超声心动图评价左房减容对二尖瓣狭窄术后左心功能的影响

目的:以超声心动图技术评价左房减容术对二尖瓣狭窄患者瓣膜置换术后左心室收缩功能的影响。方法:82例患有二尖瓣狭窄者,实施心脏瓣膜置换术50例(A组),同时行左房减容术者32例(B组),所有患者分别于手术前和手术后3个月接受经胸超声心动图检查,分别测得LVEDD、LVESD、LAEDV、LAESV、FS、EF等参数。结果:B组在心室收缩功能与A组比较改善叫显(P<0.05)。两组左心室心肌重量指数有显著差异(P<0.05)。结论:恰当的左房减容术对二尖瓣狭窄患者术后的心功能恢复有一定帮助,并且操作简单。     

FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho

The three members of the endocrine-fibroblast growth factor (FGF) family, FGF19, 21, and 23 are circulating hormones that regulate critical metabolic processes. FGF23 stimulates the assembly of a signaling complex composed of α-Klotho (KLA) and FGF receptor (FGFR) resulting in kinase activation, regulation of phosphate homeostasis, and vitamin D levels. Here we report that the C-terminal tail of FGF23, a region responsible for KLA binding, contains two tandem repeats, repeat 1 (R1) and repeat 2 (R2) that function as two distinct ligands for KLA. FGF23 variants with a single KLA binding site, FGF23-R1, FGF23-R2, or FGF23-wild type (WT) with both R1 and R2, bind to KLA with similar binding affinity and stimulate FGFR1 activation and MAPK response. R2 is flanked by two cysteines that form a disulfide bridge in FGF23-WT; disulfide bridge formation in FGF23-WT is dispensable for KLA binding and for cell signaling via FGFRs. We show that FGF23-WT stimulates dimerization and activation of a chimeric receptor molecule composed of the extracellular domain of KLA fused to the cytoplasmic domain of FGFR and employ total internal reflection fluorescence microscopy to visualize individual KLA molecules on the cell surface. These experiments demonstrate that FGF23-WT can act as a bivalent ligand of KLA in the cell membrane. Finally, an engineered Fc-R2 protein acts as an FGF23 antagonist offering new pharmacological intervention for treating diseases caused by excessive FGF23 abundance or activity.

