Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children.

Treatment of 17 children aged 2-9.5 years with a combination of pivmecillinam and pivampicillin (250-500 mumol 24 h-1) for more than 1 year resulted in a reduction of the free carnitine concentration in serum and muscle to less than 10% of the mean reference value. The decline in serum was slow, with an estimated half-life of about 5 months. Spontaneous replenishment occurred at about the same slow rate. Thus, there is no increase in endogenous carnitine synthesis as a response to increased demand of carnitine for detoxification. Supplementation with carnitine during treatment required at least a four-fold molar excess over pivalic acid to achieve and sustain a normal carnitine concentration. The replenishment of carnitine occurred with a half-life of 1.1-3.0 months. From determination of muscle-carnitine concentration in patients treated with pivaloyl-containing antibiotics and in patients with organic aciduris, we conclude that serum carnitine is a good predictor of carnitine stores in the body. Six non-supplemented patients with a serum free-carnitine concentration of 0.7-2.6 mumol l-1 had an inadequate ketone-body increase during a 24-h fast. Vomiting, nausea and tiredness occurred in three cases following the fasting period. After normalization of the serum-carnitine concentration, a normal response to fasting was observed. Thus, in some organic acidurias, for example medium-chain acyl-CoA dehydrogenase deficiency, a low liver concentration of carnitine may be an important contributing factor to hypoglycaemic and Reye-like attacks. We believe that prodrugs which contain pivalic acid should be avoided if acceptable alternatives exist. If used, supplementation with at least four-fold molar excess of carnitine is advisable.     

The tubular maximum for calcium reabsorption: normal range and correction for sodium excretion

Increased tubular reabsorption of calcium is one of the three variables which can contribute to the pathogenesis of hypercalcaemia. It is therefore important to establish the normal range for this variable in a manner which allows for its variation with the plasma calcium concentration. Graphic methods depicting the relationship between urinary calcium excretion and plasma calcium concentration are valid but cumbersome and imprecise. The notional tubular maximum for calcium reabsorption (TmCa) has therefore been calculated in 130 healthy young subjects and a normal range of 1.75-2.61 mmol/l of glomerular filtrate established. Owing to the dependence of urinary calcium on urinary sodium, TmCa was negatively related to sodium excretion. Because the latter was higher in the males than the females, mean TmCa was slightly (but not significantly) lower in our male than our female subjects. The normal range of TmCa, corrected to zero sodium excretion, is 1.98-2.76 mmol/l of glomerular filtrate. The TmCa was also calculated using plasma calcium values corrected for albumin concentration. The range of TmCa using both corrections is 1.98-2.71 mmol/l of glomerular filtrate.     

Peripheral and liver tissue oxygen tensions in hemorrhagic shock.

BACKGROUND AND METHODS: Hepatic dysfunction after severe hemorrhagic shock is common and may be a consequence of visceral tissue hypoxia. Peripheral tissue PO2 has been suggested to correlate with the development of visceral hypoxia. To test the hypothesis that changes in peripheral tissue PO2 reflect changes in hepatic PO2, we measured subcutaneous PO2, transcutaneous PO2, transconjunctival PO2, and liver tissue PO2, and their relationship with changes in mean arterial blood pressure (MAP) and systemic oxygen transport (DO2), during progressive bleeding in pigs (n = 23). In addition to the tissue PO2, portal vein PO2 and circulating lactate concentrations were also measured in six of the animals. The animals were anesthetized and bled to an MAP of 50 mm Hg within 1 hr. RESULTS: After an induced 10% reduction of MAP, only the DO2 decreased significantly (p less than .05). After a 20% reduction of MAP, the DO2 decreased further and was associated with a significant (p less than .05) reduction of all peripheral tissue PO2 values. A significant (p less than .05) reduction of liver tissue PO2 was observed later during bleeding, after induction of a 30% reduction in MAP. In the subgroup with portal venous PO2 and lactate measurements, reductions of all peripheral tissue PO2 and portal venous PO2 values occurred after a 20% reduction (p less than .05) of MAP. An increase (p less than .05) in the portal venous lactate concentration was observed after a 50% reduction of MAP, and a decrease (p less than .05) in liver tissue PO2 was noted after a 60% reduction of MAP. CONCLUSIONS: Reductions of both peripheral and portal venous PO2 values occur early during hemorrhage. The liver tissue PO2, though initially low, appears to be better defended, suggesting either redistribution of splanchnic blood flow or adaptation in hepatic oxygen demand.     

