Sex Differences in the Management and 5-Year Outcome of Young Patients (<55 Years) with Acute Coronary Syndromes

Background

Young women are usually protected against coronary artery disease due to hormonal and risk-factor profile. Previous studies have suggested poorer outcome in women hospitalized with acute coronary syndrome as compared with men. However, when adjusted for age and other risk factors, this difference does not remain significant. We compared the risk profile and outcome between young (≤55 years) women and men admitted with acute coronary syndrome.

Transplantation combinée cœur–rein au cours de la maladie de Fabry : suivi à long terme de deux patients

Introduction

Fabry disease is a lysosomal storage disorder linked to an alpha-galactosidase A deficiency that can lead to heart and kidney failure. There is little data about the prognosis of patients who undergo a combined heart and kidney transplantation.

Adsorptive stripping voltammetric determination of vanadium(V) witch chloranilic acid using cyclic renewable mercury film silver based electrode

The cyclic renewable mercury film silver based electrode (Hg(Ag)FE), applied for the determination of vanadium(V) traces using differential pulse adsorptive cathodic stripping voltammetry (DP AdCSV) with presence of chloranilic acid as a ligand is presented. The calibration graph obtained for V(V) is linear from 0.25 nM (12.7 ng L⁻¹) to 150 nM (7.6 μg L⁻¹) for a preconcentration time of 20 s, with correlation coefficient of 0.9992. For a Hg(Ag)FE with a surface area of 6.6 mm² the detection limit for a preconcentration time of 90 s is as low as 0.5 ng L⁻¹. The repeatability of the method at a concentration level of the analyte as low as 1.3 μg L⁻¹, expressed as RSD is 2.1% (n = 5). The proposed method was successfully applied and validated by studying the certified reference materials TMRAIN-95, SPS-SW1, SPS-SW2 and simultaneously recovery of V(V) from spiked water samples.     

Applicability of the silver amalgam electrode in voltammetric determination of zinc and copper in gastric juice and gastric mucosa of rats

The aim of the work was to compare two analytical methods of trace analysis in respect to their applicability in heavy metals determination in biological samples. Atomic absorption spectrometry (AAS) may be considered as the method of choice in such analyses due to its accuracy, precision and low detection limit. On the other hand, voltammetric methods seem to be as useful, but rarely applied. Having in mind that there is no universal analytical method, we have compared two AAS and voltammetric methods as the tools for Zn and Cu determination in the samples collected from rat gastric juice and gastric mucosa. Construction of the renewable silver amalgam film electrode (Hg(Ag)FE) for stripping voltammetry was described. Detailed optimization of measurements procedure and sample preparation for differential pulse anodic stripping voltammetry (DP ASV) and AAS were also performed and presented. The obtained results of quantitative analysis of the chosen parameters by means of both methods are discussed.     

Novel substrate-based inhibitors of human glutamate carboxypeptidase II with enhanced lipophilicity

Virtually all low molecular weight inhibitors of human glutamate carboxypeptidase II (GCPII) are highly polar compounds that have limited use in settings where more lipophilic molecules are desired. Here we report the identification and characterization of GCPII inhibitors with enhanced liphophilicity that are derived from a series of newly identified dipeptidic GCPII substrates featuring nonpolar aliphatic side chains at the C-terminus. To analyze the interactions governing the substrate recognition by GCPII, we determined crystal structures of the inactive GCPII(E424A) mutant in complex with selected dipeptides and complemented the structural data with quantum mechanics/molecular mechanics calculations. Results reveal the importance of nonpolar interactions governing GCPII affinity toward novel substrates as well as formerly unnoticed plasticity of the S1' specificity pocket. On the basis of those data, we designed, synthesized, and evaluated a series of novel GCPII inhibitors with enhanced lipophilicity, with the best candidates having low nanomolar inhibition constants and clogD > -0.3. Our findings offer new insights into the design of more lipophilic inhibitors targeting GCPII.     

