The Role of Parasympathetic Modulation of the Reentrant Arrhythmic Substrate in the Genesis of Sustained Ventricular Tachycardia

The influence of parasympathetic activity on the reentrant arrhythmic substrate in the genesis of sustained ventricular tachycardia remains unclear. To assess this influence, we studied the heart rate variability in 59 patients referred for invasive electrophysiological testing. In addition, the presence of late potentials and high grade ventricular ectopy, and the left ventricular ejection fraction was determined. The 28 patients with inducible sustained ventricular tachycardia were found to have lower heart rate variability by time- and frequency-domain measurements over 24 hours when compared to the 31 subjects who were noninducible. PNN50 was 4% in the inducible patients, whereas it was 9% in the subjects who were noninducible (P = 0.03). Similarly, HFP24H was 9 and 14 msec, respectively (P = 0.02). MAXHFP1H also differed (20 vs 27 msec [P = 0.04]) but not MINHFP1H (5 vs 6 msec). There was no association between heart rate variability and late potentials, degree of ventricular ectopy, or left ventricular ejection fraction. Thus, vagal tone does not appear to correlate with the presence of late potentials, ventricular ectopy, or left ventricular dysfunction. Low mean as well as maximal vagal tone, in contrast to minimal vagal tone, predicts inducibility of sustained ventricular tachycardia. Our data suggest that the inability to modulate parasympathetic tone appears to be an important determinant in the genesis of reentrant sustained ventricular tachycardia.     

Chemotherapy for advanced (stage IIIB and stage IV) non-small cell lung cancer: The Hong Kong perspective

Abstract Non-small cell lung cancer (NSCLC) accounts for about 80% of all primary lung cancers, and 60% of cases present as advanced stages IIIB and IV disease. Traditionally, treatment of stages IIIB and IV disease was only symptomatic (including radiotherapy) and supportive care, and cytotoxic chemotherapy was relatively ineffective. Our initial clinical trials, using MACC, FuAM, FAM, Hi-FAM and cisplatin-VP16, gave response rates of 5–20% and a stabilization rate of 7–25%, with no impact on median survival. Our most recent chemotherapy regimen MIP (mitomycin-C, ifosfamide and cisplatin) proved to be more effective with a 44% response rate and a 28% stabilzation rate, and produced a significantly longer median survival (32 weeks) than best supportive care alone (19.5 weeks, P < 0.05). The response rate further increased to 62.5% with dose intensification and GM-CSF support. Chemotherapy can now be recommended to motivated, well-informed patients with good performance status in institutions with experience in cancer chemotherapy on a protocol basis. The most recent addition of new effective cytotoxic agents such as paclitaxel, docetaxel, gemitabine and vinorelbine gave promising results in NSCLC, and optimal combinations and dose schedules are being defined by multicentred studies.     

Changes in cytokine secretion patterns of CD4+ T-cell clones in human immunodeficiency virus infection

In addition to the loss of CD4+ T cells in later stages of human immunodeficiency virus (HIV) infection, functional defects of Th cells can already be observed in early infection. Decreased interleukin (IL)- 2 and interferon (IFN)-gamma production by CD4+ T cells and diminished delayed type hypersensitivity reactions are indicative for impaired Th1 responses. We studied the cytokine secretion patterns of T-cell clones (TCC) generated by mitogenic stimulation of CD4+ memory T cells. Compared with TCC from HIV-negative controls, TCC isolated from HIV- infected individuals consistently showed increased IL-4 production, often paralleled by increased IL-5 and decreased IFN-gamma production. This resulted in a decreased percentage of Th1 clones with an increase in Th0 clones. To rule out the influence of interindividual differences, we studied two individuals from whom cells were available before and after infection with HIV. Indeed, an increase in Th2 cytokine secretion was observed after HIV-infection. Loss of Th1 and enhanced Th2 responses might further curtail cellular responses resulting in deficiency of cellular immunity in HIV infection.     

Structure-activity relationship of uridine 5'-diphosphoglucose analogues as agonists of the human P2Y14 receptor

UDP-glucose (UDPG) and derivatives are naturally occurring agonists of the Gi protein-coupled P2Y14 receptor, which occurs in the immune system. We synthesized and characterized pharmacologically novel analogues of UDPG modified on the nucleobase, ribose, and glucose moieties, as the basis for designing novel ligands in conjunction with modeling. The recombinant human P2Y14 receptor expressed in COS-7 cells was coupled to phospholipase C through an engineered Galpha-q/i protein. Most modifications of the uracil or ribose moieties abolished activity; this is among the least permissive P2Y receptors. However, a 2-thiouracil modification in 15 (EC50 49 +/- 2 nM) enhanced the potency of UDPG (but not UDP-glucuronic acid) by 7-fold. 4-Thio analogue 13 was equipotent to UDPG, but S-alkylation was detrimental. Compound 15 was docked in a rhodposin-based receptor homology model, which correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol. The hexose moiety of UDPG interacts with multiple H-bonding and charged residues and provides a fertile region for agonist modification.     

