Prevention of chronic diseases: a call to action

Chronic (non-communicable) diseases—principally cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes—are leading causes of death and disability but are surprisingly neglected elements of the global-health agenda. They are underappreciated as development issues and underestimated as diseases with profound economic effects. Achievement of the global goal for prevention and control of chronic diseases would avert 36 million deaths by 2015 and would have major economic benefits. The main challenge for achievement of the global goal is to show that it can be reached in a cost-effective manner with existing interventions. This series of papers in The Lancet provides evidence that this goal is not only possible but also realistic with a small set of interventions directed towards whole populations and individuals who are at high risk. The total yearly cost of the interventions in 23 low-income and middle-income countries is about US$5·8 billion (as of 2005). In this final paper in the Series we call for a serious and sustained worldwide effort to prevent and control chronic diseases in the context of a general strengthening of health systems. Urgent action is needed by WHO, the World Bank, regional banks and development agencies, foundations, national governments, civil society, non-governmental organisations, the private sector including the pharmaceutical industry, and academics. We have established the Chronic Disease Action Group to encourage, support, and monitor action on the implementation of evidence-based efforts to promote global, regional, and national action to prevent and control chronic diseases.     

Wallerian degeneration in a patient with Schilder disease: MR imaging demonstration

Wallerian degeneration in the corticospinal tract was demonstrated by magnetic resonance (MR) imaging in a patient with Schilder disease. The histochemical stages of myelin breakdown that allow its demonstration by MR imaging are reviewed.     

用细口径反相柱HPLC分离多种前列腺素

HPLC与放射性同位素联用,可同时分离鉴定多种花生四烯酸代谢产物。目前国外一般是使用普通口径(4.6 mm)的反相柱,以30%左右乙腈为流动相,流速为1～3 ml/min。这种HPLC方法乙腈用量较大,费用太贵,不适合国内实验室常规操作。据报道,细口径     

Childhood scoliosis: MR imaging

The spinal cords of 28 scoliosis patients between the ages of 1 month and 17 years were examined with magnetic resonance (MR) imaging. Complete visualization was obtained in all cases. In 15 patients (53%) neuropathologic abnormalities demonstrated by MR imaging significantly affected their clinical course, including tethered cords (n = 7), syringomyelia (n = 5), Arnold-Chiari I malformation (n = 4), spinal cord tumors (n = 2), Arnold-Chiari II malformation (n = 3), and diastematomyelia (n = 1). The advantages of MR imaging in the evaluation of the scoliotic spine in children include a high sensitivity for the occult conditions associated with scoliosis, good anatomic demonstration of the cord, and absence of bone artifacts. MR imaging is recommended as a primary imaging modality in scoliosis, following conventional radiography.     

Monoclonal antibody to human high-molecular-weight kininogen recognizes its prekallikrein binding site and inhibits its coagulant activity

We developed a mouse monoclonal antibody (MoAb 115-21) to human high- molecular-weight kininogen (HK) that recognizes its prekallikrein binding site (residues 565 through 595 of HK). The corresponding synthesized 31-amino acid peptide (peptide IV) was recently shown to retain native HK's prekallikrein binding property. The same peptide bound factor XI also, although less avidly. Our MoAb recognizes purified HK, peptide IV, and the light chain moiety of HK (where the peptide IV resides), as shown by enzyme-linked immunosorbent assay (ELISA) and Western blotting experiments. The apparent dissociation constant for the HK and MoAb 115-21 interaction was 2.2 nmol/L. It does not recognize low-molecular-weight kininogen (LK) with which HK shares its heavy chain moiety or any antigens in human plasma congenitally deficient in kininogens. The binding of MoAb 115-21 to purified light chain of HK was competitively inhibited by peptide IV. In addition, the antibody inhibits HK-dependent clotting activity of normal human plasma and dextran sulfate-mediated activation of prekallikrein in plasma and retards cleavage of HK in normal plasma after contact activation with dextran sulfate. Also, purified Fab fragments of MoAb 115-21 inhibited the HK-dependent coagulant activity and dextran sulfate-mediated prekallikrein activation in normal plasma. Since the kd for HK-MoAb 115- 21 interaction is ten times lower than that of HK-prekallikrein, our data suggest that binding of MoAb 115-21 to HK's peptide IV site increases the free prekallikrein concentration in plasma and thus results in the decreased efficiency of factor XIIa-mediated activation of prekallikrein. Decreased levels of kallikrein thus formed may be responsible for the inhibition of HK-dependent clotting activity and the decrease in rate and extent of HK cleavage in normal plasma on contact activation with dextran sulfate. MoAb 115-21 may thus prove very useful, especially with its high affinity for HK, in further delineation of the role of HK and prekallikrein in contact activation and kinin-related human pathology.     

Concordance between tramadol and dextromethorphan parent/metabolite ratios: the influence of CYP2D6 and non-CYP2D6 pathways on biotransformation.

