate, or high risk on major cardiovascular events. METHODS: A retrospective cohort study was conducted in adult outpatients aged 30 years or older initiating antipsychotic treatment from 2002 to 2007. Antipsychotic medications were divided into 3 groups (low-, intermediate-, and high-risk) according to the severity of their side-effect profiles in developing metabolic abnormalities associated with cardiovascular disease. The primary outcome measure was the time to the composite of acute myocardial infarction, acute coronary syndrome, ischemic stroke, peripheral artery disease, or a new revascularization procedure. Inverse probability weighting of a marginal structural Cox model was used to adjust for confounding. RESULTS: A total of 1,008 patients were included (mean age = 72.4 years, median follow-up = 36.5 months), and 19.6% of patients experienced the primary outcome. The adjusted hazard ratios of a major cardiovascular event for patients in the high- or intermediate-risk medication groups compared to the low-risk group were 2.82 (95% CI, 1.57-5.05) and 2.57 (95% CI, 1.43-4.63), respectively. CONCLUSIONS: Older adult patients under antipsychotic regimens with high or intermediate risk of metabolic side effects may face a higher incidence of major cardiovascular events than those under a low-risk regimen during long-term follow-up.

Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson's Disease.

Restoring dopamine production in the putamen through gene therapy is a straightforward strategy for ameliorating motor symptoms for Parkinson's disease (PD). In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity-based primate model of PD, we previously showed the safety and efficacy of adeno-associated viral (AAV) vector-mediated gene delivery to the putamen of three dopamine-synthesizing enzymes (tyrosine hydroxylase [TH], aromatic l-amino acid decarboxylase [AADC], and guanosine triphosphate cyclohydrolase I [GCH]) up to 10 months postprocedure. Although three of four monkeys in this study have previously undergone postmortem analysis, one monkey was kept alive for 15 years after gene therapy to evaluate long-term effects. Here, we report that this monkey showed behavioral recovery in the right-side limb that remained unchanged for 15 years, at which time euthanasia was carried out owing to onset of senility. Immunohistochemistry of the postmortem brain from this monkey revealed persistent expression of TH, AADC, and GCH genes in the lesioned putamen. Transduced neurons were broadly distributed, with the estimated transduction region occupying 91% of the left postcommissural putamen. No signs of cytotoxicity or Lewy body pathology were observed in the AAV vector-injected putamen. This study provides evidence of long-term safety and efficacy of the triple-transduction method as a gene therapy for PD.

Long-term lithium treatment increases intracellular and extracellular brain-derived neurotrophic factor (BDNF) in cortical and hippocampal neurons at subtherapeutic concentrations.

OBJECTIVES: The putative neuroprotective effects of lithium treatment rely on the fact that it modulates several homeostatic mechanisms involved in the neurotrophic response, autophagy, oxidative stress, inflammation, and mitochondrial function. Lithium is a well-established therapeutic option for the acute and long-term management of bipolar disorder and major depression. The aim of this study was to evaluate the effects of subtherapeutic and therapeutic concentrations of chronic lithium treatment on brain-derived neurotrophic factor (BDNF) synthesis and secretion. METHODS: Primary cultures of cortical and hippocampal neurons were treated with different subtherapeutic (0.02 and 0.2 mM) and therapeutic (2 mM) concentrations of chronic lithium treatment in cortical and hippocampal cell culture. RESULTS: Lithium treatment increased the intracellular protein expression of cortical neurons (10% at 0.02 mM) and hippocampal neurons (28% and 14% at 0.02 mM and 0.2 mM, respectively). Extracellular BDNF of cortical neurons increased 30% and 428% at 0.02 and 0.2 mM, respectively and in hippocampal neurons increased 44% at 0.02 mM. CONCLUSION: The present study indicates that chronic, low-dose lithium treatment up-regulates BDNF production in primary neuronal cell culture.

Live donor study - implications of kidney donation on cardiovascular risk with a focus on lipid parameters including lipoprotein a.