Induction of TrkA expression by differentiation inducers in human myeloid leukemia KG-1 cells

We have recently reported that retinoic acid (RA) induced the expression of trkA, the high affinity receptor for nerve growth factor (NGF), in human myeloid leukemia KG-1 cells. In the present study, we report that the expression of trkA was also induced by several other differentiation inducers, including 1alpha, 25-dihydroxyvitamin D3 (Vit D3), 1-beta-D-arabinofuranosyl cytosine (Ara-C), sodium butyrate (NaBut), and phorbol 12-myristate 13-acetate (PMA). Interestingly, RA in combination with NaBut or PMA synergistically induced cellular differentiation as well as the expression of trkA in KG-1 cells. Furthermore, activation of the induced trkA receptor by exogenous NGF potentiated the differentiating effects of RA and NaBut. Our results demonstrated that the induction of trkA is an event associated with the differentiation of KG-1 cells. Our findings suggest that NGF, in addition to its pivotal roles in the nervous system, may also play important roles in hematopoietic differentiation.     

Workforce Competencies in Behavioral Health: An Overview

Competency-based training approaches are being used more in healthcare to guide curriculum content and ensure accountability and outcomes in the educational process. This article provides an overview of the state of competency development in the field of behavioral health. Specifically, it identifies the groups and organizations that have conducted and supported this work, summarizes their progress in defining and assessing competencies, and discusses both the obstacles and future directions for such initiatives. A major purpose of this article is to provide a compendium of current competency efforts so that these might inform and enhance ongoing competency development in the varied behavioral health disciplines and specialties. These varied resources may also be useful in identifying the core competencies that are common to the multiple disciplines and specialties. This work was supported in part by Contract No. 03M00013801D from the Substance Abuse and Mental Health Services Administration.     

海带颗粒去除水中汞、镉、铅的实验研究

[目的 ]探讨汞 (Hg)、镉 (Cd)和铅 (Pb)离子在海带颗粒上的静态吸附平衡和填充柱动态吸附特性。 [方法 ]市售干海带经磨碎、筛分 ,选取 3 0～ 60目的颗粒 ,经 1%HNO3 和 1mol/LCaCl2 浸洗。用静态平衡法测定二价Hg、Cd和Pb离子在海带上的富集平衡。将动态数学模型模拟的海带颗粒填充柱流出液浓度响应曲线与实验测定值进行比较 ,得出填充柱颗粒间弥散系数和颗粒内扩散系数。 [结果 ]这 3种重金属在海带颗粒上单组分的富集量与水相浓度的依赖关系可用Langmuir方程描述 ,回归得到的 3种重金属单组分饱和富集量为 0 .2 47、0 .173和 1.2 2 0mmol/g ,颗粒内扩散系数为 1.61× 10 -7、1.0 4× 10 -7和 9.89× 10 -7cm2 /s。 [结论 ]经较高浓度钙离子预处理的海带颗粒对这 3种重金属有很强的富集能力 ,回归得到的Hg、Cd、Pb离子在海带颗粒内的扩散系数远较理论估算的主体电解质溶液中的扩散系数为小 ,反映了颗粒内扩散通道的复杂结构对离子扩散的阻碍作用     

Pulmonary hydatid disease mimicking sequestration: Differentiation on magnetic resonance imaging

A case of hydatid disease of the lung proven by thoracotomy and histopathological evaluation is described. It was clinically and radiologically suggestive of a complicated pulmonary sequestration or non-resolving consolidation.     

Presence and consequence of uracil in preneoplastic DNA from folate/methyl-deficient rats

Uracil can arise in DNA by misincorporation of dUTP into nascent DNA and/or by cytosine deamination in established DNA. Based on recent findings, both pathways appear to be promoted in the methyl-deficient model of hepatocarcinogenesis. A chronic increase in the ratio dUTP:dTTP with folate/methyl deficiency can result in a futile cycle of excision and reiterative uracil misincorporation leading to premutagenic apyrimidinic (AP) sites, DNA strand breaks, DNA fragmentation and apoptotic cell death. The progressive accumulation of unmethylated cytosines with chronic methyl deficiency will increase the potential for cytosine deamination to uracil and further stress uracil mismatch repair mechanisms. Uracil is removed by a highly specific uracil-DNA glycosylase (UDG) leaving an AP site that is subsequently repaired by sequential action of AP endonuclease, 5'-phosphodiesterase, a DNA polymerase and DNA ligase. Since the DNA polymerases cannot distinguish between dUTP and dTTP, an increase in dUTP:dTTP ratio will promote uracil misincorporation during both DNA replication and repair synthesis. The misincorporation of uracil for thymine (5-methyluracil) may constitute a genetically significant form of DNA hypomethylation distinct from cytosine hypomethylation. In the present study a significant increase in the level of uracil in liver DNA as early as 3 weeks after initiation of folate/methyl deficiency was accompanied by parallel increases in DNA strand breaks, AP sites and increased levels of AP endonuclease mRNA. In addition, uracil was also detected within the p53 gene sequence using UDG PCR techniques. Increased levels of uracil in DNA implies that the capacity for uracil base excision repair is exceeded with chronic folate/methyl deficiency. It is possible that enzyme-induced extrahelical bases, AP sites and DNA strand breaks interact to negatively affect the stability of the DNA helix and stress the structural limits of permissible uracil base excision repair activity. Thus substitution of uracil for thymine induces repair- related premutagenic lesions and a novel form of DNA hypomethylation that may relate to tumor promotion in the methyl-deficient model of hepatocarcinogenesis.