Poor Nutritional Status Is Associated with Arrhythmic Events on 24-Hour Holter Recording.

BACKGROUND: Malnutrition is associated with cardiovascular disease morbidity and mortality. Arrhythmias may be the cardiac consequences of malnutrition. OBJECTIVES: The objective of the study was to evaluate the association between prognostic nutritional index (PNI), Controlling Nutritional Status (CONUT) score, and arrhythmic events on 24-h electrocardiography (ECG) Holter recording in patients without manifested arrhythmia. METHODS: In this retrospective analysis of 477 patients who underwent 24-h ECG Holter monitoring, PNI and CONUT score were calculated and patients were divided into tertiles according to PNI and into three groups according to CONUT score; 0: normal, 1-2: mild risk of malnutrition, ≥3: moderate-severe risk of malnutrition. Arrhythmic events were compared between PNI tertiles and CONUT score groups. RESULTS: Total number of premature atrial contractions, premature ventricular contractions (PVCs), PVC burden, and incidence of paroxysmal atrial fibrillation (PAF) were significantly higher in patients within the lowest PNI tertile. Total number of PVCs, PVC burden, and incidence of PAF were significantly higher in patients with CONUT score ≥3. The cut-off value for PNI to predict the presence of PVC was defined as 39.41 using ROC curve analysis. The area under the curve was 0.650 (p < 0.001). Multivariate analysis showed that PNI was independent predictor of the presence of PVC and PAF. Also, CONUT score was independent predictor of the presence of PVC and PAF. Incidence of nonsustained ventricular tachycardia did not differ between PNI tertiles or CONUT score groups. CONCLUSION: Poor nutritional status, assessed by PNI and CONUT score, is associated with arrhythmic events on 24-h ECG Holter recording in patients without manifested arrhythmia.

Prognostic Nutritional Index as a New Prediction Tool for Coronary Collateral Development.

BACKGROUND: Nutritional status is a predictor of the prognosis of cardiovascular diseases. The association between the Prognostic Nutritional Index (PNI), which is an immunonutritional parameter, and cardiovascular diseases has been extensively studied in the literature. OBJECTIVES: The aim of this study was to investigate whether PNI is associated with coronary collateral development. METHODS: This retrospective study included 172 patients with chronic total occlusion. The patients were diagnosed with stable coronary artery disease, and all patients underwent coronary angiography. PNI was calculated using serum albumin level and lymphocyte count. Collateral circulation was classified according to Rentrop grade. RESULTS: There was a positive correlation between PNI and Rentrop grade (r = 0.168, p = 0.026) and a negative correlation between C-reactive protein and PNI (r = -0.353, p < 0.001). Multivariate logistic regression analysis showed that uric acid and PNI were independent predictors of Rentrop grade (p = 0.008 and p = 0.037, respectively). CONCLUSIONS: This study showed that PNI, which can easily be calculated using serum albumin level and lymphocyte count, was a predictor of coronary collateral development in terms of Rentrop grade.

Nutritional status and severity of coronary artery disease.

OBJECTIVE: The aim of this study is to evaluate the association between Nutritional Risk Index (NRI), a simple tool to assess nutritional status, and coronary artery disease severity and complexity in patients undergoing coronary angiography. METHODS: This study is a retrospective analysis of 822 patients undergoing coronary angiography. Patients with previous revascularization were excluded. Gensini and SYNTAX scores were calculated according to the angiographic images to determine atherosclerosis severity. NRI was calculated as follows: NRI = [15.19 × serum albumin (g/dl)] + [41.7 × (body weight/ideal body weight)]. In patients ≥65 years of age, Geriatric NRI (GNRI) was used instead of NRI. GNRI was calculated as follows: GNRI = [14.89 × serum albumin (g/dl)] + [41.7 × (body weight/ideal body weight)]. Patients were then divided into three groups as previously reported: NRI < 92, NRI 92-98 and NRI > 98. Gensini and SYNTAX scores were compared between three groups. RESULTS: The mean age of study population was 61.9 ± 11.1 years. NRI < 92, 92-98, and >98 was measured in 212, 321 and 289 patients, respectively. There was no difference regarding to sex, BMI, smoking, hypertension and diabetes mellitus between three groups. Patients with NRI < 92 had the highest mean Gensini score than the patients with NRI 92-98 and NRI > 98 (38.0 ± 40.6 vs. 31.17 ± 42.4 vs. 25.8 ± 38.4, P = 0.005). Also patients with NRI < 92 had the highest mean SYNTAX score than the patients with NRI 92-98 and NRI > 98 (11.8 ± 12.9 vs. 9.3 ± 12.4 vs. 7.7 ± 11.8, P = 0.001). Also, Gensini score of ≥20 and high SYNTAX score of ≥33 were associated with lower NRI (P < 0.001 and P < 0.001, respectively). CONCLUSION: In our study, nutritional status evaluated by the NRI was associated with more extensive and complex coronary atherosclerosis in patients undergoing coronary angiography.

