Immunodepression during Trypanosoma brucei gambiense infections in the field vole, Microtus montanus.

The effects of Trypanosoma brucei gambiense infections upon immune responses were examined in an outbred laboratory colony of field voles. Microtus montanus. Antibody levels to challenge with heterologous erythrocytes and bovine serum albumin were significantly depressed in infected animals. Trypanosome infections impaired both primary and secondary humoral responses, although previously established specific antibody levels were not affected by infection. Specific antibody-producing capabilities of previously infected, trypanoicidal drug-treated voles were found to be comparable to uninfected controls, within 3 days following chemotherapy. Cell-mediated hypersensitivity responses to oxazolone were also significantly depressed by trypanosome infection; responses to the initial sensitization of oxazolone and to secondary challenge treatments were depressed compared to uninfected controls. Possible mechanisms of trypanosome-induced immunodepression are discussed.     

Fludarabine: a new agent with major activity against chronic lymphocytic leukemia

Fludarabine was used to treat 68 patients with previously treated chronic lymphocytic leukemia (CLL). Nine (13%) patients achieved a complete remission and 30 (44%) a partial remission. The response rates for Rai stages 0 to 2, 3, and 4 were 64%, 58%, and 50% respectively. Seventeen (43%) of the 40 Rai stage 1 to 3 patients and four (19%) of the Rai stage 4 patients returned to Rai stage 0. Survival was strongly correlated with the final Rai stage achieved. The survival of the 11 partial responders with residual disease consisting only of residual bone-marrow nodules was similar to the complete responders (36+ months) and superior to the other partial response patients (16 months). The response to fludarabine was rapid, with 36 (92%) of the 39 responders having achieved at least a partial response following the first three courses. Complete responses occurred in the blood, liver, spleen, and lymph nodes in 48% to 69% of the patients. Eradication of all disease in the bone marrow occurred in only 13% of the cases. Neutropenia and thrombocytopenia occurred in 56% and 25% of evaluable courses. Major infections occurred in 9% of evaluable courses and fevers of unknown origin or minor infections in 12% of courses respectively. Myelosuppression and infection were more common in patients with initial Rai stages 3 and 4 and in nonresponding patients. Other toxicity was mild. No CNS toxicity was noted.     

A mechanism for sudden infant death syndrome (SIDS): stress-induced leak via ryanodine receptors.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality in the United States. Mutations in the RyR2-encoded cardiac ryanodine receptor cause the highly lethal catecholaminergic polymorphic ventricular tachycardia (CPVT1) in the young. OBJECTIVE: The purpose of this study was to determine the spectrum and prevalence of RyR2 mutations in a large cohort of SIDS cases. METHODS: Using polymerase chain reaction, denaturing high performance liquid chromatography, and direct DNA sequencing, a targeted mutational analysis of RyR2 was performed on genomic DNA isolated from frozen necropsy tissue on 134 unrelated cases of SIDS (57 females, 77 males; 83 white, 50 black, 1 Hispanic; average age = 2.7 months). RyR2 mutations were engineered by site-directed mutagenesis, heterologously expressed in HEK293 cells, and functionally characterized using single-channel recordings in planar lipid bilayers. RESULTS: Overall, two distinct and novel RyR2 mutations were identified in two cases of SIDS. A 6-month-old black female hosted an R2267H missense mutation, and a 4-week-old white female infant harbored a S4565R mutation. Both nonconservative amino acid substitutions were absent in 400 reference alleles, involved conserved residues, and were localized to key functionally significant domains. Under conditions that simulate stress [Protein Kinase A (PKA) phosphorylation] during diastole (low activating [Ca2+]), SIDS-associated RyR2 mutant channels displayed a significant gain-of-function phenotype consistent with the functional effect of previously characterized CPVT-associated RyR2 mutations. CONCLUSIONS: Here we report a novel pathogenic mechanism for SIDS, whereby SIDS-linked RyR2 mutations alter the response of the channels to sympathetic nervous system stimulation such that during stress the channels become "leaky" and thus potentially trigger fatal cardiac arrhythmias.     

