The differential effects of bisphosphonates,SERMS (selective estrogen receptor modulators), and parathyroid hormone on bone remodeling in osteoporosis

Osteoporosis is a skeletal metabolic disease characterized by a compromised bone fragility, leading to an increased risk of developing spontaneous and traumatic fractures. Osteoporosis is considered a multifactorial disease and fractures are the results of several different risk factors both extra- and intraskeletal. Thus bone fragility can be the end point of several different causes: a) failure to reach an optimal peak bone mass during growth; b) excessive bone resorption resulting in decreased bone mass and microarchitectural deterioration; c) inadequate formation upon an increased resorption during the process of bone remodeling. The pharmacological therapeutical options, available to date, are directed on prevention of fractures. The aim of this paper is to describe the activities and the mechanisms of action, as known at present, of the most used therapies for osteoporosis and their clinical implications. Improvement of knowledge in this field will allow us to further improve therapeutical choices and pharmacological interventions.     

Frequency mapping of the pulmonary veins in paroxysmal versus permanent atrial fibrillation

Introduction: The pulmonary veins (PVs) are a dominant source of triggers initiating atrial fibrillation (AF). While recent evidence implicates these structures in the maintenance of paroxysmal AF, their role in permanent AF is not known. The current study aims to compare the contribution of PV activity to the maintenance of paroxysmal and permanent AF.
Methods and Results: Thirty-four patients with paroxysmal AF (n = 20) or permanent AF (n = 14) undergoing ablation were studied. Prior to ablation, 32 seconds of electrograms were acquired from each PV and the coronary sinus (CS). The frequency of activity of each PV and CS was defined as the highest amplitude frequency on spectral analysis. The effects of ablation on the AF cycle length (AFCL) and frequency and on AF termination were determined. Significant differences were observed between paroxysmal and permanent AF. Paroxysmal AF demonstrates higher frequency PV activity (11.0 ± 3.1 vs 8.8 ± 3.0 Hz; P = 0.0003) but lower CS frequency (5.8 ± 1.2 vs 6.9 ± 1.4 Hz; P = 0.01) and longer AFCL (182 ± 17 vs 158 ± 21 msec; P = 0.002), resulting in greater PV to atrial frequency gradient (7.2 ± 2.2 vs 4.2 ± 2.9 Hz; P = 0.006). PV isolation in paroxysmal AF resulted in a greater decrease in atrial frequency (1.0 ± 0.7 vs −0.05 ± 0.4 Hz; P < 0.0001), greater prolongation of the AFCL (49 ± 35 vs 5 ± 6 msec; P < 0.0001), and more frequent AF termination (11/20 vs 0/14; P = 0.0007) compared to permanent AF.
Conclusion: Paroxysmal AF is associated with higher frequency PV activity and lesser CS frequency compared to permanent AF. Isolation of the PVs had a greater impact on the fibrillatory process in paroxysmal AF compared to permanent AF, suggesting that while the PVs have a role in maintaining paroxysmal AF, these structures independently contribute less to the maintenance of permanent AF.     

注氮改性纯钛表面的微观摩擦性能研究

目的改变纯钛表面的成分,提高其硬度和耐磨损性能。方法对纯钛试样表面行3×1017 ions.cm-2和9×1017 ions.cm-2两种剂量的氮离子注入。以能量散射光谱测定分析其表面元素的改变,显微硬度仪测量其显微硬度,纳米划痕仪测量其表面的耐磨损性能,扫描电子显微镜观察其注入前后的划痕形貌。综合分析其微观摩擦学性能的改变。结果氮离子注入后,纯钛试样表面成金黄色。在注入3×1017 ions.cm-2和9×1017 ions.cm-2剂量的氮离子试样表面,氮元素的原子百分率分别为24.08%和35.83%。试样表面的显微硬度值提高。纯钛的摩擦系数较氮离子注入前明显降低,其中注入剂量为9×1017 ions.cm-2的纯钛较剂量为3×1017 ions.cm-2的纯钛摩擦系数小。结论氮离子注入可提高纯钛的硬度,改善其耐磨损性能。     

单核细胞增生李斯特菌的耐药特征及机制

食源性疾病已成为当今世界重大的公共卫生问题,由单核细胞增生李斯特菌(Listeria monocytogenes, Lm)等病原细菌引起的食源性疾病是影响食品安全的主要因素之一。近年来Lm耐药率呈上升趋势,多重耐药菌株不断出现,给世界公共卫生和人类健康带来了严重威胁。Lm的耐药机制十分复杂,包括可移动元件介导的耐药基因转移、药物作用靶点的改变、抗生素的外排作用、灭活酶的产生、生物被膜的形成等多种机制。本文就近年来国内外食品及临床来源Lm的耐药特征及机制进行综述,为李斯特菌病的合理用药,耐药菌株的监测以及公共卫生策略的制定提供科学依据。     

Future of GPR109A agonists in the treatment of dyslipidaemia

Abnormal blood lipids are the major modifiable risk factor underlying the development of cardiovascular disease. Niacin has a profound ability to reduce low-density lipoprotein-C, very low-density lipoprotein-C and triglycerides and is the most effective pharmacological agent to increase high-density lipoprotein-C. Recently, the receptor for niacin, GPR109A, was discovered. GPR109A in the adipocyte mediates a niacin-induced inhibition of lipolysis, which could play a crucial part in its role as a lipid-modifying drug. GPR109A in epidermal Langerhans cells mediates flushing, an unwanted side effect of niacin therapy. For the past decade, the functions of GPR109A have been studied and full or partial agonists have been developed in an attempt to achieve the beneficial effects of niacin while avoiding the unwanted flushing side effect. This review presents what is known to date about GPR109A biology and function and the future of GPR109A as a pharmacological target.     

