Combined hyperlipidemia in transgenic mice overexpressing human apolipoprotein Cl

We have generated transgenic mice over-expressing human apolipoprotein CI (apo CI) using the native gene joined to the downstream 154-bp liver-specific enhancer that we defined for apo E. Human apo CI (HuCI)-transgenic mice showed elevation of plasma triglycerides (mg/dl) compared to controls in both the fasted (211 +/- 81 vs 123 +/- 52, P = 0.0001) and fed (265 +/- 105 vs 146 +/- 68, P < 0.0001) states. Unlike the human apo CII (HuCII)- and apo CIII (HuCIII)-transgenic mouse models of hypertriglyceridemia, plasma cholesterol was disproportionately elevated (95 +/- 23 vs 73 +/- 23, P = 0.002, fasted and 90 +/- 24 vs 61 +/- 14, P < 0.0001, fed). Lipoprotein fractionation showed increased VLDL and IDL + LDL with an increased cholesterol/triglyceride ratio (0.114 vs 0.065, P = 0.02, in VLDL). The VLDL apo E/apo B ratio was decreased 3.4-fold (P = 0.05) and apo CII and apo CIII decreased in proportion to apo E. Triglyceride and apo B production rates were normal, but clearance rates of VLDL triglycerides and postlipolysis lipoprotein "remnants" were significantly slowed. Plasma apo B was significantly elevated. Unlike HuCII- and HuCIII-transgenic mice, VLDL from HuCI transgenic mice bound heparin-Sepharose, a model for cell-surface glycosaminoglycans, normally. In summary, apo CI overexpression is associated with decreased particulate uptake of apo B-containing lipoproteins, leading to increased levels of several potentially atherogenic species, including cholesterol-enriched VLDL, IDL, and LDL.     

InGaAs PIN光电探测器的暗电流特性研究

从理论上分析了In0.53Ga0.47As PIN光电探测器在不同掺杂浓度及反向偏压下的暗电流特性,并与研制的器件的实测结果进行了比较和讨论.模拟结果表明:在低偏压下,器件中的产生复合电流起主要作用,偏压增大时,隧道电流起主要作用,且In0.53Ga0.47As光吸收层的载流子浓度对器件的暗电流有很大的影响,实测器件特性与模拟结果完全符合.文中还对器件结面积和电极尺寸等对暗电流的影响进行了比较和分析.     

Preservation of protein fluorescence in embedded human dendritic cells for targeted 3D light and electron microscopy

In this study, we present a correlative microscopy workflow to combine detailed 3D fluorescence light microscopy data with ultrastructural information gained by 3D focused ion beam assisted scanning electron microscopy. The workflow is based on an optimized high pressure freezing/freeze substitution protocol that preserves good ultrastructural detail along with retaining the fluorescence signal in the resin embedded specimens. Consequently, cellular structures of interest can readily be identified and imaged by state of the art 3D confocal fluorescence microscopy and are precisely referenced with respect to an imprinted coordinate system on the surface of the resin block. This allows precise guidance of the focused ion beam assisted scanning electron microscopy and limits the volume to be imaged to the structure of interest. This, in turn, minimizes the total acquisition time necessary to conduct the time consuming ultrastructural scanning electron microscope imaging while eliminating the risk to miss parts of the target structure. We illustrate the value of this workflow for targeting virus compartments, which are formed in HIV‐pulsed mature human dendritic cells.     

Short-term hemodynamic effects of mibefradil in dogs with chronic heart failure: comparison with diltiazem

Despite the marked vasodilator and antiischemic actions of existing calcium channel blockers, their use in the treatment of patients with chronic heart failure (HF) remains highly controversial. We compared the short-term hemodynamic effects of i.v. mibefradil, a predominant T-type calcium channel blocker with only partial L-type calcium channel antagonism, and diltiazem, a selective L-type calcium channel antagonist in dogs with chronic HF. Each of three drugs namely, mibefradil, diltiazem and normal saline (as placebo control), were studied in random order (6 days between each drug intervention), in each of 8 dogs with chronic HF produced by multiple intracoronary microembolizations. Intravenous mibefradil and diltiazem were administered as a 100 micrograms/kg bolus followed by a continuous infusion of 6 and 4 micrograms/kg/min, respectively, for 15 min. Equal volumes of normal saline were administered in an identical fashion. In all instances, hemodynamics were obtained at base line and at 5, 10, 15, 30 and 60 min after bolus drug administration. Left ventriculograms were obtained at baseline, and at 15 and 60 min after bolus drug administration. Saline infusion had no effects on hemodynamic or angiographic indexes of left ventricular (LV) function. At 15 min, mibefradil caused significant increases of LV stroke volume and LV ejection fraction compared to baseline (40 +/- 5 vs. 31 +/- 3 ml, P < .05 and 41 +/- 1 vs. 28 +/- 1%, P < .05, respectively). In contrast, at 15 min, diltiazem produced no significant changes of LV stroke volume or ejection fraction compared to baseline despite reducing mean aortic pressure to the same extent as mibefradil. Short-term i.v. mibefradil improves LV function in dogs with chronic HF. The beneficial effects of mibefradil compared to diltiazem may be a consequence of T-type calcium channel selectivity resulting in a vasodilatory response that is free of negative inotropy.     

