Modulation of physiological angiogenesis in skeletal muscle by mechanical forces: Involvement of VEGF and metalloproteinases

Growth factors are involved in physiological angiogenesis in female reproductive organs but their role in capillary growth in skeletal muscles during activity or exercise training is not proven. Evidence suggests that increases in muscle blood flow and accompanying capillary shear stress and/or wall tension, or mechanical stress due to sarcomere length changes during contraction/relaxation cycles are closely linked with angiogenesis. Time-dependent studies of rat muscles in models with increased shear stress (chronic vasodilator treatment with α₁ antagonist prazosin), altered sarcomere length (stretch-induced overload with no increase in blood flow), or both (chronic electrical muscle stimulation) showed a similar increase in capillary supply in all models but by different modes of growth. With prazosin, it occurred by intra-luminal splitting of vessels, with stretch by abluminal sprouting, and in stimulated muscles by both methods. Whole muscle matrix metalloproteinase-2 (MMP-2) was elevated during sprouting growth induced by extravascular tensile forces but not during splitting growth induced by shear. Vascular endothelial growth factor (VEGF) protein was elevated at capillary sites in all three models but with different time courses. With shear as the stimulus, the increase occurred early although there was little capillary proliferation; it matched the rise in proliferation in stretched muscles but lagged behind proliferation in stimulated muscles. Mechanical forces therefore influence MMP and VEGF expression and capillary growth patterns in skeletal muscle differentially depending upon whether they act intra- or ab-luminally. In exercise-trained muscles, the type of capillary growth remains to be determined but the most likely stimuli for angiogenesis are increased blood flow and shear forces to vessel supplying the active fibres, probably linked with metabolic factors.     

Clinical blood flow quantification with segmented k-space magnetic resonance phase velocity mapping

PURPOSE: To evaluate the accuracy of segmented k-space magnetic resonance phase velocity mapping (PVM) in quantifying aortic blood flow from through-plane velocity measurements. MATERIALS AND METHODS: Two segmented PVM schemes were evaluated, one with seven lines per segment (seg-7) and one with nine lines per segment (seg-9), in twenty patients with cardiovascular disease. A non-segmented (non-seg) PVM acquisition was also performed to provide the reference data. RESULTS: There was agreement between the aortic flow curves acquired with segmented and non-segmented PVM. The calculated systolic and total flow volume per cycle from the seg-7 and the seg-9 scans correlated and agreed with the flow volumes from the non-seg scans (differences < 5%). Sign tests showed that there were no statistically significant differences (P-values > 0.05) between the segmented and the non-segmented PVM measurements [corrected]. Seg-9, which was the fastest among the three sequences, provided adequate spatial and temporal resolution (> 10 phases per cycle). CONCLUSION: Segmented k-space PVM shows great clinical potential in blood flow quantification.     

Application of shock waves to rat skin decreases calcitonin gene-related peptide immunoreactivity in dorsal root ganglion neurons

There have been several reports on the use of extracorporeal shock waves in the treatment of pseudarthrosis, calcifying tendinitis, and tendinopathies of the elbow. However, the pathomechanism of pain relief has not been clarified. To investigate the analgesic properties of shock wave application, we analyzed changes in calcitonin gene-related peptide (CGRP)-immunoreactive (ir) dorsal root ganglion (DRG) neurons. In the nontreated group, fluorogold-labeled dorsal root ganglion neurons innervating the most middle foot pad of hind paw were distributed in the L4 and L5 dorsal root ganglia. Of these neurons, 61% were CGRP-ir. However, in the shock wave-treated group, the percentage of FG-labeled CGRP-ir DRG neurons decreased to 18%. These data show that relief of clinical pain after shock wave application may result from reduced CGRP expression in DRG neurons.     

