Anethole dithiolethione lowers the homocysteine and raises the glutathone levels in solid tissues and plasma of rats: A novel non-vitamin homocysteine-lowering agent

High homocysteine (Hcys) levels are suspected to contribute to the pathogenesis of cardiovascular disease and of other chronic conditions. Failure of B vitamins to reduce the incidence of cardiovascular events while lowering the Hcys levels, has prompted the search for alternative treatments. We tested the ability of anethole dithiolethione (ADT) to lower the Hcys levels in rats and we explored possible underlying mechanisms. Parenteral administration of 10 mg/kg ADT to normal rats for 3 days lowered the Hcys levels between 51.4% and 31.5% in kidneys, liver, testis and plasma. Concomitantly, glutathione (GSH) increased between 112% and 28% in kidneys, brain, liver and plasma whereas protein thiolation index decreased 30%. In hyperhomocysteinemic rats, the plasma Hcys levels dropped 70% following a single ip injection of 10 mg/kg ADT, while they decreased 55% following oral administration of 2 mg/kg/day ADT for one week. Significant additive effects occurred when sub-therapeutic doses of ADT and folic acid were used in combination. To test the possible mechanism(s) of these actions, we perfused isolated rat livers and kidneys with albumin-bound Hcys, the prevalent form of plasma Hcys, and physiological thiols and disulfides at different ratios. In both organ preparations, the elimination rate of albumin-bound Hcys was progressively faster as the amount of reduced thiols was increased in the perfusate. These findings indicate that ADT shifts the redox ratio of GSH and other thiols with their oxidized forms toward the reduced forms, thus favoring the dissociation of albumin-bound Hcys and its transfer to renal and hepatic cells for further processing.     

Urokinase expression in course of benign and malignant mammary lesions: comparison between nodular and healthy tissues

Purpose  

Increased expression of urokinase (uPA), a member of the serine protease family, is an effector of metastatic cascade and has been reported in various malignancies, including breast cancer. uPA overexpression in cancer tissues was correlated with a more aggressive phenotype and it is considered a strong and independent unfavorable prognostic factor in breast cancer.     

Time-course of impairment of respiratory mechanics after cardiac surgery and cardiopulmonary bypass.

OBJECTIVE: Cardiopulmonary bypass (CPB) is associated with abnormalities of lung function characterized by an increase in static elastance of the respiratory system. We examined the following: a) the effects of CPB on the total inspiratory volume-pressure (V-P) relationship of the respiratory system; b) the relative contribution of the chest wall and lung to the impairment of respiratory system mechanics; and c) the time-course of such impairment. DESIGN: Prospective, interventional study. SETTING: Surgical and medical intensive care units in a teaching hospital. PATIENTS: Eight adult patients scheduled for elective open heart surgery to correct valvular dysfunction. INTERVENTIONS: V-P curves (interrupter technique) of the respiratory system were partitioned between the chest wall and lung by measurements of esophageal pressure. Measurements were obtained before sternotomy (control), immediately after, 4 hrs after, and 7 hrs after separation from CPB. MEASUREMENTS AND MAIN RESULTS: Control V-P relationships of the respiratory system and lung showed lower inflection points (Pflex) at pressure values of 5.9+/-2.3 and 4.3+/-2.5 cm H2O, respectively. Immediately after and 4 hrs after separation from CPB, both curves had sigmoid shapes because of lower Pflex and formation of upper inflection (UIP) points. The pressures corresponding to the Pflex increased significantly (p < .001) by 56%+/-3% and 78%+/-4%, whereas the UIP corresponded to a pressure value of 42.34+/-8.5 and 35.6+/-7.8 cm H2O in the respiratory system and lung, respectively. A linear V-P relationship of the chest wall was observed during the control condition and after separation from CPB. Four hours later, no further increases in the pressure values corresponding to Pflex were observed on the inspiratory V-P curves of the respiratory system and lung, whereas the UIP occurred at a pressure of 35.6+/-9.1 and 29.7+/-8.4 cm H2O, respectively. A UIP was present on the V-P curve of the chest wall at a volume of 0.77+/-0.02 L. Seven hours after separation from CPB, the inspiratory V-P curves of the respiratory system, chest wall, and lung returned to normal. CONCLUSIONS: Sternotomy and CPB produced immediate changes in lung mechanics. Chest wall mechanics were affected only 4 hrs after sternotomy. Seven hours after disconnection from CPB, all mechanics had returned to normal.     

A novel approach to define risk of stent thrombosis after percutaneous coronary intervention with drug-eluting stents: the DERIVATION score

Recent studies of drug-eluting stents (DES) use in routine clinical practice have led to concern regarding their long-term safety and to questions about the adequacy of current antiplatelet therapy guidelines. This study sought to derivate a risk score for predicting stent thrombosis after drug-eluting stenting. The large single center DES Real-world Incremental Value in the erA of percutaneous revascularizaTION (DERIVATION) database, collecting data about 1,377 patients of any age undergoing PCI with DES as treatment for symptomatic coronary artery disease, was use for this purpose. Logistic regression and bootstrap procedure were used to select correlates of stent thrombosis that were subsequently weighted and integrated into an integer scoring system. Five variables selected from the initial multivariate model were weighted proportionally to their respective odds ratio for stent thrombosis [baseline left ventricular ejection fraction <50% (4 points), angioplasty in the setting of acute coronary syndromes (3 points), bifurcation lesion (2 points), left anterior descending as target vessel (2 points), multiple stenting (2 points)]. Three strata of risk were defined (low risk, 0–2; intermediate risk, 3–6; high risk ≥7) with good prognostic accuracy for early, late and very late thrombosis (c statistic = 0.75, 0.65 and 0.73, respectively) in the derivation set. In conclusion, the DERIVATION score may be used as a simple clinical tool for the identification of a sizable cohort in whom close monitoring and aggressive therapy may be beneficial.     

MUC5AC expression is increased in bronchial submucosal glands of stable COPD patients

Aims:  Mucus expectoration is a common feature of chronic obstructive pulmonary disease (COPD). MUC5AC and MUC5B, the major mucins, are released predominantly from submucosal glands in the central airways. The aim was to investigate gland size and MUC5AC and MUC5B expression in bronchial rings from smokers with COPD compared with control groups.
Methods and results:  Bronchial rings from 10 non-smoking subjects, 20 smokers with normal lung function and 20 smokers with COPD were studied. Periodic acid–Schiff (PAS) and Alcian blue histochemistry and MUC5AC and MUC5B immunohistochemistry followed by quantification of the immunoreactive area was performed. The area occupied by MUC5AC+ cells in bronchial submucosal glands was increased in COPD [20% (5.5–31.7%) gland area] compared with smokers with normal lung function [9.5% (2.5–17.5%); P  < 0.05] and non-smoking subjects [2% (0.4–6.2%); P  < 0.05]. The area occupied by MUC5AC+ cells in the bronchial surface epithelium was also increased in smokers (with/without COPD) [73.5% (25–92%) epithelial area] compared with non-smoking subjects [15% (2.7–32%); P  < 0.01]. Gland size, PAS, Alcian blue staining and MUC5B expression were not significantly different among groups. MUC5AC expression correlated with the degree of airflow obstruction. MUC5AC and MUC5B expression correlated with pack-years.
Conclusions:  COPD is associated with increased MUC5AC expression in submucosal glands, indicating that MUC5AC may be involved in the pathophysiology of the disease.