Salivary gland material from the sand fly Lutzomyia longipalpis has an inhibitory effect on macrophage function in vitro

Previous work from our laboratory demonstrated that the infectivity of the protozoan parasite Leishmania major was enhanced in mice if the infecting inoculum contained salivary gland lysates from the sand fly vector Lutzomyia longipalpis. The present study was designed to address the hypothesis that sand fly salivary gland material may function by inhibiting the host immune response. Results indicated that sand fly saliva inhibited the ability of macrophages to present leishmanial antigens to parasite-specific T cells.     

Lipoproteins and the inhibitory effect of human endothelial cells on platelet function.

We investigated the effect of plasma low density lipoproteins (LDL), very low density lipoproteins (VLDL), and high density lipoproteins (HDL) on the platelet inhibitory effect of primary cultures of human endothelial cell monolayers (ECM). ECM incubated with lipoprotein-deficient plasma (LDP) for 2 hours at 37 degrees C had an inhibitory effect on ADP- and collagen-induced platelet aggregation and prostaglandin production in platelet-rich plasma similar to that observed when ECM were preincubated with growth medium or plasma. Concentrations of LDL in LDP up to protein concentration of 1600 microgram/ml had an inhibitory effect on the endothelial cells' ability to modulate these platelet reactions. VLDL at the highest concentration (1600 microgram/ml) had a slightly inhibitory effect, whereas HDL showed no such effect. The inhibitory effect of LDL was not observed during the first hour of incubation. When HDL in concentrations similar to or higher than LDL were combined with LDL, the inhibitory effect of LDL was partially reduced. VLDL combined with LDL or HDL did not interfere with the effects of the later fractions. The inhibitory effect of LDL was significantly reduced when LDL were diluted in whole plasma. Prostacyclin which is synthesized and released from the endothelial cells and contributes to the inhibitory effect upon platelets did not change its effect on platelet reactivity by preincubation with the various lipoprotein fractions. The current studies may indicate that LDL have a direct effect on the endothelial cells and that this effect may be partially counteracted by HDL. This effect of LDL on the endothelial cells reduces the endothelium's ability to inhibit platelet aggregation and thus could favor the tendency to thrombus formation.     

The effects of leukaemia inhibitory factor on platelet function

Summary Leukaemia inhibitory factor (LIF) is able to promote megakaryocytopoiesis in vitro and elevate platelet counts in vivo , and is a potential new therapeutic agent for the treatment of thrombocytopenia. To determine whether platelets released under conditions of LIF-stimulated megakaryocytopoiesis have intact function, we compared aggregation responses of platelets from mice with constitutively elevated LIF levels (FD/LIF mice) and mice injected with recombinant murine LIF (rmLIF mice) with their respective control mice. We report that ex vivo platelet aggregability and thromboxane B₂ release were intact in the LIF-treated mice, and were significantly enhanced in some situations. LIF-treated mice also had significantly increased platelet counts (FD/LIF mice: 1302 ± 173 × 10⁹/1 compared to 1012 ± 99 × 10⁹/1 for FD mice; rmLIF mice: 1460 ± 193 × 10⁹/1 compared to 985 ± 67 × 10⁹/1 for FCS/NS mice), increased platelet volumes and elevated plasma fibrinogen and calcium levels. The platelet hyperreactivity seen in the LIF-treated mice is likely to reflect the larger platelet volumes and/or the effect of plasma components such as fibrinogen, elevated levels of which were due to the concomitant action of LIF as a stimulant of acute phase protein synthesis.     

The inhibitory effect of plasma fibronectin on collagen-induced platelet aggregation

Plasma fibronectin (Fn) has been proposed to have an antithrombotic effect, protecting against platelet and fibrinogen consumption after injury. The current study was designed to determine the effect of plasma fibronectin on collagen-induced platelet aggregation. In vitro aggregometry using an isolated homologous rat system, demonstrated a significant (P less than .05) inhibitory effect of 120 micrograms/mL Fn on platelet aggregation as induced by 60 micrograms/mL fibrillar collagen (type I). The inhibition was evidenced by a threefold increase in lag time and a significant decrease in the rate and extent of aggregation. The hypothesis was also tested using an in vivo model of collagen-induced platelet aggregation. The model used was intravenous injection of 2 mg/kg of homologous type I collagen into anesthetized Sprague-Dawley rats. Injection of collagen preincubated with 4 mg/kg Fn resulted in significantly less thrombocytopenia and fibrinogen consumption as compared with injection of collagen alone. The results of both the in vitro and in vivo studies are consistent with the proposed antithrombotic effect of plasma fibronectin.     

