Spermicidal activity of chelated complexes of bis(cyclopentadienyl)vanadium(IV)

Transition metal complexes containing vanadium IV have been shown to modulate the cellular redox potential and catalyse the generation of reactive oxygen intermediates (ROI). Since sperm function is exquisitely susceptible to ROI, we examined the effects of stable chelate complexes of vanadocenes on human sperm motility. We synthesized seven structurally distinct chelate complexes of bis(cyclopentadienyl)vanadium(IV) with bidentate ligands [i.e. vanadocene acetylacetonato monotriflate (VDacac), vanadocene hexafluoro acetylacetonato monotriflate (VDHfacac), vanadocene N-phenyl benzohydroxamato monotriflate (VDPH), vanadocene acethydroxamato monotriflate (VDH), vanadocene catecholate (VDCAT), vanadocene bipyridino ditriflate (VDBPY), and vanadocene dithiocarbamate monotriflate (VDDTC)], and evaluated their spermicidal activity using computer-assisted sperm analysis (CASA; Hamilton-Thorne). All seven chelate complexes of vanadocene elicited potent spermicidal activity at micromolar concentrations (EC50 values: 3.9-106 microM) without affecting the sperm acrosome integrity. The catecholate and acetylacetonate complexes of vanadocene were the most active and the bipyridyl complex the least active with an order of efficacy VDCAT > VDacac > VDDTC > VDPH > VDH > VDHfacac > VDBPY. The spermicidal activity of chelate complexes of vanadocenes was rapid and irreversible since the treated spermatozoa underwent apoptosis, as determined by the flow cytometric analysis of mitochondrial membrane potential, surface annexin V binding assay, in-situ nick-end labelling of sperm nuclei, and confocal laser scanning microscopy. These results provide unprecedented evidence that chelate complexes of vanadocene with bidentate ligands have spermicidal and apoptosis inducing properties. These vanadocene complexes, especially VDacac, may be useful as contraceptive agents.      

5种解热镇痛药的胶束电动毛细管色谱分离研究

报告了5种解热镇痛药——安替比林、4-氨基安替比林、安基比林、安乃近和保泰松的胶束电动毛细管色谱分离、紫外吸收检测法。研究了pH值、有机改性剂(甲醇)和十二烷基硫酸钠(SDS)浓度对分离的影响。在40mmol·L^-1SDS—25mmol·L^-1硼砂—15%甲醇(pH10.5)电泳介质中电泳,上述5组分可达基线分离。迁移时间批内和批间的RSD值分别小于1.3%和2.1%(n=5)。分离的理论塔板数在1.83×10⁴～4.15×10⁴之间。     

Active vs. passive resistance, dose-response relationships, high dose chemotherapy, and resistance modulation: a hypothesis

Summary With chemotherapy, the in vitro and clinical dose-response curve is steep in some situations, but is relatively flat in others, possibly due to the mechanism by which tumors are resistant to chemotherapy. For tumors with resistance due to factors that actively decrease chemotherapy efficacy (e.g., p-glycoprotein, glutathione, etc.), one would predict that high dose chemotherapy and therapy with some resistance modulating agents would increase therapeutic efficacy. Such active resistance would most likely generally arise from gene amplification or over expression, and would be characterized by a shoulder on the log response vs. dose curve, with eventual saturation of the protective mechanism. On the other hand, one would expect that high dose chemotherapy and most resistance modulating agents would be of little value for rumors with resistance due to defective apoptosis or due to a deficiency in or decreased drug affinity for a drug target, drug activating enzyme, drug active uptake system, or essential cofactor. Such passive resistance would most likely generally arise from gene down regulation, deletion, or mutation, and would probably be characterized by a relatively flat log response vs. dose curve, or by a curve in which a steep initial section is followed by a plateau, as target, etc., is saturated. (If response were plotted vs. log dose, then compared to the curve for a sensitive cell line, the curve for active resistance would be analogous to the pharmacodynamic curve seen with competitive antagonism [i.e., a sigmoid curve shifted to the right], and the curve for most types of passive resistance would be analogous to the pharmacodynamic curve seen with noncompetitive antagonism [i.e., a sigmoid curve with reduced maximal efficacy]. As such, one might also refer to active vs. passive resistance as competitive vs. noncompetitive resistance, respectively.) Many tumor types probably possess a combination of active and passive mechanisms of resistance. New in vivo strategies could be helpful in defining dose-response relationships, mechanisms of resistance, and targets for resistance modulation. Such in vivo studies would be conducted initially in animals, but might also be tested clinically if animal studies demonstrated them to be feasible and useful. These in vivo studies would be conducted by randomizing 5–25 subjects to one of 10–20 dose levels over a potentially useful therapeutic range. Nonlinear regression analysis would then be used to define the characteristics of a curve generated by plotting against dose the log percent tumor remaining after the first course of therapy. While this might offer insight into the nature of resistance mechanisms present initially, plotting further tumor shrinkage vs. dose-intensity vs. course number for each later treatment course (or plotting dose-intensity vs. time to tumor progression) might provide information on how tumors become increasingly resistant to drugs following treatment.     

