Early onset of autoimmunity in MRL/++ mice following immunization with beta 2 glycoprotein I.

Antiphospholipid antibodies (aPL) are associated with thrombosis, thrombocytopenia and recurrent fetal loss in humans and in some animal models. Immunization with beta 2 glycoprotein I (beta 2GPI) induced aPL production in normal rabbits and mice. However, the association of these antibodies with disease manifestations remains controversial. To determine whether induction of aPL by beta 2GPI immunization in an autoimmune strain of mice (MRL/++) would result in acceleration of clinical and serological autoimmune disease manifestations, three groups of 8-week-old female mice were studied. One group was immunized with beta 2GPI, and one with ovalbumin (OVA); the third was not immunized. After two booster injections, sera were analysed for the presence of anticardiolipin (aCL) and anti-DNA by ELISA and anti-nuclear antibody (ANA) by immunofluorescence. Mice were studied for thrombocytopenia, proteinuria, fecundity rates, litter sizes and the development of central nervous system dysfunction. Elevated levels of aCL, anti-DNA and ANA were detected in all beta 2GPI-immunized, in three OVA-immunized, and in none of the unimmunized mice. The anti-DNA antibodies were inhibited by CL micelles, suggesting cross-reactivity between aCL and anti-DNA. Platelet counts, fecundity rates and litter size were reduced in beta 2GPI-immunized but not in OVA-immunized or unimmunized mice. None of the mice developed neurological dysfunction or significant proteinuria over a 10-week period post-immunization. These findings suggest that beta 2GPI immunization induces aPL in MRL/++ mice associated with accelerated autoimmune manifestations resembling the antiphospholipid syndrome.     

The Protein Expression of Bcl-2, Bax, Fas/Apo-1 in Acute Myeloid Leukemia

Homeostasisof11ematopoiesisiscontrollednotoillybytheproliferationanddifferentiationofcells,butalsobycelldeath.Inadditiontolossofcontrolofcellproliferation,disruptionofapoptosis--inducedf[lnctionalsocontributestotumordevelopment.Althoughdiversesignalscaninduceapoptosisinawidevarietyofcelltypes,anumberofevolutionarilyconservedgenesregulateafinalcommoncelldeathpathway,thatisconservedinmanyspeciesfromwormstohumansll].Thehcf--2proto--oncogeneisoneofthecrucialapoptosisantagonizinggenes.Highlevelofhc…     

刺五加制剂对老年人恒定负荷下运动耐力的影响

以１３名５０～５７岁志愿者为试验对象，研究了刺五加制剂对人体运动能力的影响。结果表明服用刺五加制剂后，在４５０ｋｇ．ｍ／ｍｉｎ（７５Ｗ）持速恒定功率负荷运动时呼吸商由０．９６下降至０．８８，使运动时脂肪供能增加２７．２％；心率下降８．７％，每博摄氧量增加１６．１８％。结果均提示刺五加制剂能提高人体摄氧能力，节省肌糖元，从而发挥抗疲劳作用     

Inhibition of N-, P/Q- and other types of Ca channels in rat hippocampal nerve terminals by the adenosine A1 receptor

The effects of the adenosine A₁ receptor agonist, N⁶-cyclopentyladenosine (CPA), on both the increase in intracellular free Ca²⁺ concentration ([Ca²⁺]_i) and on the release of endogenous glutamate in rat hippocampal synaptosomes were studied. The inhibitory effect of CPA on the increase in [Ca²⁺]_i stimulated with 4-aminopyridine was neutralized by the adenosine A₁ receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). The inhibitory effect of CPA was greater in synaptosomes from the CA1 subregion than in whole hippocampal synaptosomes. The inhibitory effects of both CPA and of the Ca²⁺ channel blockers, ω-conotoxin GVIA, ω-conotoxin MVIIC or ω-conotoxin GVIA plus ω-conotoxin MVIIC, were greater than those caused by the Ca²⁺ channel blockers. The release of endogenous glutamate was inhibited by 41% by CPA. The inhibition observed when CPA and ω-conotoxin GVIA or CPA and ω-conotoxin MVIIC were present was also greater than the inhibition by the Ca²⁺ channel blockers alone. The presence of both ω-conotoxin GVIA and ω-conotoxin MVIIC did not completely inhibit the release of glutamate, and CPA significantly enhanced this inhibition. The membrane potential and the accumulation of [

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]tetraphenylphosphonium of polarized or depolarized synaptosomes was not affected by CPA, suggesting that adenosine did not increase potassium conductances. The present results suggest that, in hippocampal glutamatergic nerve terminals, adenosine A₁ receptor activation partly inhibits P/Q- and other non-identified types of Ca²⁺ channels.     

