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71.
Joanne L. Jones Chia-Ling Phuah Amanda L. Cox Sara A. Thompson Maria Ban Jacqueline Shawcross Amie Walton Stephen J. Sawcer Alastair Compston Alasdair J. Coles 《The Journal of clinical investigation》2009,119(7):2052-2061
Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity. 相似文献
72.
73.
In a retrospective study, clinical risk factors of the neonatal period were correlated with the severity of regressed retinopathy of prematurity (ROP) in a population of preterm infants (bw less than 1500 g and or gestational age less than 33 weeks). At the age of 5-11 years 134 out of 528 preterm born infants (25.4%) were found to be under ophthalmic care. Reliable information on eye fundus status could be obtained in 105 of them. Regressed ROP was found in 61, the moderate form in 48 (9.1%) and the severe form in 13 (2.5%) patients. Twelve patients (2.3%) had visual acuity of less than 0.3 on the worst eye and two (0.4%) of these patients were blind from ROP. Twenty-four clinical factors of the newborn period were correlated with the severity of regressed ROP. The results suggest that long oxygen exposure in combination with other factors interfering with retinal vasotonus are associated with the degree of the disease developed. 相似文献
74.
Martínez-Rodríguez J Iranzo A Santamaría J Genís D Molins A Silva Y Meléndez R 《Neurología (Barcelona, Spain)》2002,17(2):113-116
Introduction: Cataplexy is one of the main narcoleptic symptoms and is characterized by sudden loss of muscle tone triggered by emotional stimuli while consciousness is mantained. Clomipramine is an effective treatment of cataplexy. Cataplexy that occurs repeatedly for hours or days is referred to as status cataplecticus.Patients: We report three adults with narcolepsy in whom cataplexy was chronically and effectively treated with clomipramine (75-150 mg/day). For diverse reasons, these three patients had an abrupt withdrawal of clomipramine, and after 2-9 days patients showed an invalidant status cataplecticus characterized by a marked increase of the frequency, duration and severity of their cataplectic attacks that were now elicited by mild emotional stimuli. After introduction of anticataplectic agents (clomipramine in two patients and fluoxetine in one patient), status cataplecticus was resolved in less than a week.Conclusion: In patients with narcolepsy, abrupt withdrawal of chronic treatment with clomipramine may be associated with status cataplecticus. This condition may be resolved with the reintroduction of anticataplectic agents. 相似文献
75.
Combination therapy for postmenopausal osteoporosis 总被引:1,自引:0,他引:1
A number of agents have been shown to reduce the risk of fractures in patients with postmenopausal osteoporosis. However, the additional benefits of combination therapy as opposed to monotherapy are uncertain. We performed a MEDLINE search and reviewed the published randomized trials of agents used in combination. Combination therapy results in greater gains in bone mineral density than monotherapy and possibly greater effects on bone turnover. However, none of these studies are large enough or of sufficient duration to determine whether a greater reduction in fracture is achieved. Combination therapy has important cost implications and is likely to be associated with an increased prevalence of adverse events, reduced tolerability and a reduction in adherence. Furthermore, over-suppression of bone turnover as a result of combination antiresorptive therapy might have adverse effects on bone strength, particularly with long-term treatment. Thus, the use of combination therapy for treatment of osteoporosis cannot be recommended on the basis of currently available evidence. 相似文献
76.
Phagocytosis removes pathogens and tissue debris during inflammatory reactions, but also plays an important role in autoimmune reactions. The main phagocytes in the central nervous system (CNS) are microglial cells that are activated during CNS inflammation. In the treatment of inflammatory demyelinating diseases like multiple sclerosis (MS), administration of intravenous immunoglobulins (IVIg) has become a promising immunomodulatory therapy. Although a large number of potential mechanisms for the effects of IVIg has been suggested, the precise mode of action in CNS inflammation is unknown. We assessed the influence of IVIg on phagocytosis and endocytosis in microglia in vitro. IVIg had little effect on non-specific phagocytosis of latex particles in untreated microglia, while there was a dose-dependent inhibition in microglia activated with LPS and IFNgamma. Endocytosis of soluble myelin basic protein (MBP) was downregulated by IVIg in both untreated and activated microglia. The effect was mediated by an F(ab')(2) preparation of immunoglobulins, suggesting that Fc receptor-mediated phagocytosis is not involved. Intact IVIg, but not F(ab')(2) fragments also suppressed Fc receptor-mediated phagocytosis of opsonised erythrocytes in both untreated and activated microglia. These results show that IVIg can inhibit the phagocytic activity of microglia via different mechanisms. Such an effect could contribute to the immunomodulatory capacity of IVIg in inflammatory CNS diseases. 相似文献
77.