Cytochrome P4502D6 (CYP2D6) activity has been shown to be a determinant of both the pharmacokinetics and pharmacodynamics of tramadol in adults. This study evaluated the association between CYP2D6 activity, as determined by dextromethorphan (DM) urinary metabolite ratio, and tramadol biotransformation in 13 children (7-16 years). CYP2D6 genotype was determined by XL-PCR and PCR/RFLP. Phenotype was assessed by HPLC quantitation of DM and its metabolites from a 12- to 24-hour urine collection following a single oral dose of DM. There was only a modest correlation between tramadol/M1 (metabolite 1) plasma concentration or AUC and the DM/dextrorphan (DX) urinary molar ratio in the study cohort; however, when subjects were segregated based on the number of functional CYP2D6 alleles, a much stronger relationship was observed for subjects with two functional alleles, with essentially no relationship evident in those individuals with one functional allele. Further evaluation of these data suggested that the CYP2D6-mediated metabolite (M1) is formed to a lesser extent, and the formation of the non-CYP2D6 product (M2) is more pronounced in subjects with one versus two functional alleles. Thus, the number of functional CYP2D6 alleles and the availability of alternative cytochromes P450 capable of metabolizing tramadol may explain the poor association between DM, a well-characterized CYP2D6 probe, and tramadol in a population of CYP2D6 extensive metabolizers.     

Cellular toxicity of sulfamethoxazole reactive metabolites--I. Inhibition of intracellular esterase activity prior to cell death

Reactive metabolites produced by oxidative metabolism of the parent compound are considered responsible for the toxicity of a number of drugs, including idiosyncratic reactions to sulfonamide antibiotics. Using sulfamethoxazole hydroxylamine (SMX-HA) as a model compound, we report the use of a pH-sensitive fluorescent probe, 2',7'-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF), to identify early subcellular targets of chemically synthesized, toxic drug metabolites in peripheral blood mononuclear cells. When toxicity was assessed with this probe immediately after a 2-hr drug challenge, SMX-HA produced a concentration-dependent decrease in cellular fluorescence which was not accompanied by the development of compromised cell membrane integrity until 18 hr later. Dissipation of pH gradients across the cell membrane with nigericin and monensin demonstrated that decreased intracellular pH was only a small component of SMX-HA-induced toxicity. Loading cells with BCECF 30 min prior to SMX-HA challenge produced only a 3% decrease in cellular fluorescence at an SMX-HA concentration of 1 mM, whereas addition of BCECF after drug challenge resulted in a 71% decrease in fluorescence, consistent with a direct drug effect on cellular esterase activity. This was confirmed by monitoring BCECF cleavage in cell lysates in the presence and absence of SMX-HA. These studies demonstrate that inhibition of cellular esterase activity accounted for the observed loss of cellular fluorescence after drug exposure. Since changes in cellular fluorescence at 2 hr correlated well with cell death at 18 hr, we conclude that SMX-HA inhibition of intracellular esterase activity is an early event in the process that terminates in metabolite-induced cell death.     

力竭运动大鼠心室肌蛋白质组表达特征

目的:采用蛋白质组学技术,建立安静和递增运动负荷训练后力竭大鼠心室肌蛋白质组的差异性表达谱,初步筛选出心室肌对力竭运动产生反应的目标蛋白质。方法:实验于2007-03在湖南师范大学生命科学学院蛋白质化学与蛋白质组学国家教育部重点实验室和省级运动人体科学实验室完成。①实验分组:10只SD雄性大鼠随机分为对照组和运动组,每组5只。②实验方法:运动组经过7周的大强度递增运动负荷训练后(最后一次力竭),对两组心室肌组织的全蛋白进行双向凝胶电泳分离。结果:经图像分析,在运动组的电泳图谱上共展现蛋白质点(338±17)个,对照组展现蛋白质点(352±17)个。运动后差异表达的蛋白质点共有99个。对其中差异表达的9个蛋白质点进行质谱鉴定,共鉴定出7个蛋白质,Stress-70protein,NADH-ubiquinone oxidoreductase Mr75000subnunit,Long-chain specific acyl-CoA dehydrogenase,Tropomyosin-1alphachain在运动后"缺失",Nitrilase family,member2在运动后表达上调在5倍以上,一个相对分子质量为21000的未知蛋白在运动后表达下调在5倍以上,另外有两个点经鉴定均为Myosin-6,在运动后表达量相反。这些蛋白质属于收缩蛋白、能量代谢酶、分子伴侣等。结论:递增运动负荷训练后力竭时,大鼠心室肌蛋白质组明显地发生了反应。运动后"缺失"和下调的蛋白质点与心肌收缩的调控和能量代谢的方式转变以及细胞的应激反应有关,其中,成功筛选出6种在运动医学领域尚未涉足的、具有运动应激特点的目标蛋白质。