Activation-induced cell death of aggressive histology lymphomas by CD40 stimulation: induction of bax

CD40 is present on both normal and neoplastic B-lineage cells. CD40 stimulation of normal B cells has been shown to promote normal growth and differentiation, whereas aggressive histology B lymphomas are growth inhibited. The inhibition of neoplastic B-cell growth is believed to occur via activation-induced cell death in which stimuli that typically promote the growth of normal cells prevent the growth of their neoplastic counterparts. We show here that CD40 stimulation using either a soluble recombinant human CD40 ligand (srhCD40L) or anti-CD40 monoclonal antibody resulted in apoptosis of human Burkitt lymphoma cell lines. Additional studies examining the mechanism of CD40-mediated death revealed an increase in bax messenger RNA with a subsequent increase in Bax protein in the mitochondria of the treated cells. In vitro exposure of the cells to bax antisense oligonucleotides resulted in a significant decline in Bax protein levels and partial protection from CD40-mediated death, indicating that induction of Bax was at least one mechanism underlying this inhibitory effect of CD40 stimulation on lymphomas. When immunodeficient mice bearing Burkitt lymphoma were treated with srhCD40L, significant increases in survival were observed indicating a direct antitumor effect as a result of CD40 stimulation in vivo. Overall, these results demonstrate that CD40 ligation of aggressive histology B-lymphoma cells results in inhibition both in vitro and in vivo and thus may be of potential clinical use in their treatment.     

Long-Term Outcome of Overlapping Anal Sphincter Repair

PURPOSE: This study reviews the long-term outcome of overlapping anal sphincteroplasty for acquired anal incontinence. METHODS: Seventy-one consecutive patients underwent overlapping sphincteroplasty from 1989 to 1996. Current degree of continence and associated quality of life were determined by telephone interview using the Fecal Incontinence Severity Index and Fecal Incontinence Quality of Life Scale, as validated by The American Society of Colon and Rectal Surgeons. Both the patient-rated and the surgeon-rated Fecal Incontinence Severity Index scores were recorded. Demographic and perioperative data were obtained from patient charts. RESULTS: Forty-nine (69 percent) of the 71 patients, with a median age of 38.5 (range, 22–80) years, could be contacted at a median of 69 (range, 48–141) months after sphincter repair. Four patients were diverted at the time of follow-up. Twenty-four (54 percent) patients were incontinent to liquid or solid stool, and only six patients (14 percent) were totally continent. Fifteen patients (34 percent) had the best possible Fecal Incontinence Quality of Life score of 16. The median patient-rated and surgeon-rated Fecal Incontinence Severity Index scores were 20 (range, 0–61) and 20 (range, 0–57), respectively. The patient-rated score correlated to the surgeon-rated score (r = 0.98, P < 0.001) and the Fecal Incontinence Quality of Life score (r = 0.64, P < 0.001). CONCLUSION: Years after sphincter repair surgery more than half of the patients are incontinent to liquid or solid stool. The American Society of Colon and Rectal Surgeons-validated Fecal Incontinence Severity Index and Fecal Incontinence Quality of Life scores are useful and complementary tools for evaluation of fecal incontinence.     

Shoulder disorders—Part 2: Examination

Thorough evaluation of patients with shoulder problems should classify patients into discreet diagnostic groups—red flags, impingement syndrome, adhesive capsulitis, shoulder instability. Most rotator cuff tendonitis patients fall into the impingement category. The most important aspect of the initial evaluation is to rule out red flags suggestive of tumor, infection or fracture. If present such patients always require additional testing and often referral.A patient will be classified into the impingement category if there is (a) pain with active shoulder motions (i.e., painful arc), (b) pain with overpressure of passive shoulder elevation (i.e., a positive Neer's test) or horizontal shoulder adduction/internal rotation (Hawkins test), and (c) painfully weak resisted shoulder motions. Impingement syndrome patients should also be evaluated for partial or full-thickness rotator cuff tears, especially if the response to 4–6 weeks of rehabilitation is unsatisfactory.Patients with adhesive capsulitis have severe ROM loss. The most restricted ROMs are with shoulder abduction, external rotation, and flexion. In contrast, patients with shoulder instability are hypermobile. A history of recurrent dislocations is often present. An apprehension sign may be present. SLAP II-IV lesions are common in this patient group and the labrum can be seen to be stretched anterior during many of the functional tests.     

Mouse models of IgG- and IgM-mediated hemolysis

Well-characterized mouse models of allo-immune antibody-mediated hemolysis would provide a valuable approach for gaining greater insight into the pathophysiology of hemolytic transfusion reactions. To this end, mouse red blood cells (mRBCs) from human glycophorin A transgenic (hGPA-Tg) donor mice were transfused into non-Tg recipients that had been passively immunized with IgG or IgM hGPA-specific monoclonal antibodies (mAbs). In this novel murine "blood group system," mRBCs from hGPA-Tg mice are "antigen positive" and mRBCs from non-Tg mice are "antigen negative." Passive immunization of non-Tg mice with the IgG1 10F7 and IgG3 NaM10-2H12 anti-hGPA mAbs each induced rapid clearance of incompatible transfused hGPA-Tg-mRBCs in a dose-response manner. Using various knockout mice as transfusion recipients, both the complement system and activating Fcgamma receptors were found to be important in the clearance of incompatible mRBCs by each of these IgG mAbs. In addition, the IgM E4 anti-hGPA mAb induced complement-dependent intravascular hemolysis of transfused incompatible hGPA-Tg-mRBCs accompanied by gross hemoglobinuria. These initial studies validate the relevance of these new mouse models for addressing important questions in the field of transfusion medicine.     