Impact of Admission Blood Glucose on Coronary Collateral Flow in Patients with ST-Elevation Myocardial Infarction.

In patients with acute myocardial infarction, glucose metabolism is altered and acute hyperglycemia on admission is common regardless of diabetes status. The development of coronary collateral is heterogeneous among individuals with coronary artery disease. In this study, we aimed to investigate whether glucose value on admission is associated with collateral flow in ST-elevation myocardial infarction (STEMI) patients. We retrospectively evaluated 190 consecutive patients with a diagnosis of first STEMI within 12 hours of onset of chest pain. Coronary collateral development was graded according to Rentrop classification. Rentrop 0-1 was graded as poor collateral development, and Rentrop 2-3 was graded as good collateral development. Admission glucose was measured and compared between two groups. Mean admission glucose level was 173.0 ± 80.1 mg/dl in study population. Forty-five (23.7%) patients had good collateral development, and 145 (76.3%) patients had poor collateral development. There were no statistically significant differences in demographic characteristics between two groups. Three-vessel disease was more common in patients with good collateral development (p=0.026). Mean admission glucose level was higher in patients with poor collateral than good collateral (180.6 ± 84.9 mg/dl versus 148.7 ± 56.6 mg/dl, resp., p=0.008). In univariate analysis, higher admission glucose was associated with poor collateral development, but multivariate logistic regression analysis revealed a borderline result (odds ratio 0.994, 95% CI 0.989-1.000, p=0.049). Our results suggest that elevated glucose on admission may have a role in the attenuation of coronary collateral blood flow in acute myocardial infarction. Further studies are needed to validate our results.

A validated antibody panel for the characterization of tau post-translational modifications.

BACKGROUND: Tau is a microtubule-binding protein, which is subject to various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Aberrant PTMs such as hyperphosphorylation result in tau aggregation and the formation of neurofibrillary tangles, which are a hallmark of Alzheimer's disease (AD). In order to study the importance of PTMs on tau function, antibodies raised against specific modification sites are widely used. However, quality control of these antibodies is lacking and their specificity for particular modifications is often unclear. METHODS: In this study, we first designed an online tool called 'TauPTM', which enables the visualization of PTMs and their interactions on human tau. Using TauPTM, we next searched for commercially available antibodies against tau PTMs and characterized their specificity by peptide array, immunoblotting, electrochemiluminescence ELISA and immunofluorescence technologies. RESULTS: We demonstrate that commercially available antibodies can show a significant lack of specificity, and PTM-specific antibodies in particular often recognize non-modified versions of the protein. In addition, detection may be hindered by other PTMs in close vicinity, complicating the interpretation of results. Finally, we compiled a panel of specific antibodies and show that they are useful to detect PTM-modified endogenous tau in hiPSC-derived neurons and mouse brains. CONCLUSION: This study has created a platform to reliably and robustly detect changes in localization and abundance of post-translationally modified tau in health and disease. A web-based version of TauPTM is fully available at http://www.tauptm.org .

Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex.

Disruption of myelination during development has been implicated in a range of neurodevelopmental disorders including tuberous sclerosis complex (TSC). TSC patients with autism display impairments in white matter integrity. Similarly, mice lacking neuronal Tsc1 have a hypomyelination phenotype. However, the mechanisms that underlie these phenotypes remain unknown. In this study, we demonstrate that neuronal TSC1/2 orchestrates a program of oligodendrocyte maturation through the regulated secretion of connective tissue growth factor (CTGF). We characterize oligodendrocyte maturation both in vitro and in vivo. We find that neuron-specific Tsc1 deletion results in an increase in CTGF secretion that non-cell autonomously stunts oligodendrocyte development and decreases the total number of oligodendrocytes. Genetic deletion of CTGF from neurons, in turn, mitigates the TSC-dependent hypomyelination phenotype. These results show that the mechanistic target of rapamycin (mTOR) pathway in neurons regulates CTGF production and secretion, revealing a paracrine mechanism by which neuronal signaling regulates oligodendrocyte maturation and myelination in TSC. This study highlights the role of mTOR-dependent signaling between neuronal and nonneuronal cells in the regulation of myelin and identifies an additional therapeutic avenue for this disease.

