Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier?

Nitric oxide (NO) is a physiologically important modulator of both vasomotor tone and platelet aggregability. These effects of NO are predominantly mediated by cyclic guanosine-3,'5'-monophosphate (cGMP) via activation of soluble guanylate cyclase. However, in patients with ischemic heart disease, platelets and coronary/peripheral arteries are hyporesponsive to the antiaggregatory and vasodilator effects of NO donors. NO resistance is also associated with a number of coronary risk factors and presents in different disease states. It correlates with conventional measures of "endothelial dysfunction," and represents a multifaceted disorder, in which smooth muscle and platelet NO resistance are equally important, as sites of abnormal NO-driven physiology. NO resistance results largely from a combination of "scavenging" of NO by superoxide anion radical (O(2)(-)) and of (reversible) inactivation of soluble guanylate cyclase. It constitutes an impaired physiological response to endogenous NO (endothelium-derived relaxing factor, EDRF) and, as such, may contribute to the increased risk of ischemic events. Impairment in responsiveness to NO in ischemic patients implies a potential problem that those patients, in greatest need of nitrate therapy, may be least likely to respond. The prognostic impact of NO resistance at vascular and platelet levels has been demonstrated in patients with ischemic heart disease, and it has been shown that a number of agents (angiotensin-converting enzyme [ACE] inhibitors, perhexiline, insulin, and possibly statins) ameliorate this anomaly. The current review examines different aspects of the "NO resistance" phenomenon and discusses some related methodological issues.     

骨髓间充质干细胞生物学特性及临床应用进展

学术背景:骨髓间充质干细胞具有来源广泛、易于分离培养、不易引起免疫排斥和易于基因转染等特点,使其成为细胞治疗和基因治疗的种子细胞,具有广泛的科研和临床应用价值。目的:介绍骨髓间充质干细胞的生物学特性以及在疾病治疗方面的进展和应用前景。检索策略:由第一作者应用计算机检索Medline,Ovid,Highwire数据库1995-01/2007-09关于骨髓间充质干细胞及其临床应用方而的文章,检索词"mesenchymal stem cells,differentiation,clinical applications",并限定语言种类为"English"纳入际准:骨髓间充质干细胞在组织工程中的相关研究。排除标准:重复性研究和缺乏原创性的研究。文献评价:初检得到280篇文献,阅读文题和摘要排除220篇相关性不强的文献,对剩余60篇文献进一步查找全文,保留35篇完全符合标准的文献进行综述。资料综合:骨髓间充质干细胞不仅可以分化为造血基质细胞,还可以分化为许多造血以外的组织,特别是中胚层和神经外胚层来源组织的细胞,如成骨细胞、软骨细胞、脂肪细胞、心肌细胞、内皮细胞、肝和胆道上皮细胞、肺上皮细胞等。骨髓间充质干细胞缺乏特异性的表面标记物,由于其具有定向诱导分化能力,取材方便,取自自体,不存在免疫排斥问题等优势,使其在骨组织工程、心血管和神经系统等疾病的治疗中均显示出良好的应用前景。结论:具有多向潜能分化能力的骨髓间充质干细胞为组织工程提供了理想的种子细胞来源,但是其应用目前仍在探索阶段,还有许多需要解决的问题。寻找特定的标记物用于鉴定间充质干细胞以及明确诱导分化机制是未来的研究方向。     

Thioredoxin-Interacting Protein: Pathophysiology and Emerging Pharmacotherapeutics in Cardiovascular Disease and Diabetes

The thioredoxin system, which consists of thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate (NADPH) and thioredoxin reductase (TrxR), has emerged as a major anti-oxidant involved in the maintenance of cellular physiology and survival. Dysregulation in this system has been associated with metabolic, cardiovascular, and malignant disorders. Thioredoxin-interacting protein (TXNIP), also known as vitamin D-upregulated protein or thioredoxin-binding-protein-2, functions as a physiological inhibitor of Trx, and pathological suppression of Trx by TXNIP has been demonstrated in diabetes and cardiovascular diseases. Furthermore, TXNIP effects are partially Trx-independent; these include direct activation of inflammation and inhibition of glucose uptake. Many of the effects of TXNIP are initiated by its dissociation from intra-nuclear binding with Trx or other SH-containing proteins: these effects include its migration to cytoplasm, modulating stress responses in mitochondria and endoplasmic reticulum, and also potentially activating apoptotic pathways. TXNIP also interacts with the nitric oxide (NO) signaling system, with apparent suppression of NO effect. TXNIP production is modulated by redox stress, glucose levels, hypoxia and several inflammatory activators. In recent studies, it has been shown that therapeutic agents including insulin, metformin, angiotensin converting enzyme inhibitors and calcium channel blockers reduce TXNIP expression, although it is uncertain to what extent TXNIP suppression contributes to their clinical efficacy. This review addresses the role of TXNIP in health and in cardiovascular and metabolic disorders. Finally, the potential advantages (and disadvantages) of pharmacological suppression of TXNIP in cardiovascular disease and diabetes are summarized     

Quetiapine in refractory hyperactive and mixed intensive care delirium: a case series

Introduction  

Delirium affects up to 80% of patients admitted to intensive care units (ICUs) and contributes to increased morbidity and mortality. Haloperidol is the gold standard for treatment, although quetiapine has been successfully used in the management of delirium.     