Effect of 5-hydroxytryptamine on the peripheral chemoreceptors in the rat

5-Hydroxytryptamine (5-HT), in the doses of 2-5 mug/kg injected into the carotid body area, produced a significant increase in the respiratory rate and carotid sinus nerve activity. Selective ablation of the ipsilateral carotid sinus nerve abolished the respiratory stimulation produced by the drug. On the other hand, the same doses of 5-HT injected into the ascending aorta did not produce stimulation of respiration when the carotid sinus nerves were sectioned. The activity of the aortic nerves did not increase after injecting the drug into the ascending aorta or at the root of the right subclavian artery. These results indicate that 5-HT stimulates the chemoreceptors in the carotid body of the rat. The lack of responses to the injections of the drug in the aortic or subclavian region was due to the absence of chemoreceptors in these regions of the rat.     

Severe gastrointestinal hemorrhage due to Mycobacterium avium complex in a patient receiving immunosuppressive therapy

Intense immunosuppressive therapy is used frequently for treatment of systemic vasculitides, collagenoses, rapidly progressive glomerulonephritis, and after organ transplantation. Numerous serious treatment-related side effects include localized or disseminated opportunistic infections, and require careful monitoring of immunosuppressed patients. Gastrointestinal infections with Mycobacterium avium complex (MAC) or other nontuberculous mycobacteria have been previously identified in HIV seropositive patients only. We now report the first case of an HIV seronegative patient who received immunosuppressive therapy for rapidly progressive glomerulonephritis. The patient presented with severe lower gastrointestinal bleeding and was diagnosed to have ulcerative colitis due to infection with MAC. The patient recovered promptly after administration of antimycobacterial therapy. MAC infection should be included in the differential diagnosis of gastrointestinal bleeding in all immunodeficient patients. The significance of repeated colonoscopy to obtain multiple biopsy specimens with histological examination for foam cells and specific staining for acid-fast organisms is emphasized.     

国有企业管理创新

在市场经济条件下，国有企业要生存和发展，就必须重视和加强管理创新。文中就企业创新管理中的理念、决策、战略、组织结构、人本管理这5个方面的管理创新等问题进行了阐述，对企业创新管理具有一定的指导意义。     

Natural killer cell-mediated eradication of neuroblastoma metastases to bone marrow by targeted interleukin-2 therapy

Targeted interleukin-2 (IL-2) therapy with a genetically engineered antidisialoganglioside GD2 antibody-IL-2 fusion protein induced a cell-mediated antitumor response that effectively eradicated established bone marrow and liver metastases in a syngeneic model of neuroblastoma. The mechanism involved is exclusively natural killer (NK) cell-dependent, because NK-cell deficiency abrogated the antitumor effect. In contrast, the fusion protein remained completely effective in the T-cell-deficient mice or immunocompetent mice depleted of CD8+ T cells in vivo. A strong stimulation of NK-cell activity was also shown in vitro. Immunohistology of the leukocytic infiltrate of livers from treated mice revealed a strong staining for NK cells but not for CD8+ T cells. The therapeutic effect of the fusion protein was increased when combined with NK-cell-stimulating agents, such as poly I:C or recombinant mouse interferon-gamma. In conclusion, these data show that targeted delivery of cytokines to the tumor microenvironment offers a new strategy to elicit an effective cellular immune response mediated by NK cells against metastatic neuroblastoma. This therapeutic effect may have general clinical implications for the treatment of patients with minimal residual disease who suffer from T-cell suppression after high-dose chemotherapy but are not deficient in NK cells.