Comparison of the subacute toxicity and efficacy of 3-hydroxypyridin-4- one iron chelators in overloaded and nonoverloaded mice

Five orally effective iron chelators of the 3-hydroxypyridin-4-one series have been administered intraperitoneally to iron-overloaded and nonoverloaded male mice at a dose of 200 mg/kg/24 h for a total of 60 days to investigate the effect on iron loading and toxicity. There was a significant reduction in hepatic iron at the end of the study in the iron-overloaded mice with all compounds studied using chemical iron quantitation (P less than .001) and with Perls' stain (P less than .01). Liver iron removal with the hydroxypyridinones ranged from 37% with CP20 to 63% with CP51, compared with 46% removal for desferrioxamine (DFO). There was no significant reduction in splenic or cardiac iron with any chelator. There were no deaths in iron-overloaded animals receiving any of the hydroxypyridin-4-ones, but significantly more deaths in the nonoverloaded groups as a whole (P less than .03). No weight loss was observed with any chelator. Significant reductions in hemoglobin and white cell count were observed with CP20(L1). No histologic abnormalities of kidney, spleen, bone marrow, or stifle joints were observed. Intracytoplasmic inclusion bodies were observed in the centrilobular hepatocytes of animals administered each of the hydroxypyridin-4-ones, while the DFO-treated and control groups showed no such changes.     

Role of accessory cells in cytokine production by T cells in chronic B- cell lymphocytic leukemia

We investigated the production of cytokines by highly purified T helper cells from B-cell chronic lymphocytic leukemia (B-CLL) patients stimulated by different activation pathways, and we studied the influence of various accessory cell populations on the pattern of the secretion of cytokines, including interleukin (IL)-2, IL-4, interferon- gamma (IFN-gamma), and IL-10. Neither a qualitative nor a quantitative difference in cytokine production and proliferative capacity was observed in CLL-derived purified T cells compared with normal individuals, when T cells were stimulated by different pathways, including CD3, CD2, and costimulation with CD28. Addition of autologous accessory cells (aAC), however, dramatically influenced the cytokine pattern of normal versus B-CLL-derived T cells. CLL cells as aAC caused a marked increase of IL-2, whereas IFN-gamma was only slightly induced and IL-4 was not influenced. In contrast, in normal individuals addition of aAC, which predominantly consisted of monocytes, resulted in a significant increase of IFN-gamma and a reduction of IL-4 secretion. IL-2 production was inhibited by higher concentrations of aAC. The increased stimulation of IL-2 production by CLL cells was not specific to the leukemic cell population, as purified B cells from normal individuals had the same effect. On the other hand, purified monocytes from CLL patients and controls both induced IFN-gamma production and inhibited IL-4 secretion. After antigen-specific stimulation with tetanus toxoid, cytokine secretion was influenced by the type of aAC in a similar pattern. We conclude that T helper cells derived from patients with B-CLL are intrinsically normal and that the predominance of B cells as accessory cells in CLL significantly alters the immune function of T helper cells in vitro.     

Interferon-alpha stimulates production of interleukin-10 in activated CD4+ T cells and monocytes

In the present study, we investigated the effect of interferon-alpha (IFN-alpha) on the expression of interleukin-10 (IL-10) mRNA and protein synthesis in human monocytes and CD4+ T cells. In mononuclear cells, IFN-alpha induced expression of IL-10 mRNA and further enhanced lipopolysaccharide (LPS)-stimulated IL-10 expression. In purified monocytes, a strong expression of IL-10 mRNA induced by LPS was not further enhanced by IFN-alpha. In highly purified CD4+ T cells, IFN- alpha upregulated IL-10 mRNA upon activation with phytohemagglutinin and phorbol myristate acetate. In purified monocytes, an effect of IFN- alpha on IL-10 protein synthesis was dependent on costimulation with LPS. Maximal stimulation of IL-10 protein by IFN-alpha was seen after prolonged incubation periods of 48 to 96 hours, whereas IFN-gamma reduced IL-10 production in the early incubation period. Similar effects of IFN-alpha were observed in CD4+ T cells activated with CD3 and CD28 monoclonal antibodies. Addition of IFN-alpha caused an increase of IL-10 in culture supernatants of activated T-helper cells of more than 100% after 96 hours of incubation. In contrast, other cytokines, including IFN-gamma and IL-4, had no influence on IL-10 secretion stimulated by CD3 and CD28 in CD4+ T cells. In serum samples of IFN-alpha-treated individuals, we failed to detect an influence of cytokine treatment on IL-10 serum levels, confirming the requirement of additional activating signals for IFN-alpha-mediated effects on IL-10 synthesis. In conclusion, IFN-alpha enhances the late induction of IL- 10, which physiologically occurs upon stimulation of monocytes and T cells. Biologically, this effect might enhance the negative-feedback mechanism ascribed to IL-10, which limits inflammatory reactions.     