肾移植术后卡氏肺囊虫肺炎5例回顾性分析

目的:观察肾移植术后卡氏肺囊虫肺炎的发生率及治疗效果。方法:选择2003-01/2005-12在中山市人民医院行肾移植的患者112例,患者均知情同意。按是否使用猪抗人淋巴细胞免疫球蛋白分为2组,基础免疫抑制组(n=68)给予环孢素A/他克莫司 吗替麦考酚酯 强的松;抗体诱导组(n=44)给予猪抗人淋巴细胞免疫球蛋白 环孢素A/他克莫司 吗替麦考酚酯 强的松。两组共发生卡氏肺囊虫肺炎5例,其中基础免疫抑制组2例,抗体诱导组3例。5例患者通过普通抗感染治疗,3～7d病情未见好转,遂行支气管镜活检 深部吸痰培养,尽早明确病原体,指导抗菌治疗。比较两组患者卡氏肺囊虫肺炎的发生率,并观察其治疗效果。结果:5例卡氏肺囊虫肺炎患者全部进入结果分析,无脱落。①5例患者经支气管纤维镜肺组织活检确诊为卡氏肺囊虫肺炎,发生率为4.46%,其中抗体诱导组6.82%(3/44)明显高于基础免疫抑制组2.94%(2/68)。②5例卡氏肺囊虫肺炎中2例合并金黄色葡萄球菌感染。以复方磺胺甲恶唑为基础药物进行综合治疗,3例患者临床治愈出院,随访3个月,移植肾及肺功能正常;死亡2例。③5例患者治疗期间均无排斥反应发生。④在发病初期5例患者的CD4/CD8平均值为1.02±0.15,3例治愈患者的CD4/CD8平均值为1.42±0.23,在恢复过程中逐渐升高。2例死亡患者的CD4/CD8平均值为1.10±0.21。结论:早期支气管纤维内镜活检对肾移植术后卡氏肺囊虫肺炎的诊断非常重要,早期诊断、早期治疗是治愈的关键。猪抗人淋巴细胞免疫球蛋白可增加肾移植术后卡氏肺囊虫肺炎的发生率。     

Should we educate about the risks of medication overuse headache?

Background

Medication-overuse headache (MOH) is caused by the regular use of medications to treat headache. There has been a lack of research into awareness of MOH. We distributed an electronic survey to undergraduate students and their contacts via social networking sites. Analgesic use, awareness of MOH, perceived change in behaviour following educational intervention about the risks of MOH and preferred terminology for MOH was evaluated.

Findings

485 respondents completed the questionnaire (41% having received healthcare training). 77% were unaware of the possibility of MOH resulting from regular analgesic use for headache. Following education about MOH, 80% stated they would reduce analgesic consumption or seek medical advice. 83% indicated that over the counter analgesia should carry a warning of MOH. The preferred terminology for MOH was painkiller-induced headache.

Conclusions

This study highlights the lack of awareness of MOH. Improved education about MOH and informative packaging of analgesics, highlighting the risks in preferred lay terminology (i.e. painkiller-induced headache), may reduce this iatrogenic morbidity and warrants further evaluation.     

Facilitating the decrease in fibromyalgic pain during metabolic rehabilitation: an essential role for soft tissue therapies

Recent evidence indicates that fibromyalgia (FMS) is a manifestation of impaired metabolism. In most cases, the cause is primarily inadequate thyroid hormone regulation of cell function. The measurable features of FMS can be improved or relieved in most patients through therapy that is best termed ‘metabolic rehabilitation’. For many patients undergoing metabolic rehabilitation, however, FMS pain scores normalize only after soft tissue treatment controls or eliminates noxious neural input from the musculoskeletal system to the central nervous system. Our studies and clinical experiences convince us that effective soft tissue therapy can expedite the typical patient's improvement or recovery. Neglecting to use such therapy can hinder recovery, even when the patient undergoes expertly conducted metabolic rehabilitation. This paper describes the probable mechanisms by which musculoskeletal lesions can sustain FMS pain, and gives guidelines for treating the FMS patient's soft tissues to facilitate the reduction of pain during metabolic rehabilitation.     