Cell-type-specific miR-431 dysregulation in a motor neuron model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is an autosomal-recessive pediatric neurodegenerative disease characterized by selective loss of spinal motor neurons. It is caused by mutation in the survival of motor neuron 1, SMN1, gene and leads to loss of function of the full-length SMN protein. microRNAs (miRNAs) are small RNAs that are involved in post-transcriptional regulation of gene expression. Prior studies have implicated miRNAs in the pathogenesis of motor neuron disease. We hypothesized that motor neuron-specific miRNA expression changes are involved in their selective vulnerability in SMA. Therefore, we sought to determine the effect of SMN loss on miRNAs and their target mRNAs in spinal motor neurons. We used microarray and RNAseq to profile both miRNA and mRNA expression in primary spinal motor neuron cultures after acute SMN knockdown. By integrating the miRNA:mRNA profiles, a number of dysregulated miRNAs were identified with enrichment in differentially expressed putative mRNA targets. miR-431 expression was highly increased, and a number of its putative mRNA targets were significantly downregulated in motor neurons after SMN loss. Further, we found that miR-431 regulates motor neuron neurite length by targeting several molecules previously identified to play a role in motor neuron axon outgrowth, including chondrolectin. Together, our findings indicate that cell-type-specific dysregulation of miR-431 plays a role in the SMA motor neuron phenotype.

Association of total serum antioxidant capacity with the Tei index in echocardiography in patients with microvascular angina.

OBJECTIVES: Cardiac syndrome X (CSX) is a condition characterized by exercise-induced chest pain that occurs considering a normal coronary angiogram. We aimed to investigate the total serum antioxidant capacity (TAC) and biventricular global functions using echocardiography in patients with CSX. PATIENTS AND METHODS: The study population included 55 patients with typical anginal symptoms and a positive exercise stress test, or ischemia in myocardial perfusion scintigraphy and normal coronary arteries detected angiographically, and 49 healthy volunteers with atypical chest pain and a negative stress test. TAC was assessed from blood samples. Transthoracic echocardiography was performed for the entire study population. The Tei index was calculated using the formula IVCT+IVRT/ET. RESULTS: TAC was found to be significantly lower in the CSX group compared with the control group (0.70±0.37 vs. 1.5±0.30, respectively, P<0.001). The Tei index was significantly higher in patients with CSX than the control group (0.60±0.18 vs. 0.42±0.12, respectively, P<0.001).There was a significant and inverse relationship between TAC and the Tei index (r=-0.41, P<0.001). When we divided the study population according to the normal range of TAC into the decreased TAC group (<1.30 mmol/l), the normal TAC group (1.30-1.77 mmol/l), and the increased TAC group (>1.77 mmol/l), it was found that the Tei index was higher in the decreased TAC group compared with the other groups (0.66±0.18 vs. 0.49±0.10 and 0.46±0.13 mmol/l, P<0.001, respectively). CONCLUSION: Our study suggested that TAC was significantly decreased in CSX patients and decreased antioxidant levels were related to impaired Tei index in echocardiography in patients with microvascular angina.

The effect of emotional status and health-related quality of life on the severity of coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is the most common form of heart disease and a leading cause of death worldwide. Extensive clinical and statistical studies have identified several factors that increase the risk of CAD and myocardial infarction. AIM: To investigate the relationship between severity of CAD, anxiety, depression, and health-related quality of life (HRQoL). METHODS: A total of 225 patients (116 men, 109 women) who underwent elective coronary angiography were included. All patients were assessed for the presence of cardiovascular risk factors and ongoing medications. A biochemical examination of blood was performed in all patients before the procedure. The 225 patients were divided into three groups (a control group, and minimal and significant CAD groups) based on their Gensini score, which evaluates the severity of CAD. The Nottingham Health Profile (NHP) was used to measure HRQoL. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS). RESULTS: A significant positive correlation was found between HADS and Gensini scores (HADS-anxiety: r = 0.139, p = 0.038; HADS-depression: r = 0.156, p = 0.019). A significant positive correlation was also determined between NHP-total and Gensini scores (r = 0.145, p = 0.029). According to the NHP, energy (p = 0.048) and physical mobility status (p = 0.021) were better in the control group than they were in the CAD groups. CONCLUSIONS: Our study demonstrates that anxiety, depression, and HRQoL are related to CAD severity. Therefore, emotional status and HRQoL should be evaluated during routine clinical treatment of CAD.