The effect of plasmin on platelet function

There is controversy in the literature regarding the effects of plasmin on human platelets. We have studied the effects of plasmin on platelet glycoproteins, aggregation, shape change and secretion and found them to be dependent on experimental conditions: (a) Plasmin's effects on human platelets are only seen in gel-filtered platelets (GFP), presumably because in platelet rich plasma plasmin is bound to a2-antiplasmin; (b) in GFP to which fibrinogen has been added, platelet function remains intact; and (c) in the absence of fibrinogen, the effect of plasmin on GFP depends on whether stirring is performed or not. With stirring, platelets undergo shape change, secretion and aggregation in response to added plasmin. Aggregation is much stronger when CaCl(z) 1 mM is added. Without stirring, preincubation of GFP with plasmin leads to inhibition of platelet aggregation induced by subsequent platelet stimuli (thrombin, collagen, ristocetin or U46619). We have demonstrated that plasmin is a true platelet activating agent, in the sense that it induces platelet shape change and secretion. Plasmin will induce aggregation when added to stirred GFP. This may be because stirring protects glycoprotein (GP) IIbIIIa bound fibrinogen from being degradated by plasmin. When added to unstirred GFP, GP IIbIIIa bound fibrinogen may be readily accessible to degradation by plasmin, which may then behave like a platelet inhibitor.     

The 3'' untranslated region of the human interferon-beta mRNA has an inhibitory effect on translation.

In vitro-transcribed human interferon-beta (IFN-beta) mRNA, which contains all the sequence of the natural molecule, is poorly translated in a reticulocyte lysate or when injected in Xenopus oocytes. This low level of translation is due to an inhibition by the 5' and 3' untranslated regions (UTRs). Indeed, the replacement of these sequences by those of Xenopus beta-globin mRNA dramatically increases the translational efficiency of the mRNA, especially in oocytes. This phenomenon is not due to a difference in mRNA stability since both native and chimeric mRNAs remain undegraded, at least during the translation period considered. Construction of different chimeric molecules having various combinations of 5' and 3' UTRs from IFN-beta or Xenopus beta-globin mRNA or a small sequence of SP6 polylinker as 5' UTR has revealed that the 3' UTR of IFN-beta in itself has a pronounced inhibitory effect on translation in the two translation systems from animal cells. Indeed, the addition of this 3' UTR at the 3' end of the coding region of a chicken lysozyme mRNA also causes a large decrease of its translational capacity in both systems. However, the nature of the 5' noncoding sequence influences the degree of translation inhibition exerted by the 3' UTR. Remarkably, we observed no difference in translation level when the different mRNAs were tested in a wheat germ extract.     

The combination of type I interferon and ribavirin has an inhibitory effect on mouse hepatitis virus infection

Aim: To determine the differences in efficacy between therapy using IFN‐β and ribavirin, and using IFN‐α and ribavirin. Methods: We studied the effect of combination therapy consisting of IFN‐β and ribavirin on mouse hepatitis virus (MHV) infection in mice. Results: Combination treatment of ribavirin and IFN‐α was more effective than IFN‐α mono‐treatment in the MHV‐mouse system, and combination treatment with ribavirin and IFN‐β was more effective than IFN‐β mono‐treatment in the MHV‐mouse system. Furthermore, administering IFN‐β once or twice one day before combination treatment using ribavirin and IFN‐α was more effective than administering IFN‐α once or twice one day before the combination treatment using ribavirin and IFN‐α. Conclusion: These data indicate that this MHV‐infection system is a good animal model to assess anti‐HCV activity for therapy using IFN and ribavirin, and suggest that administering IFN‐β before the start of combination therapy with ribavirin and IFN‐α promotes the therapeutic effects of combination treatment with ribavirin and IFN‐α ?in chronic hepatitis C patients.     

The effect of plasma removal from apheresis platelet concentrates on platelet function

The effect of plasma removal on platelet function has scarcely been investigated. Plasma removal from apheresis platelet concentrates was achieved by centrifugation at 5000 g for 6 min or 2000 g for 10 min. After resting for 1 h, platelet concentrates were resuspended in 0·9% NaCl. Platelet function was tested before centrifugation and after resuspension by multiple electrode impedance aggregometry (MEA) and light transmission aggregometry (LTA). Plasma removal resulted in 10-14% lower response to TRAP-6 by MEA using both washing procedures, whereas TRAP-6-inducible aggregation by LTA increased slightly (2-5%). Neither plasma removal method affected collagen-induced aggregation. Thus, platelet function did not deteriorate significantly by either method.     

Famotidine has no significant effect on gonadal function in man

The effect of a single bedtime dose of famotidine 40 mg on gonadal function was studied in 8 male duodenal ulcer patients. The drug was orally administered for 4 weeks. Our results show that this new H2 blocker influences basal and stimulated serum levels of neither testosterone nor gonadotrophins (LH, FSH). Besides, no significant variations were observed before and after famotidine treatment in seminal fluid characteristics evaluated in 5 out of 8 cases. It can be concluded that famotidine appears to leave gonadal function unaffected in man.     

