Modulation and function of caspase pathways in B lymphocytes

Summary:  During their development, B-lineage cells are selected to mature, to die, to divide, or to survive and wait, ready to respond to external signals. The homeostatic balance between growth, death, and survival is mediated by signaling pathways through the B-cell antigen receptor (BCR) complex, cytokine and chemokine receptors or cell–cell coreceptor interactions. The BCR complex is a master regulator essential at key checkpoints during development. These checkpoints involve various processes, including negative selection (deletion), anergy, receptor editing, and positive selection. Without BCRs or downstream BCR-signaling components, B-lineage cells arrest during development. Removal of BCRs from mature B cells leads to their death. Here, we discuss signaling pathways in B cells that activate members of the caspase family of cysteine proteases. In some B-cell subsets, BCR signaling activates caspases, which in turn induce a program leading to cell death. However, in other contexts, caspases are involved in the proliferation of B cells. The outcome depends in part on the presence or absence of modifiers that affect signaling thresholds and on which caspases are activated. These mechanisms allow the coordinated regulation of proliferation and apoptosis that is essential for lymphoid homeostasis.     

Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung

Lung carcinoids occur sporadically and rarely in association with multiple endocrine neoplasia type 1 (MEN1). There are no well defined genetic abnormalities known to occur in these tumors. We studied 11 sporadic lung carcinoids for loss of heterozygosity (LOH) at the locus of the MEN1 gene on chromosome 11q13, and for mutations of the MEN1 gene using dideoxy fingerprinting. Additionally, a lung carcinoid from a MEN1 patient was studied. In four of 11 (36%) sporadic tumors, both copies of the MEN1 gene were inactivated. All four tumors showed the presence of a MEN1 gene mutation and loss of the other allele. Observed mutations included a 1 bp insertion, a 1 bp deletion, a 13 bp deletion and a single nucleotide substitution affecting a donor splice site. Each mutation predicts truncation or potentially complete loss of menin. The remaining seven tumors showed neither the presence of a MEN1 gene mutation nor 11q13 LOH. The tumor from the MEN1 patient showed LOH at chromosome 11q13 and a complex germline MEN1 gene mutation. The data implicate the MEN1 gene in the pathogenesis of sporadic lung carcinoids, representing the first defined genetic alteration in these tumors.      

Murine lupus nephritis: effect of azathioprine on glomerular permeability and localization of immunoreactants.

We investigated the effect of azathioprine on glomerular permeability and deposition of immunoreactants in NZB/W mice. Glomerular permeability, assessed by proteins excreted in the urine and by a molecular probe of anionic sites of the basement membrane, underwent negligible changes, in comparison to pre-treatment findings, and deposits of immunoreactants were largely mesangial and were decreased overall. Therapy with azathioprine preserved glomerular structure and function by decreasing the amount of immunoreactants, by inducing a preferential mesangial localization of immunoreactants, and, possibly, by interfering with factors that favor the deposition of immunoreactants in the glomerular capillary wall.     

Nonhereditary p53 mutations in T-cell acute lymphoblastic leukemia are associated with the relapse phase

We have previously reported that greater than 60% of human leukemic T- cell lines possess mutations in the p53 tumor suppressor gene. To determine whether T-cell acute lymphoblastic leukemia (T-ALL) patient samples possess p53 mutations, we screened peripheral blood-and bone marrow-derived leukemia samples, taken at diagnosis and at relapse, for p53 mutations. Exons 4 through 9 and selected intron regions of the p53 gene were analyzed using polymerase chain reaction-single-strand conformation polymorphism and direct sequencing. p53 mutations were found in 0 of 15 T-ALL diagnosis samples, as compared with 10 of 36 (28%) T-ALL relapse samples. To determine whether p53 mutations play a role in the recurrence (relapse) of T-ALL, two special groups of T-ALL patients were studied: (1) a group of 8 relapse patients whose disease was refractory to chemotherapeutic treatment, and (2) a group of 6 "paired" T-ALL cell samples from patients for whom we possess both diagnosis and relapse samples. Three of 8 relapsed patients (37.5%) whose disease was refractory to the reinduction of remission by chemotherapy possessed missense mutations of the p53 gene. All 3 cases had mutations in exon 5. Among the paired samples, 3 of 6 patients harbored p53 mutations at disease recurrence, but possessed only wild- type p53 alleles at diagnosis. One case had mutation on exon 4, 1 case in exon 5, and 1 case in exon 8 with loss of heterozygosity. These data clearly indicate that recurrence of T-ALL is associated with missense mutations in p53. Our results indicate that (1) mutations of p53 do occur in T-ALL in vivo, and such mutations are associated with the relapse phase of the disease; and (2) p53 mutation is involved in the progression of T-ALL. This conclusion is supported by our observation that the introduction of T-ALL-derived mutant p53 expression constructs into T-ALL cell lines further increases their growth rate in culture, enhances cell cloning in methylcellulose, and increases tumor formation in nude mice.     

Clinical Benchmark for Gastric Stapling Procedures

To help answer the call to cut costs of surgical care, hospitals and physicians have joined to compare methods of care for the more common Diagnosis Related Group (DRG) diagnoses to form a Benchmark. Since many bariatric surgeons are the only ones performing this surgery in their primary hospitals, they do not have two or more surgical routines for comparison. This presentation compares data for the preoperative work-up, operating-room, and methods of postoperative care used by 29 members of the American Society for Bariatric Surgery (ASBS). There was representation of both academic and private surgeons and hospitals. To target areas for possible savings, the hospital bills of 16 patients without complication were compared. The synthesis of this information revealed significant differences in the extent and cost of preoperative work-up, antibiotic coverage, other postoperative care, and length of stay. These differences are examined under the assumption that patient outcome was the same.     

碱离子水饮用后血小板聚集率的的变化(附30例报告)

目的:报告30例饮用豪斯牌碱离子水前、后血小板聚集率的变化。方法:饮用碱离子水前、后(2～3月,>3～6月)作比浊法血小板聚集试验,以1分钟、5分钟及5分钟内最大聚集率(Max％)为指标,同时检测部分血粘度指标及凝血因子,并用自动生化仪检测血糖、血脂、主要电解质及部分肝、肾功能。结果:饮碱离子水后,血小板聚集率明显下降,而以疾病组(Max>80％)下降尤为明显,P均<0.001。饮碱离子水后血小板聚集率的下降,部分可能与损伤的血管内皮得到修复有关。主要电解质及部分肝、肾功能无明显异常改变。结论:由于心、脑血管血栓性疾病患者血小板聚集率多明显升高,饮碱离子水后血小板聚集率明显下降,且长期饮用对主要电解质及部分肝、肾功能无明显异常改变,作者认为碱离子水使用方例、安全、有效、价廉,因而对心、脑血管血栓性疾病防治方面可能是一种积极的辅助方法,值得临床进一步探索。