Endothelial modulation of vasoconstrictor responses to endothelin-1 in human placental stem villi small arteries.

1. The aim of this study was to assess the role of endothelial cells in the modulation of vasocontractile responses to endothelin-1 (ET-1) of human placental vasculature. 2. Isolated stem villi small arteries (diameter = 170-250 microns) were obtained from healthy parturients who underwent caesarean surgery during the 39th week of pregnancy for cephalo-pelvic disproportion. Isometric tension was measured in vascular rings mounted in a myograph system and challenged with ET-1 (10(-12) to 10(-6) M). 3. The vasocontractile response to ET-1 was significantly (P < 0.001) increased in endothelial-denuded (active tension = 1156 +/- 214 mN mm-1) as compared with endothelial-preserved vascular rings (active tension = 458 +/- 48 mN mm-1). This difference was significantly (P < 0.05) but only partly abolished by the NO synthase inhibitor N omega-nitro-L-arginine (L-NOARG, 10(-4) M). 4. In endothelial-preserved rings submaximally precontracted with 5-hydroxytryptamine (10(-6) M), ET-1 (10(-12) to 10(-9) M) induced dose-dependent relaxation (maximum relaxation = 70 +/- 7%) at 10(-9) M, which was followed, at higher doses (10(-8) to 10(-6) M), by a contraction. In contrast, no relaxation was seen in endothelial-denuded rings. The relaxation in rings with endothelium was significantly (P < 0.001) reduced by L-NOARG (10(-4) M. Moreover, it was totally abolished by combined pretreatment with L-NOARG (10(-4) M) and the sulphonylurea glibenclamide (10(-5) M).(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined chemotherapy including rifabutin for rifampicin and isoniazid resistant pulmonary tuberculosis. G.E.T.I.M. (Group for the Study and Treatment of Resistant Mycobacterial Infection).

A prospective multicentre open study has been conducted in France in order to assess the efficacy and tolerability of an antimycobacterial regimen including rifabutin in the treatment of patients with pulmonary tuberculosis due to rifampicin and isoniazid resistant bacilli. Patients were treated with daily rifabutin (450-600 mg), associated with companion drugs to which the organisms remained susceptible; in most cases the regimen included a fluoroquinolone. The duration of treatment was initially scheduled for a minimum period of 12 months after sputum culture conversion. Thirty nine patients were enrolled, 23 of whom were treated for at least 12 months. Culture conversion was obtained at the end of the twelfth month in 14 out of 23 patients. Twenty one out of 39 patients experienced adverse events. These were, however, serious enough to discontinue treatment in only four patients. These results suggest that an antimycobacterial combination including rifabutin might contribute to the treatment of multi-resistant pulmonary tuberculosis.     

Zip14 expression induced by lipopolysaccharides in macrophages attenuates inflammatory response

Objective and design

We investigated the role and regulation of zinc transporters in the activation of the inflammatory response in macrophages. Our exploratory computational study found that Zip14 (SLC39A14) was consistently up-regulated in activated macrophages; we therefore focused subsequently on that gene in the mechanistic study.

Material

The expression and function of Zip14 was assessed in primary macrophages obtained by in-vitro differentiation of monocytes from human blood.

Methods

Primary macrophages were subjected to treatments with lipopolysaccharides, cytokines, chemicals, and pharmacological agents. SLC39A14 and inflammatory cytokine gene expressions were assessed by RT-qPCR. Zip14 siRNA knockdown was performed to explore the gene function.

Results

Lipopolysaccharide’s inflammatory stimulus was a strong inducer of SLC39A14 mRNA expression in macrophages. This induction was dependent on calcium signaling, GC-rich DNA-binding, and NF-κB down-regulation. Impregnation of lipopolysaccharide-stimulated macrophages with the glucocorticoid dexamethasone further enhanced Zip14 expression while reducing interleukin-6 and tumor necrosis factor-α production. Zip14 knockdown in macrophages attenuated the expression and secretion of cytokines, indicating a buffering function for this zinc transporter.

Conclusions

Collectively, our results identified the zinc transporter Zip14 as expressed downstream of lipopolysaccharide signals in macrophages. Zip14 induction had a regulatory function in cytokine production.     