The large family of fibroblast growth factors (FGFs) has been known for its important roles in regulating critical cellular processes during embryonic development and homeostasis of normal tissues (1–3). While most FGFs act as cytokines or hormonelike proteins that mediate their pleiotropic cellular processes by binding to cell surface receptors endowed with intrinsic tyrosine kinase activity (FGFRs), a subfamily of FGFs (FGF 11–14) was shown to be uniquely expressed intracellularly. The mechanism of action and physiological roles of intracellular FGFs are poorly understood (4–6).In contrast to most receptor tyrosine kinases (RTKs) that are activated by a single ligand molecule that binds with high affinity to the extracellular domain of its cognate RTK with a dissociation constant in the subnanomolar range, the binding affinities of FGFs to FGFRs are, at least, 1,000–10,000 fold weaker with dissociation constants in the submicromolar range (7–9). The weak binding affinities toward FGFRs of the largest subfamily of FGF molecules designated canonical FGFs are offset by interactions with cell surface heparan sulfate proteoglycans (HSPGs). Both biochemical and structural studies revealed how multiple interactions between heparin or HSPG with both FGF and FGFR mediate tight association enabling robust receptor dimerization and tyrosine kinase activation (10, 11).The three endocrine FGFs, FGF19, 21, and 23 are part of an additional subfamily of FGF molecules. Endocrine FGFs function as circulating hormones that play essential roles in the control of various metabolic processes (12). In addition to the conserved FGF-domain found in all FGF ligands, endocrine FGFs contain unique C-terminal tails (CTs) composed of 46 (FGF19), 34 (FGF21), or 89 (FGF23) amino acids that serve as specific and high-affinity ligands for the two members of the Klotho family of surface receptors. It was shown that KLA serves as a high-affinity receptor for FGF23 while β-Klotho (KLB) functions as a high-affinity surface receptor for both FGF19 and FGF21 (13–16). Structural analyses of free and ligand-occupied Klotho proteins revealed the molecular basis underlying the specificity and high affinity of KLA and KLB toward endocrine FGFs. It also showed that Klotho proteins function as the primary receptors for endocrine FGFs whereas FGFR functions as a catalytic subunit that mediates cell signaling via its tyrosine kinase domain (8, 17, 18). Accordingly, endocrine FGFs stimulate their cellular responses by forming a ternary complex with Klotho proteins and FGFRs to induce receptor dimerization, tyrosine kinase activation, and cell signaling. Unlike FGFRs that are ubiquitously expressed, the expressions of KLA and KLB are restricted to specific tissues and organs to enable precise targeting of endocrine FGFs to stimulate their physiological responses in specific cells and tissues (19–22). The ability of endocrine FGFs to circulate is attributed to the loss of conserved heparin binding sites that are essential for the function of canonical FGFs (23).FGF23 is a 32-kDa glycoprotein, mainly produced in the bone by osteoblasts and osteocytes, that serve as a key hormone in regulating phosphate homeostasis, vitamin D, and calcium metabolism (24, 25). Circulating levels of physiologically active FGF23 are regulated by proteolytic cleavage to produce a FGF23 molecule lacking its unique CT (26, 27). The cleavage resulting in FGF23 inactivation prevents assembly and stimulation of the FGF23/FGFR/KLA complex. Additionally, the processing of FGF23 includes several posttranslational modifications which affect its stability and susceptibility toward proteolysis. Secreted FGF23 was shown to be O-glycosylated in its C-terminal cleavage site (28, 29) to protect the protein from C-terminal cleavage. In order for the cleavage site to be exposed, FGF23 has to be first phosphorylated in this region (30). Phosphorylation prevents glycosylation and exposes the cleavage site to proteolysis.In this paper, we demonstrate that the CT of FGF23 contains two tandem repeats and that each repeat binds with high affinity to KLA. This contrasts with FGF19 and FGF21, whose CTs contain a single binding site to KLB. Engineered FGF23 variants containing each of the two repeats individually or both repeats bind specifically to KLA and stimulate cell signaling to a similar extent. We also demonstrate that two cysteine residues flanking the second repeat form a disulfide bridge in FGF23 secreted by mammalian cells. However, both oxidized or unbridged forms of FGF23 exhibit similar KLA binding characteristics and similar cellular stimulatory activities. We also show that FGF23-WT induces mitogen-activated protein kinase (MAPK) activation in cells expressing chimeric KLA-FGFR proteins and use TIRFM imaging of individual KLA molecules on the cell surface to demonstrate that FGF23 has the capacity for simultaneous binding to two KLA molecules. These insights reveal the complexity of FGF23 regulation and its role in assembling the FGF23/FGFR/KLA signaling complex.     

新疆牛源细粒棘球绦虫成虫发育的扫描电镜观察

本报告为用新疆阿勒泰地区牛体内采集的原头节人工感染家犬,在感染后第15、25、35天分别剖杀犬,收集虫体进行扫描电镜观察的结果。成虫体节发育在15天时为1节,25天为2节,35天为3～4节并已达到性成熟。成虫体表均被一层微毛覆盖,不同部位体表微毛的形态不同。在吻突顶部,微毛呈绒线状,纤细柔软,较稀疏,随着发育逐渐变长、变浓密,末端卷曲。吻突基部和吸盘区的微毛呈绒线状,但较顶突微毛粗短。体节部位微毛在不同发育时间形态不同,呈现圆锥形绒线状,锯齿形鳞片状。成熟虫体体表微毛呈圆锥形绒线状,较坚硬,有规律排列。性成熟虫体生殖孔为圆形,有的虫体可见伸出的雄茎,雄茎表面也被有纤细的微毛。生殖孔周围体表微毛较密短,呈地毯样,间有大小不等的乳头状突起,可能为感觉乳头。     

Can source reduction of mosquito larval habitat reduce malaria transmission in Tigray,Ethiopia?

