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.

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.

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.

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.