Duration of migraine is associated with cardiac diastolic dysfunction.

OBJECTIVE: Migraine is a common type of headache accompanied or preceded by signs of central and autonomic nervous system dysfunction. Autonomic dysfunction has been suggested to be a potential contributor to impaired cardiac diastolic function. Cardiac diastolic dysfunction is characterized by normal left ventricular contractility but impaired ventricular relaxation. It is a growing clinical entity implicated in morbidity and mortality due to heart failure. The aim of this study was to determine if any relationship exists between migraine and diastolic dysfunction. METHODS: Migraineurs (N = 55), and age- and sex-matched healthy controls (N = 52) were evaluated by conventional and tissue Doppler echocardiography. Migraine-related disability in the previous 3 months was assessed by the Migraine Disability Assessment questionnaire. Baseline characteristics were recorded, and blood samples were collected. RESULTS: The groups did not differ in terms of sex or age. The migraine group had higher lipid levels compared with the control group. Diastolic dysfunction was significantly higher among the 30 migraineurs with a history of migraine of 10 years or more compared with the 25 migraineurs with a history of less than 10 years, (P = 0.003). In logistic regression analysis, migraine duration was shown to be an independent predictor of diastolic dysfunction (odds ratio 1.130, 95% confidence interval, P = 0.044). CONCLUSIONS: Cardiac diastolic dysfunction is associated with migraine. A long history of migraine is an independent predictor of diastolic dysfunction.

Di-arginine signals and the K-rich domain retain the Ca²âº sensor STIM1 in the endoplasmic reticulum.

STIM1 is a core component of the store-operated Ca²âº-entry channel involved in Ca²âº-signaling with an important role in the activation of immune cells and many other cell types. In response to cell activation, STIM1 protein senses low Ca²âº concentration in the lumen of the endoplasmic reticulum (ER) and activates the channel protein Orai1 in the plasma membrane by direct physical contact. The related protein STIM2 functions similar but its physiological role is less well defined. We found that STIM2, but not STIM1, contains a di-lysine ER-retention signal. This restricts the function of STIM2 as Ca²âº sensor to the ER while STIM1 can reach the plasma membrane. The intracellular distribution of STIM1 is regulated in a cell-cycle-dependent manner with cell surface expression of STIM1 during mitosis. Efficient retention of STIM1 in the ER during interphase depends on its lysine-rich domain and a di-arginine ER retention signal. Store-operated Ca²âº-entry enhanced ER retention, suggesting that trafficking of STIM1 is regulated and this regulation contributes to STIM1s role as multifunctional component in Ca²âº-signaling.

Factors associated with increased carotid intima-media thickness and being nondipper in nonobese and normotensive young patients affected by PCOS.

Polycystic ovary syndrome (PCOS) is characterized by chronic unovulation, hyperandrogenism, and insulin resistance. We evaluated factors that affect "nondipper" status during 24-hour ambulatory blood pressure monitoring (ABPM) and carotid intima-media thickness (cIMT) in PCOS. Forty-two nonobese women newly diagnosed as PCOS and 32 healthy women were included. After biochemical and hormonal measurements, the ovaries were imaged by pelvic ultrasonography and cIMT was measured by B-mode ultrasonography. A 24-hour ABPM was performed thereafter. Carotid IMT and the ratio of nondippers were elevated compared with controls. Homeostasis model assessment insulin resistance index (HOMA-IR) and low-density lipoprotein cholesterol (LDL-C) were found to be related with being a nondipper in PCOS. None of the parameters evaluated were found to correlate with cIMT. In conclusion, patients with PCOS had increased nondipping ratios and cIMT when compared with controls. Insulin resistance and LDL cholesterol are factors that are related to diurnal variation in normotensive and young patients with PCOS.

Interaction between Sec7p and Pik1p: the first clue for the regulation of a coincidence detection signal.