Adaptive response and its variation in human normal and tumour cells.

PURPOSE: Adaptive responses in mammalian cells appear to be highly variable. Six human cell lines were used to evaluate whether adaptive response could be related to radiation sensitivity or tumour versus normal cell lines. MATERIALS AND METHODS: Six human cell lines (two fibroblasts, two melanoma, two breast carcinoma) were cultured under identical conditions to plateau phase. The cells were given inducing doses of 0, 0.2, 0.5, 1.0, 2.0 and 4.0 Gy followed after incubation at 37 degrees C by challenge doses to assess radiation response. RESULTS: An adaptive response (AR) was observed in some but not all the cell lines. The AR was observed at 2 h and persisted for up to 24 h. It was observed for doses as low as 0.2 and 0.5 Gy and declined with higher doses. In the resistant melanoma cell line there was no adaptive response; instead it showed sensitization for all inducing doses. CONCLUSIONS: Human cells can demonstrate an adaptive response. This response is variable among cell lines and appears not to be related to radiosensitivity nor differences between tumour and normal cell lines.     

T cell expansions in lymph nodes and peripheral blood in HIV-1-infected individuals: effect of antiretroviral therapy.

OBJECTIVE: To evaluate dynamics in CD8 T cell expansions during highly active antiretroviral therapy (HAART). DESIGN: Various T cell subsets were isolated from blood and lymph nodes and analysed for T cell receptor (TCR) diversity. METHODS: TCR complementarity determining region 3 (CDR3) spectratyping and single-strand conformation polymorphism (SSCP) analyses were performed in combination with sequencing to assess clonality of the subsets. RESULTS: Strongly skewed CDR3 patterns in total CD8 cells and the CD8 subsets CD45RO+CD27+ and CD45RO-CD27+ showed substantial dynamics in dominant CDR3 sizes, resulting in relative improvement of CDR3 size diversity in the first months of therapy. During sustained treatment, TCR diversity changed only moderately. SSCP profiles confirmed oligoclonality of TCR CDR3 perturbations. Various dominant CDR3 sizes for CD4 and CD8 T cells present in lymph nodes, but not in peripheral blood mononuclear cells, before the start of therapy emerged in peripheral blood early during therapy. CONCLUSIONS: HAART induces substantial changes in CD8 TCR diversity, eventually resulting in improvement of the repertoire. Clonal expansions observed in lymph nodes before therapy were observed in peripheral blood after therapy, suggesting that recirculation of CD4 and CD8 T cells from lymph nodes contributes to the early T cell repopulation. Decreased immune activation and possibly naive T cell regeneration subsequently decreased clonal expansions and perturbations in the CD8 TCR repertoire.     