氯沙坦对高脂血症大鼠血小板功能的影响

目的：分析高脂血症大鼠血小板功能的变化,探讨氯沙坦对高脂血症大鼠血小板功能的影响。方法：34只Wistar大鼠被随机分为正常对照组、高脂血症模型组、氯沙坦组（科素亚,20mg／kg·d）组。分组进行干预后检测3组大鼠的血脂：总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL—C）、高密度脂蛋白胆固醇（HDL—C）的水平。应用酶联免疫法测定血浆中血小板颗粒膜蛋白（GMP140）浓度、流式细胞术检测血小板表面CD62P的表达。结果：分组干预4周后,高脂血症组和氯沙坦组的TC[（13．779±5．219）mmol／L,（14．570±8．357）mmol／L],LDL-C[（10．680±4．727）mmol／L,（11．393±7．623）mmol／L]含量显著高于正常对照组[（1．846±0．196）mmol／L,（0．164±0．031）mmol／L],P均〈0．001,HDL-C／TC[（0．195±0．079）mmol／L,（0．216±0．053）mmol／L]含量显著低于正常对照组（0．583＋0．062）mmol／L,P〈0．001;高脂血症组和氯沙坦组的血脂含量无显著差异（P均〉0．05）。高脂血症组和氯沙坦组的GMP140[（27．045±2．849）ng／ml,（20．665±1．701）ng／ml]、CD62P[（25．169±5．324）％,（20．144±1．290）％]含量显著高于正常对照组的[（10．655±1．682）ng／ml,（10．089±1．333）%],P〈0．001。氯沙坦组GMP140及CD62P水平均显著低于高脂血症组（P〈0．05）。结论：高脂血症能够促使血小板活化。氯沙坦具有抑制血小板活化的作用。     

The effect of noradrenalin infusion on plasma and platelet lipids and platelet function in man.

Noradrenalin was given as an intravenous infusion in a dosage of 0.1 mu-g/kg/h over a period of 30 minutes to 5 healthy male subjects. Blood samples were collected before, at the end of and 24 hours after the infusion. A significant increase in the number of circulating platelets and a marked increase of plasma FFA, reflecting an increase of all the main components of the FFA fraction were observed. No significant changes were observed in the similar lipid fraction in platelets and except for a moderate increase in platelet factor 3 activity, no significant changes in other platelet function tests were present.     

Cigar smoking has an acute detrimental effect on arterial stiffness

BACKGROUND: Despite a decline in cigarette smoking, cigar smoking is increasing, partly due to the perception that it is a "safe" alternative to cigarettes. However, cigar smoking increases cardiovascular risk, but the mechanisms involved are not fully explored. Aortic stiffness and arterial wave reflection are important factors for the efficient performance of the cardiovascular system and have been identified as prognosticators of cardiovascular risk. We investigated the acute effect of cigar smoking on aortic elastic properties and wave reflection. METHODS: We studied the effect of smoking one cigar in 12 healthy subjects according to a randomized, sham procedure-controlled, cross-over design. Aortic stiffness was evaluated with carotid-femoral pulse wave velocity and wave reflection with augmentation index of the aortic pressure waveform. RESULTS: Cigar smoking produced a significant increase in pulse wave velocity (by 0.80 m/sec, P = .001) denoting an increase in aortic stiffness. Augmentation index increased significantly (by 6.1%, P < .05) denoting an increase of wave reflections. These increases in arterial stiffness indices were evident promptly after the initiation of cigar smoking and lasted throughout the duration of the study (2 h). Concurrently, both radial and aortic systolic, and pulse pressure increased significantly throughout the study. CONCLUSIONS: The present study shows for the first time that cigar smoking increases acutely stiffness of large arteries and wave reflection, thus providing further evidence that it is not a safe alternative to cigarettes.     

Diabetes mellitus has an additional effect on coronary artery disease

We investigated whether plasma levels of adiponectin in patients with both coronary artery disease (CAD) and diabetes mellitus (DM) are lower than in patients with CAD alone. We examined plasma adiponectin levels in 113 patients, 82 with CAD (40 of whom had both CAD and type 2 DM) and 31 normal controls. We found differences in plasma adiponectin levels between CAD patients with and without DM (7.8 +/- 4.75 versus 12.1 +/- 6.87 microg/mL, P = 0.002), between patients with CAD and controls (10.0 +/- 6.27 versus 15.3 +/- 5.38 microg/mL, P < 0.0001), and between men and women (10.2 +/- 6.41 versus 13.1 +/- 6.22 microg/mL, P = 0.017). Plasma adiponectin levels were correlated negatively with body mass index, triglyceride, total cholesterol, hemoglobin A1c, and fibrinogen levels (r = -0.456, P < 0.0001; r = -0.355, P < 0.0001; r = -0.286, P = 0.002; r = -0.299, P < 0.0001; r = -0.400, P < 0.0001, respectively), but were not significantly correlated with high sensitivity C-reactive protein or low density lipoprotein levels (r = -0.088, P = 0.352; r = -0.167, P = 0.077, respectively). Plasma adiponectin levels correlated positively with high density lipoprotein levels (r = 0.410, P < 0.0001). Our study demonstrates that plasma adiponectin levels in patients with both CAD and DM are lower than in patients with CAD alone. We speculate that people who have very low plasma adiponectin levels may be at increased risk of developing both CAD and DM.     

