Multiple Sclerosis: Fas Signaling in Oligodendrocyte Cell Death

Fas is a cell surface receptor that transduces cell death signals when cross-linked by agonist antibodies or by fas ligand. In this study, we examined the potential of fas to contribute to oligodendrocyte (OL) injury and demyelination as they occur in the human demyelinating disease multiple sclerosis (MS). Immunohistochemical study of central nervous system (CNS) tissue from MS subjects demonstrated elevated fas expression on OLs in chronic active and chronic silent MS lesions compared with OLs in control tissue from subjects with or without other neurologic diseases. In such lesions, microglia and infiltrating lymphocytes displayed intense immunoreactivity to fas ligand. In dissociated glial cell cultures prepared from human adult CNS tissue, fas expression was restricted to OLs. Fas ligation with the anti-fas monoclonal antibody M3 or with the fas–ligand induced rapid OL cell membrane lysis, assessed by LDH release and trypan blue uptake and subsequent cell death. In contrast to the activity of fas in other cellular systems, dying OLs did not exhibit evidence of apoptosis, assessed morphologically and by terminal transferase–mediated d-uridine triphosphate-biotin nick-end-labeling staining for DNA fragmentation. Other stimuli such as C2-ceramide were capable of inducing rapid apoptosis in OLs. Antibodies directed at other surface molecules expressed on OLs or the M33 nonactivating anti-fas monoclonal antibody did not induce cytolysis of OLs. Our results suggest that fas-mediated signaling might contribute in a novel cytolytic manner to immune-mediated OL injury in MS.     

Accuracy of multislice computed tomography in the preoperative assessment of coronary disease in patients with aortic valve stenosis.

OBJECTIVES: To evaluate multislice computed tomography (MSCT) as an alternative to coronary angiography, we prospectively studied its diagnostic accuracy for the detection of significant coronary artery lesions in patients with significant aortic valve stenosis undergoing valve surgery. BACKGROUND: In patients with aortic valve stenosis, coronary angiography is still recommended before surgery. Multislice computed tomography is a promising noninvasive technique for the detection of significant coronary artery lesions. METHODS: Fifty-five consecutive patients scheduled for coronary angiography in the preoperative assessment of aortic valve stenosis underwent 16-slice MSCT 24 h before coronary angiography. We analyzed coronary lesions, image quality, and arterial calcium score. RESULTS: The sensitivity of the MSCT-based strategy in detecting significant stenosis was 100%, and its specificity 80%. The positive and negative predictive values were respectively 55% and 100%. For calcium scores <1,000 (77% of patients), MSCT detected all patients without coronary artery disease, enabling conventional coronary angiography to be avoided in 35 of 55 cases (80%). For calcium scores >1,000, MSCT enabled conventional coronary angiography to be avoided in only 6% of cases, either because significant stenosis was found with a possible indication of revascularization, or because the examination was not interpretable. CONCLUSIONS: The results of this initial experience in relatively few patients suggest that MSCT-based coronary angiography may serve as an alternative to invasive coronary angiography to rule out significant coronary artery disease in patients scheduled for elective aortic valve replacement. Larger studies are necessary to fully explore the potential of coronary MSCT to improve preoperative risk stratification.     

A neutralizing monoclonal antibody (mAb A24) directed against the transferrin receptor induces apoptosis of tumor T lymphocytes from ATL patients

Adult T-cell leukemia/lymphoma (ATL) is an aggressive lymphoid proliferative disease that exists under diverse clinical forms ranging from chronic to acute. Although leukemic cells from patients with ATL exhibit an intrinsic resistance to chemotherapy, monoclonal antibodies directed against CD25 (interleukin 2 receptor alpha [IL-2Ralpha] antibody) have been used as specific therapeutic agents. However, significant clinical results with these antibodies have been demonstrated only in chronic forms of ATL. In contrast to resting T cells, human T-cell lymphotropic virus type 1 (HTLV-1)-infected cells constitutively express high levels of surface transferrin receptor (TfR). Herein, we report the characterization of a new monoclonal antibody (mAb A24) directed against the human TfR and the evaluation of its capacity to block the proliferation of ATL cells ex vivo. We determined that A24 binds TfR with an equilibrium constant (K'd) of 2.7 nM and competes with transferrin for binding to TfR. A24 also inhibited [55Fe]-transferrin uptake in activated T cells and blocked T-cell proliferation. Moreover, A24 reduced and impaired TfR expression and recycling, respectively. Most important, we showed that A24 blocked the ex vivo proliferation of malignant T cells from both acute and chronic forms of ATL, through induction of programmed cell death. Therefore efficient therapeutic tools to treat acute forms of ATL might be derived from A24.     