The development of irrigation schemes by dam construction has led to an increased risk of malaria in Tigray, Ethiopia. We carried out a pilot study near a microdam to assess whether environmental management could reduce malaria transmission by Anopheles arabiensis, the main vector in Ethiopia. The study took place in Deba village, close to a dam; Maisheru village, situated 3-4 km away from the dam, acted as a control. Baseline entomological and clinical data were collected in both villages during the first 12 months. Source reduction, involving filling, draining and shading of potential mosquito-breeding habitats was carried out by the community of Deba in the second year and routine surveillance continued in both villages during the second year. Anopheles arabiensis was highly anthropophilic (Human Blood Index=0.73), biting early in the night before people went to bed. The major breeding habitats associated with the dam were areas of seepage at the dam base (28%), leaking irrigation canals (16%), pools that formed along the bed of streams from the dam (13%), and man-made pools (12%). In the pre-intervention year, 5.9-7.2 times more adult vectors were found in the dam village compared with the control village. There was a 3.1% higher prevalence of an enlarged spleen in children under 10 years in the dam village than in the control village during the pre-intervention period, but no statistically significant difference was found in the incidence of falciparum malaria between the two villages during the same period. Source reduction was associated with a 49% (95% CI=46.6-50.0) relative reduction in An. arabiensis adults in the dam village compared with the pre-intervention period. There were very few cases of malaria during the intervention period in both villages making it impossible to judge whether malaria incidence had been reduced. These preliminary findings suggest that in areas of low intensity transmission community-led larval control may be a cheap and effective method of controlling malaria. Further, large-scale studies are needed to confirm these findings.     

Monovalent binding of autoantibodies to beta2-glycoprotein I, detected using surface plasmon resonance at low antigen density

The precise mechanism of interaction between autoantibodies and beta2-glycoprotein I (beta2GPI) and the experimental conditions to be used for their detection are still under debate. Until now, these interactions have been studied under static conditions. We have investigated the interactions of purified IgG from 25 lupus anticoagulant-positive patients with immobilized beta2GPI under flow conditions by real-time analysis based on surface plasmon resonance technology. Sensor chips were coated with purified human beta2GPI coupled to dextran via amino groups at low densities (1.4, 1.8 or 2. 4 ng beta2GPI/mm2). Four patients' IgG displayed efficient binding and had the highest so-called antiphospholipid IgG levels by enzyme-linked immunosorbent assay (ELISA) and the highest absorbance values in an anti- beta2GPI ELISA at a beta2GPI density reported to be around 12 ng/mm2. Binding of antibodies to the beta2GPI sensor chips proved to be dependent upon the IgG concentration and beta2GPI density and was inhibited by a rabbit antibody against beta2GPI. Similar association and dissociation profiles were observed for the four efficient binders. The fast rate of dissociation limited the binding of autoantibodies to beta2GPI and was highly suggestive of a monovalent association, confirmed by binding of Fab fragments under similar experimental conditions. In conclusion, monovalent binding of low-affinity antibodies to beta2GPI immobilized at a density as low as 1.8 ng/mm2 could be detected using surface plasmon resonance.     

Preventing osteoporotic fractures with antiresorptive therapy: implications of microarchitectural changes

Prospective studies have demonstrated that low bone mass correlates well with increased risk of osteoporotic fractures at various skeletal sites. Trials have likewise confirmed that enhancing bone mass with antiresorptive therapy reduces fracture incidence in individuals at risk. However, correlation of bone mineral density (BMD) increases with therapeutic risk reduction has proved less consistent than correlation of BMD decreases with greater fracture risk in the untreated. Indeed, various analyses have indicated that - even during treatment with potent bisphosphonates like alendronate and risedronate - BMD changes from baseline account for <30% of the reduction in vertebral fractures in treated women. It is clearly, therefore, that factors other than BMD are involved in the reduction of fracture risk achieved by antiresorptive therapies. According to recent micro-computed tomography imaging and other studies, antiresorptive therapy can help rebuild the microarchitecture of bone as well as strengthen the materials that go into it. When treating individuals with osteoporosis, these microarchitectural changes contribute to the reduction of fracture risk achieved by antiresorptive therapies.     