老年慢性呼吸衰竭患者血小板活化因子及血小板功能改变

目的 探讨老年慢性呼吸衰竭患者血小板活化因子（ＰＡＦ）及血小板粘附、聚集、释放功能的改变及与老年慢笥肺心病和呼吸衰竭发展的关系。方法 生物定量法观察老年慢性呼吸衰竭组患者（５５例）、老年健康人组（４０组）及非老年健康人组（３５例）血以激活因子（ＰＡＦ）的改变,放免法观察血以膜ＧＭＰ１４０、血小板释放功能、血小板粘附功能（ＰＡＤＴ）和血小板聚集功能（ＰＡｇＴ）的变化。结果 老年慢性呼吸衰竭组ＰＡＦ为     

左西孟旦对顽固性心衰的疗效及对室性心律失常影响的研究

目的 通过左西孟旦对顽固性心衰患者脑钠肽前体（pro-BNP）、心脏彩超左室射血分数（LVEF）及左室舒张末容积（LVEDV）、室性心律失常的影响,观察研究左西孟旦治疗顽固性心衰患者的效果.方法 筛选出顽固性心衰患者80例,随机分成2组,分别给予左西孟旦和米力农治疗,治疗前后分别测pro-BNP、LVEF、LVEDV和室性心律失常的次数.结果 与对照组相比,经左西孟旦治疗后患者的pro-BNP和室性心律失常的次数显著下降;两组间LVEDV下降值差异无统计学意义;左西孟旦组LVEF显著升高.结论 左西孟旦治疗顽固性心衰优于传统正性肌力药物.     

Characterization of the effect of plasma lipoproteins on platelet function in vitro

Thrombin-induced platelet activation is enhanced by very low and low density lipoproteins but decreased by high density lipoprotein. Plasma lipoproteins maximally affect platelet aggregation and 14C-serotonin release in a gel-filtered platelet preparation within 10 min of incubation at 37 degrees C. This effect is saturable and physiologic concentrations of lipoproteins are required in order to attain this saturation. When no aggregating agent is added to the incubation medium, the lipoproteins alone did not alter platelet aggregation. However, 14C-serotonin release is increased by very-low- and low-density lipoproteins alone more than by high density lipoprotein. On removal of the lipoproteins after incubation with the platelets, and subsequent testing of platelet function, minimal influence of these lipoproteins on the platelet function remains. Arachidonic acid causes similar results to thrombin when added to the platelet suspension after incubation with the lipoprotein. Our results further emphasize the 'opposing effects' of very low and low density lipoproteins as compared to high density lipoproteins on platelets and/or platelet-thrombin interaction.     

The effect of pharmacologic inhibition of phospholipid methylation on human platelet function

Human platelets are capable of synthesizing their major membrane phospholipid, phosphatidylcholine, by a methylation pathway. This involves the sequential transfer of methyl groups from S-adenosyl-L- methionine (AdoMet) to phosphatidylethanolamine, and in the process, AdoMet is converted to S-adenosylhomocysteine (AdoHcy). The activity of this methylation pathway is decreased upon stimulation of platelets by various agonists. We inhibited methylation reactions pharmacologically to see whether this inhibition plays any role in the process of platelet activation. Two inhibitors of AdoHcy hydrolase, 3-deaza- adenosine and 3-deaza-(+/-)aristeromycin (500 microM each), were effective in increasing platelets levels of AdoHcy and preventing turnover of AdoMet. Also, these compounds were equipotent in inhibiting platelet phospholipid methylation. However, while 3-deaza-adenosine potentiated platelet aggregation and 14C-serotonin release induced by epinephrine or adenosine diphosphate (ADP) (p less than 0.01), 3-deaza- aristeromycin had no such effect. Neither compound affected platelet responses to thrombin or collagen. Inhibition of methylation reactions was not the only biochemical effect of 3-deaza-adenosine since it also blunted significantly the elevation of platelet cyclic adenosine monophosphate (AMP) levels induced by prostaglandin E1 (p less than 0.02). Therefore, these studies demonstrate that inhibition of platelet phospholipid methylation, per se, has no discernable effect on the function of human platelets. The methylation pathway, though active in platelets, does not appear to be primarily involved in membrane events responsible for platelet activation.