Correlation between soluble transferrin receptor and serum ferritin levels following bone marrow transplantation for thalassemia

Abstract: This study analyzes the serum transferrin receptor (sTfR) levels in a series of 230 ex-thalassemics with a follow-up of 1 to 9 years after bone marrow transplantation (BMT) for homozygous β thalassemia. Ex-thalassemics are individuals, cured of homozygous β thalassemia by BMT, who maintain different degrees of iron overload acquired during the pretransplant period. Both in experimental and clinical conditions, sTfR concentrations have been shown to be a quantitative measure of body iron status. This study was carried out to assess whether the level of sTfR may be of help in determining the extent of iron overload in ex-thalassemics. Patients who received the marrow from their HLA-identical sibling donor heterozygous for β thalassemia, namely heterozygous ex-thalassemics, displayed significantly higher levels of sTfR than patients transplanted from their normal sibling donors (normal ex-thalassemics). This finding suggests that increased erythropoiesis, albeit in part ineffective in heterozygous ex-thalassemics, is responsible for the sTfR increment. Both heterozygous and normal ex-thalassemics had significant lower sTfR levels than their heterozygous (p < 0.003) or normal (p < 0.0001) donors, respectively. These differences may be ascribed to the presence of iron overload in ex-thalassemics in comparison to their normal or heterozygous donors who did not present excess of iron in the body. A significant inverse correlation between sTfR and serum ferritin levels (r = –0.54, p < 0.0001) was found when normal ex-thalassemics were considered. In heterozygous ex-thalassemics, the lack of correlation between these two parameters may be explained by the enhanced erythropoietic activity of individuals with thalassemic trait. These results suggest that the level of sTfR may be a useful indicator of iron overload in normal ex-thalassemics.     

Are cytokines possible mediators of cancer cachexia?

The possible role of cytokines in the development of cancer cachexia was reviewed from the literature. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, interferon (IFN)-gamma and leukemia inhibitory factor (LIF) can elicit many but not all host changes seen in cancer cachexia, including loss of appetite, loss of body weight, and the induction of acute-phase protein synthesis. However, these cytokines are not always demonstrated in the circulation of the cancer patients. The inability to detect circulating cytokines may be due to their low rate of production, their short half-life and rapid clearance from plasma, or their mode of action (autocrine or paracrine). Different cytokines are induced to stimulate the same response. This is very different from hormonal regulation, where a hormone acts on a cell directly through a specific receptor without depending on other mediators. Specific antibodies including anti-IFN-gamma, anti-TNF and anti-IL-6 antibodies, as well as the cyclooxygenase inhibitor indomethacin, have been used to reverse cancer cachexia. Overlapping physiologic activities make it unlikely that a single substance is the sole cause of cancer cachexia. It is hoped that further investigation on other cytokines and their possible relationships with hormones will help to clarify the mechanisms of cancer cachexia in the near future.This work was supported by a grant from the Japan-Sweden Foundation in 1991.     

β-Adrenergic agonists suppress chronic/relapsing experimental allergic encephalomyelitis (CREAE) in Lewis rats

Chronic/relapsing experimental allergic encephalomyelitis (CREAE) serves as an animal model for relapsing/remitting multiple sclerosis. Treatment with the β-adrenergic agonist isoproterenol or the β₂-adrenergic agonist terbutaline significantly suppressed both the first acute attack and the number of relapses in CREAE Lewis rats. The number of relapses was decreased even when treatment with β-adrenergic agonist was started after the onset of the first acute attack of CREAE. β-adrenergic receptor number was increased significantly on splenocytes from CREAE rats as compared to healthy controls or CFA-injected rats. Terbutaline treatment of CREAE rats lowered the splenocyte receptor number to normal values.     