Regional neurovascular coupling and cognitive performance in those with low blood pressure secondary to high-level spinal cord injury: improved by alpha-1 agonist midodrine hydrochloride

Individuals with high-level spinal cord injury (SCI) experience low blood pressure (BP) and cognitive impairments. Such dysfunction may be mediated in part by impaired neurovascular coupling (NVC) (i.e., cerebral blood flow responses to neurologic demand). Ten individuals with SCI >T6 spinal segment, and 10 age- and sex-matched controls were assessed for beat-by-beat BP, as well as middle and posterior cerebral artery blood flow velocity (MCAv, PCAv) in response to a NVC test. Tests were repeated in SCI after 10 mg midodrine (alpha₁-agonist). Verbal fluency was measured before and after midodrine in SCI, and in the control group as an index of cognitive function. At rest, mean BP was lower in SCI (70±10 versus 92±14 mm Hg; P<0.05); however, PCAv conductance was higher (0.56±0.13 versus 0.39±0.15 cm/second/mm Hg; P<0.05). Controls exhibited a 20% increase in PCAv during cognition; however, the response in SCI was completely absent (P<0.01). When BP was increased with midodrine, NVC was improved 70% in SCI, which was reflected by a 13% improved cognitive function (P<0.05). Improvements in BP were related to improved cognitive function in those with SCI (r²=0.52; P<0.05). Impaired NVC, secondary to low BP, may partially mediate reduced cognitive function in individuals with high-level SCI.     

Initial Evaluation of AF78: a Rationally Designed Fluorine-18-Labelled PET Radiotracer Targeting Norepinephrine Transporter

Molecular Imaging and Biology - Taking full advantage of positron emission tomography (PET) technology, fluorine-18-labelled radiotracers targeting norepinephrine transporter (NET) have potential...     

Leukapheresis in rheumatoid arthritis association of clinical improvement with reversal of anergy

In order to study the clinical and immunologic effects of a brief course of leukapheresis, 14 patients with clinically similar rheumatoid arthritis were segregated into 2 subgroups. Group A (7 patients) had subnormal lymphocyte tritiated thymidine incorporation to soluble antigens. After a brief course of leukapheresis, 6 of these 7 patients demonstrated substantial clinical improvement associated with significantly enhanced lymphocyte tritiated thymidine incorporation to soluble antigens. In contrast, none of the 7 patients in group B (normal immune functions) demonstrated similar changes in articular indices or lymphocyte proliferation. Thus, clinical improvement induced in a subset of rheumatoid arthritis patients appears to reflect modulation of function, and not simply immuno-suppression.     

内镜短期内重复筛查观察食管和贲门癌癌前自然史301例

目的:了解进展较快的食管和贲门癌前病变的时间,为寻找合适的筛查间隔提供线索.方法:在食管癌高发区河北涉县对40～69岁人群开展重复的内镜筛查.结果:301例重复筛查共观察到40例病情发生进展者,其中7例重度不典型增生中:1例首检为正常,间隔13个月检出重度不典型增生,1例首检为基底细胞增生,间隔7个月检出,4例首检为轻度不典型增生,分别间隔3个月、4个月、4个月、10.5个月检出,1例首检为中度不典型增生,间隔12.5个月检出;6例原位癌及黏膜内癌中:1例首检为轻度不典型增生,间隔48个月检出,2例中度不典型增生分别间隔4个月、13个月检出2例,3例重度不典型增生分别间隔3.5个月、9个月、17.5个月检出;3例浸润性癌中:1例中度不典型增生,间隔50个月检出、2例重度不典型增生间隔14个月和19个月检出.结论:食管和贲门癌前病变的滞留时间变异较大,有必要适当缩短筛查间隔,通过及时复查捕获那些进展较快、多点起源和首检遗漏的癌前病变.