Effect of a Contrast Modulation System on Contrast Media Use and the Rate of Acute Kidney Injury After Coronary Angiography

Objectives

The aim of the AVERT (AVERT Clinical Trial for Contrast Media Volume Reduction and Incidence of CIN) trial was to test the efficacy of the AVERT system to reduce the contrast media volume (CMV) used during coronary angiographic procedures without impairing image quality and to prevent contrast-induced acute kidney injury (CI-AKI) in patients at risk for CI-AKI.

Lung volume reduction surgery in lieu of pneumonectomy in an infant with severe unilateral pulmonary interstitial emphysema

A male infant with a prenatal diagnosis (at 20 weeks' gestation) of cystic adenomatoid malformation was delivered after 38 weeks' gestation (birth weight, 3 kg) and admitted to the neonatal intensive care unit. During the first few days of life, he developed mild respiratory distress; a chest radiograph and computed tomography scan showed multiple cystic areas in the left lower lobe with hyperinflation and herniation of the upper lobe across the midline. At 3 weeks of age, a left lower lobectomy was performed for presumed cystic malformation. To our surprise the pathology reports revealed pulmonary interstitial emphysema. The postoperative chest radiograph was unchanged, and mechanical ventilation was necessary and required progressively increasing ventilatory settings to provide adequate support. High-frequency oscillatory ventilation and selective right bronchus intubation failed to improve lung function. After 3 weeks, a left thoracotomy was repeated and lung volume reduction was performed with removal of 50' of the peripheral hyperinflated parenchyma. Postoperative recovery was rapid; the child was weaned from the ventilator after 3 days and discharged after 3 weeks. Follow-up chest X-rays showed a normally expanded right lung with mediastinal structures back to midline and a small left lung. Favorable results persisted at 3 years of follow-up. This first and successful experience with lung volume reduction in a neonate suggests that infants who need removal of a large portion of lung parenchyma to achieve adequate ventilation and gas exchange, lung volume reduction surgery should be considered as an alternative to pneumonectomy.     

Contactless magnetocardiographic study of ventricular repolarization in intact Wistar rats: Evidence of gender-related differences

Abstract.Introduction: Magnetocardiographic (MCG) mapping is increasingly used for the non-invasive study of coronary artery disease (CAD), cardiomyopathy (CMP) and arrhythmias. MCG study of small animals with ischemia or CMP would provide useful experimental models for the interpretation of abnormal human patterns. The aim of this study was to assess the range of normality of MCG ventricular repolarization parameters, in intact adult rats.Methods and results: 10 adult Wistar rats (weight 250 – 350 grams) were investigated with a 36-channel MCG mapping instrumentation (sensitivity is 20 fT/ Hz, at 1 Hz), designed for clinical recordings in unshielded hospital laboratories. To assess ventricular repolarization, MCG Q-T_peak, Q-T_end, J-T_peak, J-T_end, T_peak-T_end intervals were measured. MCG imaging was obtained by automatic calculation of isofield contour maps, and with inverse source localization based on the Equivalent Current Dipole and Effective Magnetic Dipole models, in a semi-infinite space with homogeneous conductance. Magnetic field (MF) orientation, dynamics and stability during the J-T_end segment were also calculated. After averaging 300 s of continuous MCG recording, the S/N ratio was good enough for reproducible reconstruction of both atrial and ventricular magnetic maps and for three-dimensional localization of the underlying cardiac generators. Clear gender-related differences in ventricular repolarization duration were found, evidenced by significantly longer Q-T_end, J-T_end and T_peak-T_end intervals in females. The differences in MF orientation, and stability during the J-T_end segment were not significant. For J-T_peak MF dynamics, only the ratio between the strengths of the positive and negative poles was significantly lower in the female group (p < 0.05).Conclusions: Contactless MCG recording is a novel approach, which simplifies non-invasive mapping in small animals. In normal rats, gender-related differences of ventricular repolarization parameters equivalent to those reported in previous ECG studies were demonstrated.