CD8+ T lymphocytes specific for glutamic acid decarboxylase 90-98 epitope mediate diabetes in NOD SCID mouse

During the past decade, glutamic acid decarboxylase (GAD) has been considered a crucial beta-cell autoantigen involved in type 1 diabetes in the NOD mouse and human. Recently, the etiological role of GAD has remained controversy. In the NOD mouse, some previous studies argued in favor of a regulatory role for GAD-specific CD4+ T cells, and no diabetogenic CD8+ T cells specific for GAD have been identified so far, discrediting the importance of GAD in beta-cell injury. Here, we identified, in the NOD model, a relevant GAD CD8+ T cell epitope (GAD(90-98)) using immunization with a plasmid encoding GAD, a protocol relying on in vivo processing of peptides from the autoantigenic protein. In pancreatic lymph nodes of na?ve female NOD mice, CD8+ T lymphocytes recognizing GAD(90-98) peptide were detected during the initial phase of invasive insulitis (between 4 and 8 weeks of age), suggesting an important role for these cells in the first stage of the disease. GAD(90-98) specific CD8+ lymphocytes lysed efficiently islet cells in vitro and transferred diabetes into NOD(SCID) mice (100%). Finally, diabetes was accelerated greatly in 3-week-old female NOD mice injected i.p. with GAD(90-98), strengthening the role of GAD-specific CTLs in diabetes pathogenesis.     

Sex Differences in Cardiac Electrophysiology and Clinical Arrhythmias: Epidemiology,Therapeutics, and Mechanisms

Sex differences in cardiac electrophysiological properties and arrhythmias are evident in epidemiologic and investigative studies as well as in daily patient care. At the supraventricular level, women are at increased risk of sick sinus syndrome and atrioventricular (AV) node re-entrant tachycardia, whereas men manifest more AV block and accessory pathway–mediated arrhythmias. At the ventricular level, women are generally at higher risk of long QT–associated arrhythmias, whereas men are more likely to present with early repolarization, idiopathic ventricular fibrillation, and Brugada syndromes. Great advances have been made in unraveling the fundamental mechanisms underlying sex differences in ventricular arrhythmias, particularly those associated with abnormal repolarization. Conversely, the basis for male-predominant arrhythmia risk in structural heart disease and differences in supraventricular arrhythmia susceptibility are poorly understood. Beyond biological differences, arrhythmia occurrence and patient care decisions are also influenced by gender-related factors. This article reviews the current knowledge regarding the nature and underlying mechanisms of sex differences in basic cardiac electrophysiology and clinical arrhythmias.     

Enhancing the chloramphenicol sensing performance of Cu–MoS2 nanocomposite-based electrochemical nanosensors: roles of phase composition and copper loading amount

The rational design of nanomaterials for electrochemical nanosensors from the perspective of structure–property–performance relationships is a key factor in improving the analytical performance toward residual antibiotics in food. We have investigated the effects of the crystalline phase and copper loading amount on the detection performance of Cu–MoS₂ nanocomposite-based electrochemical sensors for the antibiotic chloramphenicol (CAP). The phase composition and copper loading amount on the MoS₂ nanosheets can be controlled using a facile electrochemical method. Cu and Cu₂O nanoparticle-based electrochemical sensors showed a higher CAP electrochemical sensing performance as compared to CuO nanoparticles due to their higher electrocatalytic activity and conductivity. Moreover, the design of Cu–MoS₂ nanocomposites with appropriate copper loading amounts could significantly improve their electrochemical responses for CAP. Under optimized conditions, Cu–MoS₂ nanocomposite-based electrochemical nanosensor showed a remarkable sensing performance for CAP with an electrochemical sensitivity of 1.74 μA μM⁻¹ cm⁻² and a detection limit of 0.19 μM in the detection range from 0.5–50 μM. These findings provide deeper insight into the effects of nanoelectrode designs on the analytical performance of electrochemical nanosensors.

In this work, we clarify the roles of phase composition and copper loading amount on the CAP sensing performance of Cu–MoS₂ nanocomposite-based electrochemical nanosensors.     

Gold nanoparticle-based optical nanosensors for food and health safety monitoring: recent advances and future perspectives

Modern society has been facing serious health-related problems including food safety, diseases and illness. Hence, it is urgent to develop analysis methods for the detection and control of food contaminants, disease biomarkers and pathogens. As the traditional instrumental methods have several disadvantages, including being time consuming, and having high cost and laborious procedures, optical nanosensors have emerged as promising alternative or complementary approaches to those traditional ones. With the advantages of simple preparation, high surface-to-volume ratio, excellent biocompatibility, and especially, unique optical properties, gold nanoparticles (AuNPs) have been demonstrated as excellent transducers for optical sensing systems. Herein, we provide an overview of the synthesis of AuNPs and their excellent optical properties that are ideal for the development of optical nanosensors based on local surface plasmon resonance (LSPR), colorimetry, fluorescence resonance energy transfer (FRET), and surface-enhanced Raman scattering (SERS) phenomena. We also review the sensing strategies and their mechanisms, as well as summarizing the recent advances in the monitoring of food contaminants, disease biomarkers and pathogens using developed AuNP-based optical nanosensors in the past seven years (2015–now). Furthermore, trends and challenges in the application of these nanosensors in the determination of those analytes are discussed to suggest possible directions for future developments.

We provide an overview of the synthesis of AuNPs and their excellent optical properties for the development of optical nanosensors including colorimetric, fluorescence resonance energy transfer, and surface-enhanced Raman scattering sensors.