Effect of aerobic training on plasma levels and subcutaneous abdominal adipose tissue gene expression of adiponectin, leptin, interleukin 6, and tumor necrosis factor alpha in obese women

Adipocytokines secreted by adipose tissue are suggested to play a role in the development of obesity-related complications. Regular aerobic exercise has been shown to reduce the risk of metabolic complications in obese subjects. The aim of this study was to investigate the effect of aerobic training on gene expression in subcutaneous abdominal adipose tissue (SCAAT) and on plasma levels of several adipocytokines in obese women. Twenty-five obese sedentary premenopausal women (body mass index, 32.18 +/- 3.17 kg/m(2)) underwent a 12-week aerobic exercise program, with a frequency of 5 d/wk and intensity corresponding to 50% of individual maximal oxygen consumption (V(.-)(O(2)max)) consisting of 2 sessions per week of supervised aerobic exercise and 3 sessions per week of home-based exercise on a bicycle ergometer. Before and after the aerobic training, (V(.-)(O(2)max)) and body composition were measured and plasma and SCAAT biopsy samples (in a subgroup of 8 subjects) were obtained for determination of plasma and messenger RNA levels of adipocytokines (leptin, adiponectin, interleukin 6, tumor necrosis factor alpha). The aerobic training resulted in an increase of subjects' V o(2)max by 12.8% (24.6 +/- 3.9 vs 27.7 +/- 4.8 mL x min(-1) x kg(-1), P < .05). Body weight and fat mass were reduced by 5.9% (88.5 +/- 8.2 vs 83.3 +/- 7.7 kg, P < .001) and 6.4% (38.8 +/- 4.2% vs 36.3 +/- 4.6%, P < .001), respectively, and the revised QUantitative Insulin sensitivity ChecK Index (QUICKI) increased (0.43 +/- 0.06 vs 0.48 +/- 0.06, P < .05) during the aerobic training. No aerobic training-induced changes in messenger RNA levels of the investigated genes in SCAAT were observed. A decrease of plasma leptin (24.3 +/- 8.7 vs 18.1 +/- 8.3 ng/mL, P < .05) was detected, whereas plasma levels of other cytokines remained unchanged. In moderately obese females, 3 months' aerobic training did not promote changes in the adipose tissue gene expression or plasma levels of the adipocytokines (except for leptin) involved in a regulation of lipid and carbohydrate metabolism.     

Dasatinib enhances megakaryocyte differentiation but inhibits platelet formation

Dasatinib is a novel, potent, ATP-competitive inhibitor of Bcr-Abl, cKIT, and Src family kinases that exhibits efficacy in patients with imatinib-resistant chronic myelogenous leukemia. Dasatinib treatment is associated with mild thrombocytopenia and an increased risk of bleeding, but its biological effect on megakaryocytopoiesis and platelet production is unknown. In this study, we show that dasatinib causes mild thrombocytopenia in mice without altering platelet half-life, suggesting that it inhibits platelet formation. Conversely, the number of megakaryocytes (MKs) in the bone marrow of dasatinib-treated mice was increased and the ploidy of MKs derived from bone marrow progenitor cells in vitro was elevated in the presence of dasatinib. Furthermore, a significant delay in platelet recovery after immune-induced thrombocytopenia was observed in dasatinib-treated mice even though the number of MKs in the bone marrow was increased relative to controls at all time points. Interestingly, the migration of MKs toward a gradient of stromal cell-derived factor 1α (SDF1α) and the formation of proplatelets in vitro were abolished by dasatinib. We propose that dasatinib causes thrombocytopenia as a consequence of ineffective thrombopoiesis, promoting MK differentiation but also impairing MK migration and proplatelet formation.     