Transport and pharmacodynamics of albitiazolium, an antimalarial drug candidate

BACKGROUND AND PURPOSE

Choline analogues, a new type of antimalarials, exert potent in vitro and in vivo antimalarial activity. This has given rise to albitiazolium, which is currently in phase II clinical trials to cure severe malaria. Here we dissected its mechanism of action step by step from choline entry into the infected erythrocyte to its effect on phosphatidylcholine (PC) biosynthesis.

EXPERIMENTAL APPROACH

We biochemically unravelled the transport and enzymatic steps that mediate de novo synthesis of PC and elucidated how albitiazolium enters the intracellular parasites and affects the PC biosynthesis.

KEY RESULTS

Choline entry into Plasmodium falciparum-infected erythrocytes is achieved both by the remnant erythrocyte choline carrier and by parasite-induced new permeability pathways (NPP), while parasite entry involves a poly-specific cation transporter. Albitiazolium specifically prevented choline incorporation into its end-product PC, and its antimalarial activity was strongly antagonized by choline. Albitiazolium entered the infected erythrocyte mainly via a furosemide-sensitive NPP and was transported into the parasite by a poly-specific cation carrier. Albitiazolium competitively inhibited choline entry via the parasite-derived cation transporter and also, at a much higher concentration, affected each of the three enzymes conducting de novo synthesis of PC.

CONCLUSIONS AND IMPLICATIONS

Inhibition of choline entry into the parasite appears to be the primary mechanism by which albitiazolium exerts its potent antimalarial effect. However, the pharmacological response to albitiazolium involves molecular interactions with different steps of the de novo PC biosynthesis pathway, which would help to delay the development of resistance to this drug.     

Transient molten globules and metastable aggregates induced by brief exposure of a monoclonal IgG to low pH

The presence of aggregates in therapeutic protein formulations is of great concern due to quality, safety, and efficacy issues. Nonetheless, the mechanisms and kinetics of protein aggregation are only partly understood. In this study, metastable immunoglobulin G (IgG) aggregates induced by a brief exposure to pH 1 were kept at 4°C and analyzed over time by size-exclusion chromatography (SEC), nanoparticle tracking analysis, light obscuration, dynamic light scattering, fluorescence spectroscopy, and circular dichroism. The results show the formation of polydisperse aggregates (from dimers to 10-μm particles) shortly after the pH-shift stress. These aggregates increased in size and number over time until a pseudo-equilibrium was reached after 5-7 days. The presence of transient, partially unfolded monomers (molten globules) was detected by SEC with online fluorescent dye detection. The molten globules seemed to either refold into the native state or become involved in aggregation pathways. Seeding pH-shift-induced aggregates into unstressed IgG did not accelerate aggregation during incubation for 3 weeks at 55°C. These results reinforce the role of partially unfolded species in the aggregation of therapeutic proteins. We conclude that the formation of pH-shift-induced IgG aggregates is likely driven by downhill polymerization, as a consequence of successive additions of molten globular monomers.     

Long-term treatment of ovariectomized mice with estradiol or phytoestrogens as a new model to study the role of estrogenic substances in the heart

Epidemiological data reveal that the overall risk for heart disease is lower for premenopausal women compared to age-matched men. However, the beneficial effect for the female sex is lost upon menopause. Thus, it has been suggested that estrogens convey the protective effect for the female sex against heart disease. Numerous natural plant products, i.e., phytoestrogens (PE), interfere with or alter the development or function of the endocrine system. Although PEs have been studied intensively with regard to the effects on the reproductive organs, such as the uterus or mammary gland, surprisingly little data are available about the effects of PEs on the heart. Here, we conducted a long-term study with ovariectomized mice to examine putative estrogenic effects of the PEs genistein (GEN), resveratrol (RES), and equol (EQ), using estradiol (E2) as a reference compound on heart size, morphology, and cardiac gene expression. We report for the first time significant changes in these parameters by GEN and E2. Changes in the size of cardiomyocytes were observed by GEN and E2. In line with these observations, cardiac expression of insulin-like growth factor 1 ( IGF1) was significantly induced by both GEN and E2. Thus, we speculate that endocrine active compounds, like the isoflavone GEN, which is used as a food additive or as a drug for the treatment of menopausal symptoms, may directly affect heart function.