Doctor-patient communication with people with intellectual disability - a qualitative study

Background

Patients' priorities and views on quality care are well-documented in Western countries but there is a dearth of research in this area in the East. The aim of the present study was to explore Chinese patients' views on quality of primary care consultations in Hong Kong and to compare these with the items in the CARE measure (a process measure of consultation quality widely used in the UK) in order to assess the potential utility of the CARE measure in a Chinese population.

Methods

Individual semi-structured interviews were conducted on 21 adult patients from 3 different primary care clinics (a public primary healthcare clinic, a University health centre, and a private family physician's clinic). Topics discussed included expectations, experiences, and views about quality of medical consultations. Interviews were typed verbatim, and a thematic approach was taken to identify key issues. These identified issues were then compared with the ten CARE measure items, using a CARE framework: Connecting (Care Measure items 1–3), Assessing (item 4), Responding (items 5,6), and Empowering (items 7–10).

Results

Patients judged doctors in terms of both the process of the consultation and the perceived outcomes. Themes identified that related to the interpersonal process of the consultation fitted well under the CARE framework; Connecting and communicating (18/21 patients), Assessing holistically (10/21 patients), Responding (18/21 patients) and Empowering (19/21 patients). Patients from the public clinic, who were generally of lower socio-economic status, were least likely to expect holistic care or empowerment. Two-thirds of patients also judged doctors on whether they performed an adequate physical examination, and three-quarters on the later outcomes of consultation (in terms of relief or cure and/or side-effects of prescribed drugs).

Conclusion

These findings suggest that Chinese patients in Hong Kong value engaged, empathic primary care doctors and judge the quality of consultations largely on these human skills and the attitudes and values that underpin them, as well as on the perceived outcomes of treatment. The match between themes relating to consultation process and the CARE Measure items suggests utility of this measure in this population, but further quantitative validation is required.     

倾斜试验中真假阳性的血流动力学和神经激素的研究

目的探讨血管迷走性晕厥患者和正常人倾斜试验阳性时不同的触发机制.方法倾斜试验采用静息平卧10min和80°直立30min.心脏监测仪连续监测心率和血压.试验阳性标准为晕厥先兆伴收缩压＜90imHg(1mmHg=O.133kPa)和(或)心率＜60次/min.超声心动图于基础平卧,直立2min和每隔3min直至试验结束时连续记录左室内径及降低速率,左室短轴缩短分数(SF)和每分心输出量(CO).同时测量平卧和直立时儿茶酚胺血浆浓度.试验分组为正常自愿者且倾斜试验阴性者8例(组1),平均年龄(34±5)岁;正常自愿者伴倾斜试验阳性者8例(组2),平均年龄(31±6)岁;原因不明晕厥伴倾斜试验阳性者16例(组3),平均年龄(30±9)岁.结果三组间年龄、性别以及基础状态下心率,平均动脉压、左室内径、SF、CO和儿茶酚胺血浆浓度无明显差异.直立时各组发生改变为(1)组3出现阳性反应时间明显短于组2[(10±4)min比(17±8)min,P＜0.05];(2)组3平均动脉压有即刻和持续性降低;(3)组3左室舒张末期内径降低速率明显大于其他两组;(4)SF在组3显著增强;(5)肾上腺素浓度在组3升高显著,试验终止时组1为(65±35)pg/ml,组2为(78±29)pg/ml,组3为(126±80)pg/ml(P均＜0.05);去甲肾上腺素在三组均增高但组间比较差异无显著性.结论血管迷走性晕厥患者和部分正常人倾斜试验虽均呈阳性反应,但血流动力学反应和触发机制不同.前者可能与外周血管张力异常,回心血量及左室容量聚降,肾上腺素分泌增多,促使左室收缩力增强触发Bezold-Jarisch神经反射有关;而后者在发生假阳性反应时,其左室内径和SF及肾上腺素血浆浓度与阴性组无明显不同.倾斜试验时血管迷走性晕厥患者肾上腺素分泌异常在血管舒缩反应损害和左室收缩力异常方面可能起恶化作用.