Identification of plasma glucocorticoids in pallid sturgeon in response to stress

Compared to teleosts, little is known about the stress response in chondrosteans, and the glucocorticoid(s) most responsive to stress have never been definitively determined in sturgeon. In terms of cortisol production, pallid sturgeon (Scaphirhynchus albus) have a low physiological response to stress compared to other sturgeons (Acipenser s.p.). Because of this, our null hypothesis was that cortisol is not the predominant glucocorticoid secreted in response to stress in pallid sturgeon. Our objective was to identify the putative glucocorticoids present in the plasma of pallid sturgeon during the stress response. Pallid sturgeon were subjected to a severe confinement stress (12 h) with an additional handling stressor for the first 6 h. Control fish were not subjected to confinement but were handled only to collect blood. Blood plasma was collected at time 0, 6, and 12 h. Gas chromatography/mass spectrometry was used to screen the plasma for the spectrum of glucocorticoids and determine the putative steroid secreted during the stress response. Cortisol was the primary glucocorticoid detected in stressed pallid sturgeon. In addition, the cortisol metabolites cortisone, alloTHE (5alpha-pregnane-3alpha,17alpha,21-triol-11,20-dione), allo-alpha-cortolone (3alpha,17alpha,20alpha,21-tetrahydro-5alpha-pregnan-11-one), and allo-beta-cortolone (3alpha,17alpha,20beta,21-tetrahydro-5alpha-pregnan-11-one) were detected. Plasma cortisol increased from a resting concentration of 0.67 ng/ml to 10.66 ng/ml at 6h followed by a decrease to 6.78 ng/ml by 12 h. Plasma glucose increased significantly by time 6 and 12 h in both stressed and unstressed groups and remained elevated at time 12h, while resting lactate concentrations were low to non-detectable and did not increase significantly with the stressor over time. Cortisol was the primary glucocorticoid synthesized and secreted in response to a stressor in pallid sturgeon. Though the proportional increase in plasma cortisol in stressed pallid sturgeon was lower than many other species of sturgeon, the concentration was high enough to elicit a secondary stress response as seen by changes in plasma glucose.     

Pathology of extrinsic ligaments: a pictorial essay

The role of the extrinsic ligaments, together with the intrinsic ligaments, appears to be much more important than previously thought in the setting of carpal stability. The anatomy and pathology of the extrinsic wrist ligaments is complex. Magnetic resonance imaging (MRI) with thin slices is essential for visualization. This article describes the pathological appearance of the extrinsic palmar and dorsal radiocarpal and ulnocarpal ligaments on MRI, correlated with arthroscopy (performed by two skilled hand surgeons), clinical findings, and follow-up. High-resolution MRI, especially using isotropic three-dimensional sequences with orthogonal multiplanar reconstructions on 3T MR systems, allows detailed depiction of many of the extrinsic ligaments affected in carpal injuries. Recognition of ligament abnormalities is improved by intra-articular or intravenous injection of contrast before the examination. Both techniques may help to determine the precise localization, size, and extent of dorsal and palmar radiocarpal and ulnocarpal ligament lesions. Further experience with these techniques is needed to define the place of MRI in the management of traumatic wrist injuries.     

Serial adoptive transfer of murine experimental allergic encephalomyelitis: successful transfer is dependent on active disease in the donor

In an attempt to understand the mechanisms underlying disease progression in adoptively transferred experimental allergic encephalomyelitis (EAE), and perhaps multiple sclerosis (MS), this study has examined the transfer of EAE serially from primary to secondary and tertiary recipients using myelin basic protein (MBP)-responsive lymphocytes. It was found that EAE could be serially transferred only when there was acute or relapsing disease activity in the donor animal. Cells from donors with quiescent disease did not transfer EAE. Autoradiographic attempts to locate primary adoptively transferred cells in the central nervous system of secondary and tertiary recipients were uniformly unsuccessful. These findings implicate the requirement of effector cell activation in the donor and the recruitment of augmenting autoimmune cells in lesion formation.