补气活血法治疗糖尿病周围神经病变的临床观察

目的：观察补气活血法治疗糖尿病周围神经病变(DPN)的临床疗效。方法：选取气虚血瘀的2型糖尿病住院患者68例,随机分为两组(各34例),两组均用西医常规处理,治疗组同时加用补气活血中药,疗程均2个月,并分别测定两组治疗前后血糖、甘油三酯、总胆固醇、神经传导速度(NCV)。结果：治疗组治疗后空腹血糖、餐后2h血糖、甘油三酯、总胆固醇及NCV均有显著改善(P<0．05),且优于对照组(P<0．05)。对照组仅空腹血糖及NCV治疗后有显著改善(P<0．05)。结论：补气活血法治疗DPN不仅能改善其临床症状,同时能显著提高其NCV。     

Preclinical factors affecting the interindividual variability in the clearance of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid

Cancer chemotherapy is characterized by significant interindividual variations in systemic clearance, therapeutic response, and toxicity. These variations are due mainly to genetic factors, leading to alterations in drug metabolism and/or target proteins. The aim of this study was to determine, using a human liver bank (N=14), the interindividual variations in the expression and activity of liver enzymes that metabolize the investigational anticancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), i.e cytochrome P450 (CYP1A2) and uridine diphosphate glucuronosyltransferase (UGT1A9/2B7). In addition, interindividual variations in enzyme inhibition, hydrolysis of DMXAA acyl glucuronide (DMXAA-G) by plasma and hepatic microsomes, and the binding of DMXAA by plasma proteins also were examined. The results indicated that there was approximately one order of magnitude of interindividual variation in the expression of CYP1A2 and UGT2B7, activity of the enzymes toward DMXAA, and inhibition potency (IC(50)) by diclofenac, cyproheptadine, and alpha-naphthoflavone. The enzyme activities toward DMXAA and IC(50) values were closely correlated with enzyme expression. There was a smaller (2- to 3-fold) variation in the enzyme-catalyzed hydrolysis of DMXAA acyl glucuronide in human plasma and liver microsomes (N=6) and in the binding of DMXAA by plasma proteins in humans. In conclusion, the interindividual variability of DMXAA disposition observed in vitro might reflect the greater elimination variability (>one order of magnitude) in Phase I cancer patients. The variability in DMXAA clearance in these cancer patients would be due mainly to differences in its metabolism and its metabolic inhibition by co-administered drugs. To a lesser extent, variability in the clearance of DMXAA could be due to the hydrolysis of its acyl glucuronide and/or its binding to plasma proteins. Further study is needed to examine the genotype-phenotype relationship, and the result, together with therapeutic drug monitoring may provide a useful strategy for optimizing DMXAA treatment.     

Square wave voltammetric determination of the angiotensin-converting enzyme inhibitors cilazapril,quinapril and ramipril in pharmaceutical formulations

The angiotensin-converting enzyme inhibitors cilazapril, quinapril and ramipril are reduced at a hanging mercury drop electrode in the pH range 3.5-13 using Britton-Robinson buffers as supporting electrolyte and KCl as ionic medium. Square wave voltammetry has proved to be the most suitable electroanalytical technique for the quantitative voltammetric determination of these antihypertensive drugs. Optimisation of the chemical and instrumental variables was carried out. Analyses were performed in 0.02 M borate buffer at pH 9.5 and 0.5 M KCl as ionic medium, using a pulse amplitude of 50 mV and a frequency of 150 Hz. A linear relationship between peak current and concentration was found in the interval 0.5-8 microg/ml for cilazapril and up to 6 microg/ml for quinapril and ramipril, allowing the direct determination of their pharmaceutical formulations alone or mixed with hydrochlorothiazide. Good accuracy and repeatativity were obtained.     

Canalisation in human growth: a widely accepted concept reconsidered

According to the concept of canalisation, infants and children stay within one or two growth channels, and therefore, any crossing of height centiles always warrants further evaluation. In view of evidence against this concept we re-investigated the variability of individual growth in the First Zürich Longitudinal Growth Study. The investigation is based on height measurements of 232 children (112 females, 120 males) measured at annual intervals during childhood and half-yearly during adolescence. Height data were transformed into height standard deviation scores (SDS) and canalisation defined by the width of an individual's growth channel, i.e., by the differences between maximum and minimum height SDS, in the individual series of measurements. Many subjects of the First Zürich Longitudinal Growth Study crossed numerous centiles with patterns that often seemed to show characteristic features. For approximately two thirds of the subjects, the SDS channel during the whole growth process covers more than one SDS. In childhood, between the age of two and age of minimal height velocity, only about one fourth of the subjects have an SDS channel below 0.5, indicating acceptable canalisation. During childhood, growth in boys appeared slightly more canalised than in girls (P=0.02). Conclusion The present investigation does not support the concept of strict canalisation of individual growth. We suggest to consider crossing of centiles a normal event in child development, though in a clinical setting crossing centiles should still be taken seriously, at least at first until a medical cause for this has been excluded. Received: 25 July 2000 / Accepted: 11 October 2000     