A phenytoin-sensitive cationic current participates in generating the afterdepolarization and burst afterdischarge in rat neocortical pyramidal cells

We report here on the ionic mechanisms underlying the depolarizing afterpotential (DAP) in neocortical pyramidal cells, with special interest in those underlying the burst afterdischarge. Injections of short depolarizing current pulses under whole-cell current clamp with a CsCl-based internal medium generated, in most pyramidal cells, a single action potential with a plateau phase (plateau-AP), followed by a slowly decaying DAP both in the absence and presence of TTX. Under voltage-clamp, the same cells displayed a slow tail current (tail-I) at the offset of depolarization. When intracellular free Ca²⁺ was chelated with 10 mm BAPTA or when extracellular Ca²⁺ was replaced with equimolar Ba²⁺, neither the slow DAP nor the slow tail-I was observed. Extracellular application of Co²⁺ or Cd²⁺ reduced Ca²⁺ currents and the slow tail-I. Cation substitution experiments revealed that the channel generating the slow tail-I was permeable to K⁺ and Cs⁺ more than to Na⁺ (P_K≈P_Cs > P_Na > P_NMDG≈P_TEA). The cationic slow tail-I was not reduced by applying antagonists of the metabotropic glutamate receptor (MCPG, 1 mm ) and the muscarinic receptor (atropine, 1–10 μm ). Thus, the slow DAP was produced by activation of the cationic channel whose gating is solely dependent on [Ca²⁺]_i. An increase in [K⁺]_o from 3 to 6 or 9 mm enhanced the slow DAP, and resulted in a generation of burst afterdischarges. An anticonvulsant, phenytoin (PT; 1–10 μm ) suppressed the slow DAP while enhancing the plateau-AP in the presence of TTX, most likely by blocking the cationic channel.     

Feedback Stimulation of Somatodendritic Serotonin Release: A 5-HT3 Receptor-Mediated Effect in the Raphe Nuclei of the Rat

Slices from rat midbrain containing the raphe nuclei and from hippocampus were prepared, loaded with [³H]5-HT and superfused and the resting and the electrically stimulated [³H]5-HT release was measured. The 5-HT₃ receptor agonist 2-methyl-5-HT (1 to 10 μmol/l) increased the resting tritium outflow in superfused raphe nuclei slices, EC₅₀ 5.3 μmol/l. The 2-methyl-5-HT-induced increase of tritium outflow was an external Ca²⁺-independent process and was not altered by reserpine pretreatment but it was reversed by addition of the 5-HT uptake inhibitor fluoxetine (1 μmol/l). The 5-HT₃ receptor antagonists ondansetron and GYKI-46 903 (1 μmol/l) did not antagonize the stimulatory effect of 2-methyl-5-HT on resting tritium outflow. 2-Methyl-5-HT in lower concentration increased the electrically induced tritium overflow from raphe nuclei slices (EC₅₀ 0.56 μmol/l) and also from hippocampal slices preloaded with [³H]5-HT. These effects were reversed by 1 μmol/l of ondansetron and GYKI-46903. The 5-HT₃ receptor antagonists (1 μmol/l) were without effects on depolarization-evoked [³H]5-HT release at 2 Hz stimulation, when 10 Hz stimulation was used, ondansetron and GYKI-46 903 reduced the tritium overflow from raphe nuclei slices. These data indicate that 5-HT₃ receptors positively alter depolarization-induced somatodendritic 5-HT release in the raphe nuclei. They also show that 2-methyl-5-HT is able to evoke 5-HT release not only from vesicles but also from cytoplasmic stores via a transporter-dependent exchange process.     

CYP1A2 activity, gender and smoking, as variables influencing the toxicity of caffeine

We have investigated several factors that might be related to the occurrence of toxic effects during the performance of a urinary test with caffeine (300  mg p.o), in 120 healthy volunteers. A total of 218 toxic effects were self-reported by eighty-two (68%) subjects. Females and nonsmokers were at the highest risk (chi-square test, P =0.01). Furthermore, two nonsmoking females experienced a symptomatology with delirium, restlessness, muscle tremor, vomiting and wakefulness. Among females and nonsmokers, those subjects who experienced toxic effects had lower caffeine N3-demethylation index (CYP1A2 activity) compared with unaffected females (1.87±0.51 vs 1.47±0.27, P <0.0005) and nonsmokers (1.69±0.23 vs 1.49±0.31, P <0.02). Caffeine N1- and N7-demethylations indices were also lower among females ( P <0.0005) and nonsmokers ( P <0.02) who reported toxic symptoms. We conclude that CYP1A2 activity, gender and smoking are variables to be considered as influencing the toxicity of caffeine.