N-terminal pro-brain natriuretic protein levels in takotsubo cardiomyopathy

Takotsubo cardiomyopathy (TTC) is characterized by reversible left ventricular (LV) systolic dysfunction independent of fixed coronary disease or coronary spastic pathogenesis. A number of investigators have documented marked elevation of natriuretic peptide levels at presentation in such patients. We sought to determine the pattern, extent, and determinants of the release of N-terminal pro-B type natriuretic peptide/B type natriuretic peptide (NT-proBNP/BNP) in patients with TTC. We evaluated NT-proBNP/BNP release acutely and during the first 3 months in 56 patients with TTC (96% women, mean age 69 ± 11 years). The peak plasma NT-proBNP levels were compared to the pulmonary capillary wedge pressure and measures of regional and global LV systolic dysfunction (systolic wall stress, wall motion score index, and LV ejection fraction) as potential determinants of NT-proBNP/BNP release. In patients with TTC, the plasma concentrations of NT-proBNP (median 4,382 pg/ml, interquartile range 2,440 to 9,019) and BNP (median 617 pg/ml, interquartile range 426 to 1,026) were substantially elevated and increased significantly during the first 24 hours after the onset of symptoms (p = 0.001), with slow and incomplete resolution during the 3 months thereafter. The peak NT-proBNP levels exhibited no significant correlation with either pulmonary capillary wedge pressure or systolic wall stress. However, the peak NT-proBNP level correlated significantly with the simultaneous plasma normetanephrine concentrations (r = 0.53, p = 0.001) and the extent of impairment of LV systolic function, as measured by the wall motion score index (r = 0.37, p = 0.008) and LV ejection fraction (r = -0.39, p = 0.008). In conclusion, TTC is associated with marked and persistent elevation of NT-proBNP/BNP levels, which correlated with both the extent of catecholamine increase and the severity of LV systolic dysfunction.     

Contribution of SNRNP200 sequence variations to retinitis pigmentosa

Purpose

Mutations in the SNRNP200 gene have been reported to cause autosomal dominant retinitis pigmentosa (adRP). In this study, we evaluate the mutation profile of SNRNP200 in a cohort of southern Chinese RP patients.

Methods

Twenty adRP patients from 11 families and 165 index patients with non-syndromic RP with mixed inheritance patterns were screened for mutations in the mutation hotspots of SNRNP200. These included exons 12–16, 22–32, and 38–45, which covered the two helicase ATP-binding domains in DEAD-box and two sec-63 domains. The targeted regions were amplified by polymerase chain reaction and analyzed by direct DNA sequencing, followed by in silico analyses.

Results

Totally 26 variants were identified, 18 of which were novel. Three non-synonymous variants (p.C502R, p.R1779H and p.I698V) were found exclusively in patients. Two of them, p.C502R and p.R1779H, were each identified in one simplex RP patient, whereas p.I698V occurred in one patient with unknown inheritance pattern. All three residues are highly conserved in SNRNP200 orthologs. Nevertheless, only p.C502R and p.R1779H were predicted to affect protein function by in silico analyses, suggesting these two variants are likely to be disease-causing mutations. Notably, all mutations previously identified in other study populations were not detected in this study.

Conclusions

Our results reveal a distinct mutation profile of the SNRNP200 gene in a southern Chinese cohort of RP patients. The identification of two novel candidate mutations in two respective patients affirmed that SNRNP200 contributes to a proportion of overall RP.     

Composite polarization systems for independent controlling polarization of two beams with different wavelengths

The usage of independent and simultaneous control of the state of light polarization at different wavelengths can expand the capabilities of polarization methods for biomedical application. Unfortunately, all known methods of polarization conversion cannot convert the state of light polarization at different wavelengths independently. We propose a method and device for independent and simultaneous control of the polarization state at two wavelengths. We have theoretically proved the possibility of maintaining the phase shift at the first wavelength unchanged while simultaneously and independently changing the phase shift at the second wavelength from 0 to 180 degrees. The capabilities of the method were for the first time demonstrated for radiation with wavelengths λ = 632.8 nm and λ = 488 nm. At the wavelength λ = 632.8 nm, the phase shift remained equal to 180° whereas at the wavelength λ = 488 nm, it varied in the range from 121° to 136°.