糖尿病血管病变研究进展

对糖尿病血管病变的病因病机、防治原则、遣方用药等进行了论述.提出本病病机为气阴两虚,痰浊不化,痰浊瘀血互结淤脉络(血管)壁,而致脉络(血管)闭阻.益气养阴、化痰散结、活血化瘀为防治原则.     

Respiratory syncytial virus impairs T cell activation by preventing synapse assembly with dendritic cells

Respiratory syncytial virus (RSV) infection is one of the leading causes of infant hospitalization and a major health and economic burden worldwide. Infection with this virus induces an exacerbated innate proinflammatory immune response characterized by abundant immune cell infiltration into the airways and lung tissue damage. RSV also impairs the induction of an adequate adaptive T cell immune response, which favors virus pathogenesis. Unfortunately, to date there are no efficient vaccines against this virus. Recent in vitro and in vivo studies suggest that RSV infection can prevent T cell activation, a phenomenon attributed in part to cytokines and chemokines secreted by RSV-infected cells. Efficient immunity against viruses is promoted by dendritic cells (DCs), professional antigen-presenting cells, that prime antigen-specific helper and cytotoxic T cells. Therefore, it would be to the advantage of RSV to impair DC function and prevent the induction of T cell immunity. Here, we show that, although RSV infection induces maturation of murine DCs, these cells are rendered unable to activate antigen-specific T cells. Inhibition of T cell activation by RSV was observed independently of the type of TCR ligand on the DC surface and applied to cognate-, allo-, and superantigen stimulation. As a result of exposure to RSV-infected DCs, T cells became unresponsive to subsequent TCR engagement. RSV-mediated impairment in T cell activation required DC-T cell contact and involved inhibition of immunological synapse assembly among these cells. Our data suggest that impairment of immunological synapse could contribute to RSV pathogenesis by evading adaptive immunity and reducing T cell-mediated virus clearance.     

The in vivo mechanism of action of CD20 monoclonal antibodies depends on local tumor burden

Background

CD20 monoclonal antibodies are widely used in clinical practice. Antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and direct cell death have been suggested to be important effector functions for CD20 antibodies. However, their specific contributions to the in vivo mechanism of action of CD20 immunotherapy have not been well defined.

Design and Methods

Here we studied the in vivo mechanism of action of type I (rituximab and ofatumumab) and type II (HuMab-11B8) CD20 antibodies in a peritoneal, syngeneic, mouse model with EL4-CD20 cells using low and high tumor burden.

Results

Interestingly, we observed striking differences in the in vivo mechanism of action of CD20 antibodies dependent on tumor load. In conditions of low tumor burden, complement was sufficient for tumor killing both for type I and type II CD20 antibodies. In contrast, in conditions of high tumor burden, activating FcγR (specifically FcγRIII), active complement and complement receptor 3 were all essential for tumor killing. Our data suggest that complement-enhanced antibody-dependent cellular cytotoxicity may critically affect tumor killing by CD20 antibodies in vivo. The type II CD20 antibody 11B8, which is a poor inducer of complement activation, was ineffective against high tumor burden.

Conclusions

Tumor burden affects the in vivo mechanism of action of CD20 antibodies. Low tumor load can be eliminated by complement alone, whereas elimination of high tumor load requires multiple effector mechanisms.     

Dynamics of alpha-helical subdomain rotation in the intact maltose ATP-binding cassette transporter

ATP-binding cassette (ABC) transporters are powered by a nucleotide-binding domain dimer that opens and closes during cycles of ATP hydrolysis. These domains consist of a RecA-like subdomain and an α-helical subdomain that is specific to the family. Many studies on isolated domains suggest that the helical subdomain rotates toward the RecA-like subdomain in response to ATP binding, moving the family signature motif into a favorable position to interact with the nucleotide across the dimer interface. Moreover, the transmembrane domains are docked into a cleft at the interface between these subdomains, suggesting a putative role of the rotation in interdomain communication. Electron paramagnetic resonance spectroscopy was used to study the dynamics of this rotation in the intact Escherichia coli maltose transporter MalFGK(2). This importer requires a periplasmic maltose-binding protein (MBP) that activates ATP hydrolysis by promoting the closure of the cassette dimer (MalK(2)). Whereas this rotation occurred during the transport cycle, it required not only trinucleotide, but also MBP, suggesting it is part of a global conformational change in the transporter. Interaction of AMP-PNP-Mg(2+) and a MBP that is locked in a closed conformation induced a transition from open MalK(2) to semiopen MalK(2) without significant subdomain rotation. Inward rotation of the helical subdomain and complete closure of MalK(2) therefore appear to be coupled to the reorientation of transmembrane helices and the opening of MBP, events that promote transfer of maltose into the transporter. After ATP hydrolysis, the helical subdomain rotates out as MalK(2) opens, resetting the transporter in an inward-facing conformation.