Sec7p, a guanine nucleotide exchange factor, regulates the activation of small Arf GTPases, which function in the formation of distinct classes of transport carriers from the Golgi. The recruitment of a subset of Arf effectors depends on the cooperation between these GTPases and phosphatidylinositol 4-phosphate. Here, we show that the catalytic domain of Sec7p interacts with a conserved region of the Golgi phosphatidylinositol 4-kinase Pik1p. We found that Sec7p and Pik1p as well as its product, colocalize at the late Golgi. Gea1p/Gea2p, an alternative pair of Arf activators, do not bind to Pik1p and function on a different Golgi sub-compartment. Sec7p and Pik1p interact with each other and cooperate in the formation of clathrin-coated vesicles. This interaction reveals a distinct role for Sec7p among the Golgi Arf-GEFs and provides a working model for the coordinated generation of Arf-GTP and phosphatiylinositol 4-phosphate as dual signal for specific recruitment of clathrin coats to the late Golgi.

A conserved, lipid-mediated sorting mechanism of yeast Ist2 and mammalian STIM proteins to the peripheral ER.

Sorting of yeast Ist2 to the plasma membrane (PM) or the cortical endoplasmic reticulum (ER) requires a cortical sorting signal (CSS(Ist2)) that interacts with lipids including phosphatidylinositol-4,5-bisphosphate (PI(4,5)P(2)) at the PM. Here, we show that the expression of Ist2 in mammalian cells resulted in a peripheral patch-like localization without any detection of Ist2 at the cell surface. Attached to C-termini of mammalian integral membrane proteins, the CSS(Ist2) targeted these proteins to PM-associated domains of the ER and abolished trafficking via the classical secretory pathway. The interaction of integral membrane proteins with PI(4,5)P(2) at the PM created ER-PM contacts. This process is similar to the regulated coupling of ER domains to the PM via stromal interaction molecule (STIM) proteins during store-operated Ca(2+) entry (SOCE). The CSS(Ist2) and the C-terminus of the ER-located Ca(2+) sensor STIM2 were sufficient to bind PI(4,5)P(2) and PI(3,4,5)P(3) at the PM, showing that an evolutionarily conserved mechanism is involved in the sorting of integral membrane proteins to PM-associated domains of the ER. Yeast Ist2 and STIM2 share a common basic and amphipathic signal at their extreme C-termini. STIM1 showed binding preference for liposomes containing PI(4,5)P(2), suggesting a specific contribution of lipids to the recruitment of ER domains to the PM during SOCE.

Binding of plasma membrane lipids recruits the yeast integral membrane protein Ist2 to the cortical ER.

Recruitment of cytosolic proteins to individual membranes is governed by a combination of protein-protein and protein-membrane interactions. Many proteins recognize phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)] at the cytosolic surface of the plasma membrane (PM). Here, we show that a protein-lipid interaction can also serve as a dominant signal for the sorting of integral membrane proteins. Interaction with phosphatidly-inositolphosphates (PIPs) at the PM is involved in the targeting of the polytopic yeast protein Ist2 to PM-associated domains of the cortical endoplasmic reticulum (ER). Moreover, binding of PI(4,5)P(2) at the PM functions as a dominant mechanism that targets other integral membrane proteins to PM-associated domains of the cortical ER. This sorting to a subdomain of the ER abolishes proteasomal degradation and trafficking along the classical secretory (sec) pathway. In combination with the localization of IST2 mRNA to the bud tip and other redundant signals in Ist2, binding of PIPs leads to efficient accumulation of Ist2 at domains of the cortical ER from where the protein may reach the PM independently of the function of the sec-pathway.

The clathrin adaptor Gga2p is a phosphatidylinositol 4-phosphate effector at the Golgi exit.

Phosphatidylinositol 4-phosphate (PI(4)P) is a key regulator of membrane transport required for the formation of transport carriers from the trans-Golgi network (TGN). The molecular mechanisms of PI(4)P signaling in this process are still poorly understood. In a search for PI(4)P effector molecules, we performed a screen for synthetic lethals in a background of reduced PI(4)P and found the gene GGA2. Our analysis uncovered a PI(4)P-dependent recruitment of the clathrin adaptor Gga2p to the TGN during Golgi-to-endosome trafficking. Gga2p recruitment to liposomes is stimulated both by PI(4)P and the small GTPase Arf1p in its active conformation, implicating these two molecules in the recruitment of Gga2p to the TGN, which ultimately controls the formation of clathrin-coated vesicles. PI(4)P binding occurs through a phosphoinositide-binding signature within the N-terminal VHS domain of Gga2p resembling a motif found in other clathrin interacting proteins. These data provide an explanation for the TGN-specific membrane recruitment of Gga2p.