The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy

BACKGROUND: The administration of blood components from donors who subsequently develop Creutzfeldt-Jakob disease has raised the issue of blood as a possible vehicle for iatrogenic disease. STUDY DESIGN AND METHODS: We examined infectivity in blood components and Cohn plasma fractions in normal human blood that had been "spiked" with trypsinized cells from a scrapie-infected hamster brain, and in blood of clinically ill mice that had been inoculated with a mouse-adapted strain of human transmissible spongiform encephalopathy. Infectivity was assayed by intracerebral inoculation of the blood specimens into healthy animals. RESULTS: Most of the infectivity in spiked human blood was associated with cellular blood components; the smaller amount present in plasma, when fractionated, was found mainly in cryoprecipitate (the source of factor VIII) and fraction I+II+III (the source of fibrinogen and immunoglobulin); almost none was recovered in fraction IV (the source of vitamin-K-dependent proteins) and fraction V (the source of albumin). Mice infected with the human strain of spongiform encephalopathy had very low levels of endogenous infectivity in buffy coat, plasma, cryoprecipitate, and fraction I+II+III, and no detectable infectivity in fractions IV or V. CONCLUSION: Convergent results from exogenous spiking and endogenous infectivity experiments, in which decreasing levels of infectivity occurred in cellular blood components, plasma, and plasma fractions, suggest a potential but minimal risk of acquiring Creutzfeldt-Jakob disease from the administration of human plasma protein concentrates.     

大肠癌免疫组化表达与临床病理的关系

目的:探讨大肠癌CEA、P53、nm23、Ki-67、MRP免疫组化表达特点和相互关系,及其与临床病理的关系．方法:回顾性分析2003-01／2006-07我院收治的73例大肠癌患者的临床病理及随访资料,并对其石蜡标本采用免疫组化SP染色法检测CEA、P53、nm23、Ki-67、MRP,分析其免疫组化特点及其与临床病理之间的关系．结果:CEA、P53、nm23、Ki-67、MRP在大肠癌中的阳性表达率依次为82．2％、68．5％、75.3％、84．9％和64．4％．CEA、MRP与大肠癌患者的各因素无统计学差异．P53、Ki-67和nm23与肿瘤的Dukes分期和淋巴结转移有关, P53、Ki-67在Dukes C、D期的阳性表达率(依次为82．8％和100％1明显高于Dukes A、B期者(59．1％和75．0％)(P<0．05),而nm23在Dukes C、D期的阳性表达率(58．6％)明显低于Dukes A、B期者(86．4％)(P<0．05)．CEA与nm23的表达呈明显的负相关(r=-0．296,P=0．011),而P53和Ki-67表达之间呈现明显的正相关(r= 0．308,P=0．008),其他各指标间的表达无相关性．nm23、P53和Ki-67与预后因素关系明显,nm23在生存期≥3 a患者的阳性表达率(92．9%)高于生存期<3 a者(71．2％)(P<0．05),而P53和Ki-67在生存期≥3 a患者的阳性表达率(依次为42．9％和64.3％)明显低于生存期<3 a者(74．6％和89．8％)(P<0．05)．结论:P53、Ki-67和nm23的表达与大肠癌的侵袭转移和预后密切相关．CEA可能是大肠癌的侵袭转移的促进因素．MRP所引起的耐药机制是一个相对独立的机制．CEA、P53、nm23、Ki-67可作为判断大肠癌恶性程度、侵袭转移以及预后的指标．     

Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation

In an attempt to decrease the relapse rate after bone marrow transplantation (BMT) for advanced acute leukemia, we initiated studies using 131I-labeled anti-CD45 antibody (BC8) to deliver radiation specifically to hematopoietic tissues, followed by a standard transplant preparative regimen. Biodistribution studies were performed in 23 patients using 0.5 mg/kg trace 131I-labeled BC8 antibody. The BC8 antibody was cleared rapidly from plasma with an initial disappearance half-time of 1.5 +/- 0.2 hours, presumably reflecting rapid antigen- specific binding. The mean radiation absorbed doses (cGy/mCi131I administered) were as follows: marrow, 7.1 +/- 0.8; spleen, 10.8 +/- 1.4; liver, 2.7 +/- 0.2; lungs, 2.1 +/- 0.1; kidneys, 0.7 +/- 0.1; and total body, 0.4 +/- 0.03. Patients with acute myelogenous leukemia (AML) in relapse had a higher marrow dose (11.4 cGy/mCi) than those in remission (5.2 cGy/mCi; P = .001) because of higher uptake and longer retention of radionuclide in marrow. Twenty patients were treated with a dose of 131I estimated to deliver 3.5 Gy (level 1) to 7 Gy (level 3) to liver, with marrow doses of 4 to 30 Gy and spleen doses of 7 to 60 Gy, followed by 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI). Nine of 13 patients with AML or refractory anemia with excess blasts (RAEB) and two of seven with acute lymphocytic leukemia (ALL) are alive disease-free at 8 to 41 months (median, 17 months) after BMT. Toxicity has not been measurably greater than that of CY/TBI alone, and the maximum tolerated dose has not been reached. This study demonstrates that with the use of 131I-BC8 substantially greater doses of radiation can be delivered to hematopoietic tissues as compared with liver, lung, or kidney, which may improve the efficacy of marrow transplantation.