氯磷酸二钠表面改性羟基磷灰石血清蛋白吸附行为的改变

目的:观察二磷酸盐药物对羟基磷灰石进行表面改性后对材料表面蛋白吸附的影响。方法:实验于2005-06/08在口腔生物医学工程教育部重点实验室完成。①将羟基磷灰石制成10mm×10mm×2mm大小的块状,共48块,随机分为实验组与对照组,每组24块。②实验组羟基磷灰石与氯磷酸二钠复合制成氯磷酸二钠-羟基磷灰石,对照组不复合氯磷酸二钠,用乙醇和蒸馏水超声波清洁,干燥备用。③将两组标本分别置入100g/L小牛血清(蛋白吸附溶液)和0.2mol/LPBS磷酸缓冲液(对照吸附溶液)中浸泡吸附,每种溶液中12块。④通过X射线光电子能谱分析检测和蛋白质电泳对两组材料表面吸附的蛋白进行对比分析。结果:①X射线光电子能谱分析检测提示吸附小牛血清后,实验组和对照组表面氮元素百分含量分别是(9.83±1.33)%和(10.11±1.67)%,差异无显著性意义(P>0.01)。②十二烷基磺酸钠-聚丙烯酰胺凝胶电泳提示两组材料均可以吸附大量白蛋白,实验组表面吸附的白蛋白要少于对照组。③双向电泳提示两组材料表面吸附的蛋白相对分子质量均大于50000;对照组吸附的酸性蛋白量要多一些,实验组表面吸附的碱性蛋白和中性蛋白要多一些;偏酸性的蛋白中,β球蛋白和玻璃粘连蛋白在实验组表面吸附量较对照组表面多。结论:氯磷酸二钠复合羟基磷灰石对材料表面吸附蛋白的种类有一定影响,但对总量没有明显影响。     

国人全膝关节假体置换胫骨近端截骨面至腘血管距离的测量及意义

目的:测量国人全膝关节假体置换术胫骨近端截骨面后缘至腘窝血管之间的距离,以期为临床全膝关节置换术中避免损伤腘窝血管提供参考数据。方法:选择2006-06/12于解放军第二军医大学长征医院体检的50名正常成人(53膝),男29名(31膝),女21名(22膝)。所有观察对象均知情同意,且得到医院伦理道德委员会批准。对所有膝关节进行MRI扫描,在胫骨外侧平台以下10mm水平横断面上辨认腘动静脉,并测量胫骨近端截骨面后缘至腘窝动静脉的距离。结果:53膝全部进入结果分析,无脱落。①男性胫骨近端截骨面后缘至腘动脉、腘静脉平均距离为(6.7±2.5,7.3±2.3)mm,95%可信区间分别为5.8～7.6mm,6.5～8.1mm。②女性胫骨近端截骨面后缘至腘动脉、腘静脉平均距离为(6.6±1.9,7.1±2.7)mm,95%可信区间分别为:5.8～7.4mm,5.9～8.3mm。③不同性别观察对象胫骨近端截骨面后缘至腘血管的距离差异无显著性意义(P>0.05)。结论:腘窝血管紧邻全膝关节假体置换术胫骨近端截骨面后缘,不同性别间无明显差异。全膝关节假体置换术中进行胫骨近端截骨,特别是后方操作时需特别谨慎,以避免损伤腘窝血管。     

Clinical and biochemical effects during treatment of depression with nortriptyline: the role of 10-hydroxynortriptyline