Enhanced and prolonged cross-presentation following endosomal escape of exogenous antigens encapsulated in biodegradable nanoparticles

CD8(+) T-cell responses are critical in the immunological control of tumours and infectious diseases. To prime CD8(+) T cells against these cell-associated antigens, exogenous antigens must be cross-presented by professional antigen-presenting cells (APCs). While cross-presentation of soluble antigens by dendritic cells is detectable in vivo, the efficiency is low, limiting the clinical utility of protein-based vaccinations. To enhance the efficiency of presentation, we generated nanoparticles from a biodegradable polymer, poly(D,L-lactide-co-glycolide) (PLGA), to deliver antigen into the major histocompatibility complex (MHC) class I antigen presentation pathway. In primary mouse bone marrow-derived dendritic cells (BMDCs), the MHC class I presentation of PLGA-encapsulated ovalbumin (OVA) stimulated T cell interleukin-2 secretion at 1000-fold lower concentration than soluble antigen and 10-fold lower than antigen-coated latex beads. The microparticles also served as an intracellular antigen reservoir, leading to sustained MHC class I presentation of OVA for 72 hr, decreasing by only 20% after 96 hr, a time at which the presentation of soluble and latex bead-associated antigens was undetectable. Cytosol extraction demonstrated that antigen delivery via PLGA particles increased the amount of protein that escaped from endosomes into the cytoplasm, thereby increasing the access of exogenous antigen to the classic MHC class I loading pathway. These data indicate that the unique properties of PLGA particle-mediated antigen delivery dramatically enhance and sustain exogenous antigen presentation by MHC class I, potentially facilitating the clinical use of these particles in vaccination.     

WHO生存质量评估简表的等价性评价

目的评价WHO生存质量评估简表(WHOQOL-BREF)在13个国家的等价性。方法采用多组验证性因子分析方法,对世界卫生组织生存质量研究小组提供的13个国家的数据进行分析,评价WHOQOL-BREF不同国家的等价性。结果各个国家的各个领域的Cronbachα系数均大于0·7,分布在0·7至0·88之间。除了英国和挪威之外,其它国家的社会关系领域的Cronbachα系数均大于0·65。采用根据世界卫生组织生存质量研究小组研制量表时构建的四因子模型对数据分别进行拟合,拟合优度指数(CFI)均大于0·8,其中德国、西班牙和美国的拟合优度指数大于0·9。多组验证性因子分析发现模型拟合尚可,CFI等于0·88,各个国家的因子负荷不全相等,因子负荷的轮廓相似。结论WHOQOL-BREF在13个国家具有相同的因子结构,且有等价性。     

Manubriosternal subluxation/dislocation can lead to manubriosternal septic arthritis in patients with kyphoscoliosis

Locally deranged joint anatomy can predispose to septic arthritis which can be managed by surgical debridement. We present a case of manubriosternal subluxation/dislocation caused by kyphoscoliosis leading to manubriosternal septic arthritis.     

Stressful life events precede exacerbations of multiple sclerosis

OBJECTIVE: We longitudinally monitored life events and health changes in patients with multiple sclerosis (MS) to determine whether stressful events may trigger exacerbation of MS. METHODS: Twenty-three women with MS were followed for 1 year. Each subject completed the Psychiatric Epidemiologic Research Interview on a weekly basis. Further information on potentially stressful events was acquired using the Life Events and Difficulties Schedule. Neurologic symptoms were also monitored on a weekly basis throughout the year. Potential MS exacerbations were confirmed by a neurologist who was blind to the presence and timing of stressors. RESULTS: Eighty-five percent of MS exacerbations were associated with stressful life events in the preceding 6 weeks. Stressful life events occurred an average of 14 days before MS exacerbations, compared with 33 days before a randomly selected control date (p < .0001). Survival analysis confirmed that an increase in frequency of life events was associated with greater likelihood of MS exacerbations (hazard ratio = 13.18, p < .05). CONCLUSIONS: These results are consistent with the hypothesis that stress is a potential trigger of disease activity in patients with relapsing-remitting MS.