Noninvasive assessment of arterial distensibility in adolescents using the second derivative of photoplethysmogram waveform

To clarify the clinical usefulness of the second derivative of the waveform of the fingertip photoplethysmogram (SDPTG), we examined the relationship between the pattern of the SDPTG waveform and risk factors related to atherosclerosis in 1,495 boys and girls aged 9–17 years. The fingertip photoplethysmogram and its second derivative wave were automatically recorded from the second digit of the right hand with the subjects lying in a supine position. The SDPTG waveform consisted of a, b, c and d waves in systole and an e wave in diastole. The heights of the a and d waves were measured from the baseline, and the ratio of the height of the d wave to that of the a wave (d/a ratio) was calculated. The d/a ratio had a negative correlation with the systolic (SBP) and diastolic blood pressures (DBP), atherogenic index (AI) and immunoreactive insulin concentrations (IRI) after adjustment for age. Multiple linear regression analysis revealed that the d/a ratio was associated more with body height than the risk factors for atherosclerosis in boys and girls at the growth period. The effect of sex- and height-specific cutoff values of the 10th percentile for the d/a ratio was therefore tested. The results showed that subjects with d/a ratios lower than the 10th percentile had significantly higher SBP, DBP, AI and IRI values compared to those with higher d/a ratios. These findings suggest that differences in the length of the vascular system, which are related to increases in body height, may modify the SDPTG waveform pattern during adolescence. When the body height as well as age and sex is adequately allowed for, the d/a ratio may be useful for the evaluation of arterial distensibility and for identification of individuals at an increased risk of developing atherosclerosis. Electronic Publication     

中国急性心肌缺血综合征患者临床特征

目的 分析中国地区急性心肌缺血综合征病人的临床特点和治疗现状。方法 此项研究为国际性多中心关于急性心肌缺血综合征登记试验(OASIS)的一部分。采用加拿大心血管合作协会统一设计的病例记录表(CRF),自1999年4月开始,收集因急性心肌缺血入院病人的资料,记录病人主要临床特征和院内事件。结果 来自中国38家医院急性心肌缺血综合征(包括不稳定心绞痛及非Q波心肌梗死)病人2290例,平均年龄62．8岁,男性占62．3％。就诊时胸痛仍未缓解者48．9％;心电图异常89．7％,其中41．4％为相邻导联ST压低≥2mm;入院诊断不稳定心绞痛90．9％,非Q波心肌梗死9．0％。住院期间溶栓3．3％,冠状动脉(冠脉)造影34．9％,经皮冠脉腔内成形术(PTCA)17．6％,冠脉旁路移植术(CABG)4．2％,应用硝酸酯剂99．3％,抗血小板治疗94．5％。院内发生重要并发症15．2％,其中死亡1．4％。结论 中国地区急性心肌缺血病人以不稳定心绞痛就诊居多。住院期间PTCA治疗率相对较高,CABG治疗率较低。死亡主要原因为严重心律失常或猝死。     

Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium

The extracellular concentrations of Ca(2+) and Mg(2+) are well known to play important roles in the function of the central nervous system. We examined the effects of extracellular Ca(2+) and Mg(2+) on ATP release and intercellular signaling in astrocytes. The extent of propagation of intercellular Ca(2+) waves evoked by mechanical stimulation was increased by reduction of extracellular Ca(2+) ([Ca(2+)](o)) or Mg(2+) concentration ([Mg(2+)](o)) and was decreased by elevated [Mg(2+)](o). Reduction of extracellular Ca(2+) concentration ([Ca(2+)](o)) evokes intercellular Ca(2+) signaling in astrocytes; a similar effect was observed in response to change from 5 mM [Mg(2+)](o) to 0 [Mg(2+)](o). Release of low-molecular-weight dyes and ATP was also activated by low [Ca(2+)](o) or [Mg(2+)](o) and inhibited by high [Ca(2+)](o) or [Mg(2+)](o). Astrocytes showed low [Ca(2+)](o)-activated whole cell currents consistent with currents through connexin hemichannels. These currents were inhibited by extracellular Mg(2+). We conclude that extracellular divalent cations modulate intercellular Ca(2+) signaling in astrocytes by modulating the release of ATP, possibly via connexin hemichannels.