In this prospective observational cohort study, we evaluate the change in cardiovascular risk parameters, with a focus on lipids, in live kidney donors 1 year post donation. Body mass index, systolic/diastolic blood pressure, kidney function (chromium-51 ethylenediaminetetraacetic acid estimated glomerular filtration) and lipid parameters were measured at baseline and 1 year. Data on 87 live kidney donors were collected. Body mass index increased from 26.5 ± 2.7 pre to 27.4 ± 3.0 kg/m(2) post donation (p < 0.0001). Chromium-51 ethylenediaminetetraacetic acid estimated glomerular filtration decreased from 111.8 ± 20.0 pre to 72.1 ± 13.1 mL/min/1.73 m(2) post donation (p < 0.0001). Serum triglyceride levels increased from 0.8 (interquartile range 0.6-1.3) pre to 1.0 mmol/L (interquartile range 0.7-1.6) post donation (p = 0.0004). Statin use increased from 11.5% pre to 21% post donation (p < 0.005). Low-density lipoprotein remained stable, and other lipids (high-density lipoprotein, apolipoprotein B and lipoprotein a) did not change post donation.

New Options for Iron Supplementation in Maintenance Hemodialysis Patients.

End-stage renal disease results in anemia caused by shortened erythrocyte survival, erythropoietin deficiency, hepcidin-mediated impairment of intestinal absorption and iron release, recurrent blood loss, and impaired responsiveness to erythropoiesis-stimulating agents (ESAs). Iron malabsorption renders oral iron products generally ineffective, and intravenous (IV) iron supplementation is required in most patients receiving maintenance hemodialysis (HD). IV iron is administered at doses far exceeding normal intestinal iron absorption. Moreover, by bypassing physiologic safeguards, indiscriminate use of IV iron overwhelms transferrin, imposing stress on the reticuloendothelial system that can have long-term adverse consequences. Unlike conventional oral iron preparations, ferric citrate has recently been shown to be effective in increasing serum ferritin, hemoglobin, and transferrin saturation values while significantly reducing IV iron and ESA requirements in patients treated with HD. Ferric pyrophosphate citrate is a novel iron salt delivered by dialysate; by directly reaching transferrin, its obviates the need for storing administered iron and increases transferrin saturation without increasing serum ferritin levels. Ferric pyrophosphate citrate trials have demonstrated effective iron delivery and stable hemoglobin levels with significant reductions in ESA and IV iron requirements. To date, the long-term safety of using these routes of iron administration in patients receiving HD has not been compared to IV iron and therefore awaits future investigations.

Long-term consequences of chronic fluoxetine exposure on the expression of myelination-related genes in the rat hippocampus.

The selective serotonin reuptake inhibitor (SSRI) fluoxetine is widely prescribed for the treatment of symptoms related to a variety of psychiatric disorders. After chronic SSRI treatment, some symptoms remediate on the long term, but the underlying mechanisms are not yet well understood. Here we studied the long-term consequences (40 days after treatment) of chronic fluoxetine exposure on genome-wide gene expression. During the treatment period, we measured body weight; and 1 week after treatment, cessation behavior in an SSRI-sensitive anxiety test was assessed. Gene expression was assessed in hippocampal tissue of adult rats using transcriptome analysis and several differentially expressed genes were validated in independent samples. Gene ontology analysis showed that upregulated genes induced by chronic fluoxetine exposure were significantly enriched for genes involved in myelination. We also investigated the expression of myelination-related genes in adult rats exposed to fluoxetine at early life and found two myelination-related genes (Transferrin (Tf) and Ciliary neurotrophic factor (Cntf)) that were downregulated by chronic fluoxetine exposure. Cntf, a neurotrophic factor involved in myelination, showed regulation in opposite direction in the adult versus neonatally fluoxetine-exposed groups. Expression of myelination-related genes correlated negatively with anxiety-like behavior in both adult and neonatally fluoxetine-exposed rats. In conclusion, our data reveal that chronic fluoxetine exposure causes on the long-term changes in expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders.