Lipoprotein (a): Structure, Pathophysiology and Clinical Implications

The chemical structure of lipoprotein (a) is similar to that of LDL, from which it differs due to the presence of apolipoprotein (a) bound to apo B100 via one disulfide bridge. Lipoprotein (a) is synthesized in the liver and its plasma concentration, which can be determined by use of monoclonal antibody-based methods, ranges from < 1 mg to > 1,000 mg/dL. Lipoprotein (a) levels over 20-30 mg/dL are associated with a two-fold risk of developing coronary artery disease. Usually, black subjects have higher lipoprotein (a) levels that, differently from Caucasians and Orientals, are not related to coronary artery disease. However, the risk of black subjects must be considered. Sex and age have little influence on lipoprotein (a) levels. Lipoprotein (a) homology with plasminogen might lead to interference with the fibrinolytic cascade, accounting for an atherogenic mechanism of that lipoprotein. Nevertheless, direct deposition of lipoprotein (a) on arterial wall is also a possible mechanism, lipoprotein (a) being more prone to oxidation than LDL. Most prospective studies have confirmed lipoprotein (a) as a predisposing factor to atherosclerosis. Statin treatment does not lower lipoprotein (a) levels, differently from niacin and ezetimibe, which tend to reduce lipoprotein (a), although confirmation of ezetimibe effects is pending. The reduction in lipoprotein (a) concentrations has not been demonstrated to reduce the risk for coronary artery disease. Whenever higher lipoprotein (a) concentrations are found, and in the absence of more effective and well-tolerated drugs, a more strict and vigorous control of the other coronary artery disease risk factors should be sought.

Use of Short-term Circulatory Support as a Bridge in Pediatric Heart Transplantation

Background:Heart transplantation is considered the gold standard therapy for the advanced heart failure, but donor shortage, especially in pediatric patients, is the main limitation for this procedure, so most sick patients die while waiting for the procedure.Objective:To evaluate the use of short-term circulatory support as a bridge to transplantation in end-stage cardiomyopathy.Methods:Retrospective clinical study. Between January 2011 and December 2013, 40 patients with cardiomyopathy were admitted in our Pediatric Intensive Care Unit, with a mean age of 4.5 years. Twenty patients evolved during hospitalization with clinical deterioration and were classified as Intermacs 1 and 2. One patient died within 24 hours and 19 could be stabilized and were listed. They were divided into 2 groups: A, clinical support alone and B, implantation of short-term circulatory support as bridge to transplantation additionally to clinical therapy.Results:We used short-term mechanical circulatory support as a bridge to transplantation in 9. In group A (n=10), eight died waiting and 2 patients (20%) were transplanted, but none was discharged. In group B (n=9), 6 patients (66.7%) were transplanted and three were discharged.The mean support time was 21,8 days (6 to 984h). The mean transplant waiting list time was 33,8 days. Renal failure and sepsis were the main complication and causeof death in group A while neurologic complications were more prevalent en group B.Conclusion:Mechanical circulatory support increases survival on the pediatric heart transplantation waiting list in patients classified as Intermacs 1 and 2.

Pharmacokinetic aspects of Tert-Butylaminoethyl disulfide, an experimental drug against schistosomiasis in mice

A preliminary study of the pharmacokinetic parameters of t-Butylaminoethyl disulfide was performed after administration of two different single doses (35 and 300 mg/kg) of either the cold or labelled drug. Plasma or blood samples were treated with dithiothreitol, perchloric acid, and, after filtration, submitted to further purification with anionic resein. In the final step, the drug was retained on a cationic resin column, eluted with NaCl 1M and detected according to the method of Ellman (1958). Alternatively, radioactive drug was detected by liquid scintillation counting. The results corresponding to the smaller dose of total drug suggested a pharmacokinetic behavior related to a one open compartment model with the following parameters: area under the intravenous curve (AUC i.v.):671 ± 14; AUC oral: 150 ± 40 µg.min. ml [raised to the power of -1]; elimination rate constant: 0.071 min [raised to the power of -1]; biological half life: 9.8 min; distribution volume: 0.74 ml/g. For the higher dose, the results seemed to obey a more complex undertermined model. Combining the results, the occurence of a dose-dependent pharmacokinetic behavior is suggested, the drug being rapidly absorbed and rapidly eliminated; the elimination process being related mainly to metabolization. The drug seems to be more toxic when administered I.V. because by this route it escapes first pass metabolism, while being quickly distributed to tissues. The maximum tolerated blood level seems to be around 16 µg/ml.

A structural bridge between alternant and non-alternant hydrocarbons

A simple set of trimethylene-substituted even, fully-pi-bonded, non-alternant monocycles is shown to have several key features in common with acyclic, even alternant polyenes at the Hückel level. These non-alternant molecules provide a bridge between alternant and non-alternant hydrocarbons. This topic might serve as a useful addition to Hückel theory courses targeted at senior undergraduate students.

An Inspection System to Identify Fatigue Damage on Steel-Bridge Structures

Crack formation and growth in steel bridge structural elements may be due to loading oscillations. The welded elements are liable to internal discontinuities along welded joints and sensible to stress variations. The evaluation of the remaining life of a bridge is needed to make cost-effective decisions regarding inspection, repair, rehabilitation, and replacement. A steel beam model has been proposed to simulate crack openings due to cyclic loads. Two possible alternatives have been considered to model crack propagation, which the initial phase is based on the linear fracture mechanics. Then, the model is extended to take into account the elastoplastic fracture mechanic concepts. The natural frequency changes are directly related to moment of inertia variation and consequently to a reduction in the flexural stiffness of a steel beam. Thus, it is possible to adopt a nondestructive technique during steel bridge inspection to quantify the structure eigenvalue variation that will be used to localize the grown fracture. A damage detection algorithm is developed for the proposed model and the numerical results are compared with the solutions achieved by using another well know computer code.

Participation of the endoplasmic reticulum protein chaperone thio-oxidoreductase in gonadotropin-releasing hormone receptor expression at the plasma membrane

Chaperone members of the protein disulfide isomerase family can catalyze the thiol-disulfide exchange reaction with pairs of cysteines. There are 14 protein disulfide isomerase family members, but the ability to catalyze a thiol disulfide exchange reaction has not been demonstrated for all of them. Human endoplasmic reticulum protein chaperone thio-oxidoreductase (ERp18) shows partial oxidative activity as a protein disulfide isomerase. The aim of the present study was to evaluate the participation of ERp18 in gonadotropin-releasing hormone receptor (GnRHR) expression at the plasma membrane. Cos-7 cells were cultured, plated, and transfected with 25 ng (unless indicated) wild-type human GnRHR (hGnRHR) or mutant GnRHR (Cys14Ala and Cys200Ala) and pcDNA3.1 without insert (empty vector) or ERp18 cDNA (75 ng/well), pre-loaded for 18 h with 1 µCi myo-[2-3H(N)]-inositol in 0.25 mL DMEM and treated for 2 h with buserelin. We observed a decrease in maximal inositol phosphate (IP) production in response to buserelin in the cells co-transfected with hGnRHR, and a decrease from 20 to 75 ng of ERp18 compared with cells co-transfected with hGnRHR and empty vector. The decrease in maximal IP was proportional to the amount of ERp18 DNA over the range examined. Mutants (Cys14Ala and Cys200Ala) that could not form the Cys14-Cys200 bridge essential for plasma membrane routing of the hGnRHR did not modify maximal IP production when they were co-transfected with ERp18. These results suggest that ERp18 has a reduction role on disulfide bonds in wild-type hGnRHR folding.

Growth inhibitory effect and Chk1-dependent signaling involved in G2/M arrest on human gastric cancer cells induced by diallyl disulfide

Diallyl disulfide (DADS) inhibits growth and induces cell cycle G2/M arrest in human gastric cancer MGC803 cells. In this study, 15 mg/L DADS exerted similar effects on growth and cell cycle arrest in human gastric cancer BGC823 cells. Due to the importance of cell cycle redistribution in DADS-mediated anti-carcinogenic effects, we investigated the role of checkpoint kinases (Chk1 and Chk2) during DADS-induced cell cycle arrest. We hypothesized that DADS could mediate G2/M phase arrest through either Chk1 or Chk2 signal transduction pathways. We demonstrated that DADS induced the accumulation of phosphorylated Chk1, but not of Chk2, and that DADS down-regulated Cdc25C and cyclin B1. The expression of mRNA and total protein for Chkl and Chk2 was unchanged. Chk1 is specifically phosphorylated by ATR (ATM-RAD3-related gene). Western blot analysis showed that phospho-ATR was activated by DADS. Taken together, these data suggest that cell cycle G2/M arrest, which was associated with accumulation of the phosphorylated forms of Chk1, but not of Chk2, was involved in the growth inhibition induced by DADS in the human gastric cancer cell line BGC823. Furthermore, the DADS-induced G2/M checkpoint response is mediated by Chk1 signaling through ATR/Chk1/Cdc25C/cyclin B1, and is independent of Chk2.

Macau in China's relations with the lusophone world

After the transfer of the Portuguese administration to China, Macau kept its role as a bridge between East and West, inspired in the Portuguese settlement 500 years ago. The pragmatism of the Chinese central government, using the Lusophone specificities of this Special Administrative Region, supported the creation of the Forum for Economic and Trade Cooperation between China and the Portuguese-speaking Countries, reviving the statute of the Portuguese language and culture in its own territory.