Plasma concentrations of nortriptyline (NT) and its major metabolite 10-hydroxy-NT (10-OH-NT) were measured in 30 patients with depression, treated with NT for 3 weeks. Nine patients who recovered completely had plasma concentrations of NT and 10-OH-NT ranging from 358 to 728 nmol/L and from 428 to 688 nmol/L, respectively. Of the 21 patients who did not recover completely, only four had plasma concentrations within the window limited by these two plasma concentration ranges. A correlation was found between the degree of amelioration and the plasma concentration of NT (rs = 0.469; P less than 0.01). Lumbar punctures were performed in 26 patients before and after 3 weeks of NT treatment. During treatment there was a 30.9% mean decrease in the noradrenaline metabolite 4-hydroxy-3-methoxyphenylglycol (HMPG) in cerebrospinal fluid (CSF). We could not evaluate the extent to which this decrease was caused by NT or 10-OH-NT, respectively, because both are strong inhibitors of noradrenaline uptake. The ratio between the concentration of NT and 10-OH-NT in CSF correlated to the reduction of HMPG in CSF (r = 0.397; P less than 0.05) and to the amelioration of depression (rs = 0.623; P less than 0.001). This might indicate that NT and 10-OH-NT interact on the noradrenaline system in a nonadditive way. During treatment there was a 15.2% decrease in CSF concentration of the serotonin metabolite 5-hydroxyindoleacetic acid. The reduction was significantly correlated to the CSF concentration of NT but not to that of 10-OH-NT. This is in accordance with the fact that NT is a more potent inhibitor of serotonin uptake than is 10-OH-NT. The dopamine metabolite homovanillic acid in CSF decreased significantly by 10.0%. The biochemical data indicate that noradrenergic, serotoninergic, and dopaminergic systems are affected by NT treatment and that 10-OH-NT might be more selective on noradrenergic neurons than the parent drug.     

Electrophysiologic characteristics of single myocytes isolated from hypertrophied guinea-pig hearts

To determine whether the electrical changes associated with cardiac hypertrophy are due to alterations in the membrane properties of individual hypertrophied cells, we recorded action potentials in single myocytes isolated from normal and hypertrophied hearts. Cardiac hypertrophy was produced by a gradual pressure overload created by placing a band around the ascending aorta in young guinea-pigs (200-250 g). Almost half the animals that developed left ventricular (LHV) hypertrophy also developed evidence of cardiac dysfunction. Action potentials were recorded with standard microelectrodes in single ventricular myocytes isolated by enzymatic dispersion of the heart. The action potential duration at 1 Hz was significantly longer in hypertrophied cells than in control cells. The degree of action potential prolongation in isolated cells did not correlate with the degree of hypertrophy but did correlate with the degree of myocardial disease, the duration being longer in hypertrophied myocytes from dyspneic than in those from non-dyspneic animals. The resting potential was significantly lower in hypertrophied myocytes from dyspneic animals than in hypertrophied cells from non-dyspneic animals or control cells stimulated at 5 Hz. The relationship between the frequency of stimulation (0.33, 1, and 5 Hz) and action potential duration was steeper in hypertrophied than normal myocytes. The mean membrane capacitance (cm) of hypertrophied myocytes increased by 31% over the control value. Thus, isolated hypertrophied myocytes retain the prolonged duration of the action potential and the exaggerated dependence of duration on rate observed in intact hypertrophied muscle. The increased duration of the action potential in hypertrophied cells cannot be readily attributed to the observed increase in cm. Our results indicate that the membrane changes responsible for the altered electrical properties of hypertrophied myocardium are due to an effect of hypertrophy on individual myocytes and that the prolonged duration of the action potential is probably due to changes in active currents flowing during repolarization.     

(Re)framing school as a setting for promoting health and well-being: a double translation process

The aim of this paper is to discuss the ways in which the setting approach to health promotion in schools, as part of knowledge-based international policies and guidelines, is embedded in the Danish policy landscape and enacted at the local governance level. The study draws on the sociology of translation and treats policy implementation as a non-linear process of (re)interpretation involving different actors in plural, mutually interwoven, non-hierarchical networks. Data were generated and analysed using a three-tiered process: the first tier focused on key international guidelines, the second on national policies, and the third on policies in selected municipalities. Through these tiers, we discuss actors and actor networks involved in the translation processes, their interactions and the dynamics of problematisation at the national and local levels. The results point to two different, but entangled, processes of translation. At the national level, despite resistance by a number of actors with differing priorities, the translation resulted in the integration of selected key principles of the setting approach to health promotion in the national curriculum for health education. At the municipal level, however, the principles seem to be ‘lost in translation’, as the treatment of schools as settings for promoting health and well-being remains largely subordinate to the discourses of disease prevention and individual behaviour regulation, dominated by the agenda of actors in the health sector.