Feakes R Sawcer S Broadley S Coraddu F Roxburgh R Gray J Clayton D Compston A 《Journal of neuroimmunology》2000,105(1):96-101
The autoimmune nature of multiple sclerosis introduces cytokine genes as logical candidates for the loci determining susceptibility to the disease, and/or influencing disease progression. Working on this principle, several groups have investigated the relevance of polymorphism in the interleukin 1 receptor antagonist gene (IL1RN) but with conflicting results. In an effort to clarify this situation, we typed the functionally significant variable number of tandem repeat (VNTR) polymorphism from intron 2 of IL1RN in 536 simplex families with multiple sclerosis. In order to improve the information extracted from these families, we also typed a closely mapped single nucleotide polymorphism (SNP) from the promoter of IL1B (the gene for IL-1beta). Disease associations were assessed by transmission disequilibrium testing (TDT), alone and after haplotype construction. There was highly significant (P=2.48.10(-16)) linkage disequilibrium (LD) between the two polymorphisms studied, illustrating that LD adjacent to an SNP can be considerably more extensive than has recently been suggested. None of the alleles from the VNTR, the SNP or their haplotype showed statistically significant evidence for association. We stratified patients for current disability status but using this manoeuvre found no evidence that either of the polymorphisms influences disease severity. Combining the available data on the IL1RN VNTR suggests that any effect of this gene on susceptibility to multiple sclerosis, or its progression is, at best, small. 相似文献
78.
背景:阿德福韦双酯(ADV) 是一种有效治疗野生型和耐拉米夫定乙肝病毒(HBV)的核苷酸类药物。在使用核苷酸类药物治疗慢性乙肝时,当治疗时间为 48、96、144周时,耐ADV变异体出现的累积发生率分别为0、 0.8-3%和0-5.9%。目的:研究67例对拉米夫定耐药且接受ADV治疗的慢性乙肝患者耐ADV病毒变异体的表型和基因型特点。方法:HBV DNA含量采用实时定量PCR技术。ADV变异体检测采用基质辅助激光解吸电离/飞行时间质谱为基础的基因分型 相似文献
79.
80.
Resistance of Copenhagen rats to chemical induction of glutathione S- transferase 7-7-positive liver foci 总被引:2,自引:0,他引:2
Copenhagen (Cop) rats are completely resistant to the chemical induction of
mammary adenocarcinomas, but their susceptibility to hepatocarcinogenesis
is virtually unknown. Rat liver is a well- characterized and easily
manipulated tissue in which to study carcinogenesis. Therefore, if Cop rats
are resistant to hepatocarcinogenesis, studies into resistance mechanisms
may be feasible. Male Cop and F344 rats, 7-8 weeks old, were initiated
using either N-nitrosodiethylamine (DEN) (200 mg/kg, i.p.) or a two-thirds
partial hepatectomy (PH) followed by N-methyl-N-nitrosourea (MNU) (60
mg/kg, i.p.). The rats were then promoted using a modified resistant
hepatocyte (RH) protocol (a combination of four doses of 2-
acetylaminofluorene (2-AAF) and a single dose of CCl4 that provides a
selective mitotic stimulus for initiated cells). Six weeks after initiation
the rats were killed and liver sections were stained for glutathione
S-transferase 7-7 (GST 7-7), a marker for putative preneoplastic
hepatocytes. Cop rats were found to be highly resistant, having a
approximately 9- and approximately 27-fold smaller percentage of liver area
occupied by GST 7-7-positive foci than susceptible F344 rats following
initiation by DEN and MNU respectively. Furthermore, gross liver nodules
did not form in any of the Cop rats, whereas all F344 rat livers contained
nodules. Hepatic necrosis caused by DEN during initiation, and CCl4 during
promotion is necessary to stimulate compensatory hepatocyte division. We
demonstrated that these agents do indeed increase serum transaminase levels
and produce histologic evidence of necrosis in Cop rats. In order for liver
foci to grow rapidly in the RH protocol, the surrounding normal hepatocytes
must be mito-inhibited by 2-AAF. We found that the degree of
mito-inhibition of normal hepatocytes by 2-AAF is the same in Cop and F344
rats. These results show that the Cop rat is highly resistant to the
chemical induction of putative preneoplastic liver foci and nodules.
相似文献