Triglycerides predict plasma fibronectin in children with type I diabetes mellitus rather than diabetes

Fibronectins are adhesive proteins considered as markers of endothelial activation. Plasma fibronectin levels in diabetes mellitus (DM) have been found to be associated with atherosclerotic risk factors. This study was carried out to investigate plasma fibronectin and its relation with serum lipids, apolipoproteins AI, B100 and lp(a) in diabetic children. 35 children (19F/16M) with type I DM and 30 non-diabetic age and gender-matched controls were enrolled. Apolipoprotein and fibronectin concentrations were determined with nephelometric methods. Plasma fibronectin levels of the children with type I DM and the control group are not statistically different. HbA1c and triglycerides concentration are found to be significant predictors of plasma fibronectin in diabetic children, while effect of plasma cholesterol, apolipoprotein AI, B100 and lp(a) are insignificant. Diabetic children with triglycerides 1.13 mmol/l have elevated plasma fibronectin (median, 25th-75th percentiles; 29.6, 8.3-40.8 mg/dL) compared to the diabetic > or = 19.9, 8.6-30.7 mg/dL, p < 0.05) and non-diabetic children (16.6, 12.7-32.4 mg/dL, p < 0.01) with triglycerides < 1.13 mmol/L. On the other hand plasma fibronectin concentrations of diabetic and non-diabetic children with high triglycerides are not significantly different. In conclusion our data does not support the concept that plasma fibronectin is elevated in type I diabetes mellitus at least in children, but high plasma triglycerides secondary to diabetes or not is associated with higher FNp concentrations which may have implications on atherogenesis. Plasma cholesterol, apolipoproteins AI, B100 and lp(a) are not significant determinants of FNp in type I diabetic children.     

Contribution of Rho-kinase in human gallbladder contractions

Rho/Rho-kinase-mediated pathway has been involved in a variety of physiological processes, including Ca²⁺ sensitization, which enhances smooth muscle contraction. In this study, first of all we investigated the expression of Rho-kinase (ROCK-2) and then the role of this protein in the control of smooth muscle contraction in the isolated human gallbladder. For this purpose, we examined the effects of a selective Rho-kinase inhibitor, (+)- (R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632, 10^− 8 − 3 × 10^− 5 M) on carbachol (10^− 8–10^− 4 M), cholecystokinin-8 (10^− 8 M), endothelin-1 (10^− 8 M), histamine (10^− 5 M), neurokinin A (10^− 7–10^− 6 M), 5-hydroxytryptamine (10^− 6–10^− 5 M) and potassium chloride (KCl, 25–50 mM)-induced contractions as well as spontaneous contractile activity. Y-27632 (10^− 5 M) significantly reduced 5-hydroxytryptamine, neurokinin A and KCl-induced contractions. Moreover, this Rho-kinase inhibitor (10^− 8 − 3 × 10^− 5 M, cumulatively) relaxed the contractions produced by cholecystokinin-8, endothelin-1 and histamine in a concentration-dependent manner, being the pEC₅₀ values for Y-27632 5.74 ± 0.12, 5.33 ± 0.09 and 5.95 ± 0.18, respectively. Carbachol (10^− 8–10^− 4 M) pfroduced concentration-dependent contractions, which were also inhibited significantly by Y-27632. In addition, the spontaneous contractile activity was suppressed in the presence of Y-27632 (10^− 6–10^− 5 M). Moreover, Western blot analysis has revealed that Rho-kinase is expressed in homogenates of the human gallbladder. Taken together, these results show that Rho-kinase is expressed in the human gallbladder, and it has an essential role in agonists and depolarization-induced contractions as well as spontaneous contractile activity.     

The investigation of prooxidant-antioxidant balance in serum of children with family histories of essential hypertension

It has been accepted that essential hypertension is associated with a loss of the balance between prooxidation and antioxidation. Thus, excessive oxygen free radical production may be an early event in the pathogenesis of hypertension. To compare lipid peroxidation and antioxidant system in serum of children of essential hypertensive and normotensive parents. Serum malondialdehyde (MDA) levels were measured spectrofluorometrically. Antioxidant activity, glutathione peroxidase, selenium levels in serum were measured as indices of antioxidant power. The peroxidation of apo B containing lipoproteins (VLDL+LDL) was measured as the susceptibility to oxidation in vitro. Serum MDA levels increased, but no marked differences in total antioxidant activity, glutathione peroxidase activity, selenium levels and VLDL+LDL oxidation were found in serum of children with family histories of essential hypertension as compared to children of normotensive parents.     

Enhancement of vascular endothelial growth factor’s angiogenic capacity by the therapeutic modulation of notch signalling improves tram flap survival in rats submitted to nicotine

Background: Smoke of cigarettes, and specifically nicotine, has been shown to diminish pedicled transverse rectus abdominis musculocutaneous (TRAM) flap survival. Considering that Notch signalling through its ligand Delta-like 4 (Dll4) functions as anti-angiogenic factor by inhibiting the pro-angiogenic effects of vascular endothelial growth factor (VEGF), it is hypothesised that inhibition of the Notch would promote angiogenesis and increase TRAM flap survival in rats submitted to nicotine.

Methods: Twenty rats were treated with nicotine for 28 days preoperatively. Thereafter, a pedicled TRAM flap was created in all animals. The Notch inhibitor N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine-t-butyl-ester was administered in animals of the treatment group. Animals in the control group were given the same amount of solvent. Five days after the surgery, viable flap areas were determined. Skin samples were evaluated for VEGF and Dll4 mRNA levels. Immunohistochemical analysis was used for the assessment of endothelial Dll4 expression. Vascular density was determined histologically. Plasma levels of VEGF and Dll4 were measured.

Results: A significant improvement in TRAM flap surviving area was observed in the treatment group (53.50?±?14.25%) compared with the controls (32.20?±?9.15%). Immunohistochemical analysis revealed a significant increase in the number of Dll4 stained vessels in animals of the treatment group (9.2?±?1.6) in comparison with the controls (5.7?±?1.9). VEGF mRNA levels (0.22?±?0.08) in the treatment group were significantly lower than those in the control group (0.36?±?0.09).

Conclusion: Notch inhibition significantly improved TRAM flap survival in animals exposed to nicotine by promoting VEGF-induced angiogenesis.     

Rechallenge with dabrafenib plus trametinib in anaplastic thyroid cancer: A case report and review of literature

Introduction: Anaplastic thyroid carcinoma (ATC) is a highly aggressive, undifferentiated rare tumor. Median overall survival is usually between 8 and10 months, with a 1-year survival rate of 20%. Conventional anthracycline based chemotherapy regimens demonstrate low response rates with short duration. Novel therapeutic agents including BRAF and MEK inhibitors based on the molecular landscape of ATC have been investigated. Case presentation: We herein report the rechallenge of a 52-year-old ATC patient with BRAF V600E mutation with dabrafenib plus trametinib. She presented with recurrent and progressive disease despite surgery, radiation therapy, 3 different chemotherapy regimens, and combination of dabrafenib-trametinib in different settings. She was rechallenged with dabrafenib-trametinib, and had a good response. Conclusion: To our knowledge, this is the first ATC case who responded to dabrafenib-trametinib rechallenge, reported in the literature. We want to emphasize that combination of dabrafenib and trametinib might be a good choice for resistant locoregional and metastatic ATC patients with BRAF V600E mutation, particularly in whom rapid clinical response is urgently needed. Moreover, rechallenge with this combination should be kept in mind in selected cases.