Delayed bowel erosion by tension-free vaginal tape (TVT).

A 71-year-old woman who had had a previous abdominal hysterectomy and Burch operation presented with stress urinary incontinence due to intrinsic urethral sphincter deficiency. She underwent a technically difficult placement of a TVT tape in April 2002. After an uneventful recovery she was discharged after 72 hours but presented almost 5 months later with small bowel obstruction. At laparotomy she had a loop of ileum adherent to the left lower side wall of the pelvis, with the TVT tape penetrating and traversing this loop. The ileal segment was excised and an end-to-end anastomosis performed. Her recovery was uneventful and she is maintaining her urinary continence. Patients who have had previous combined pelvic intra- and extraperitoneal surgery should be operated on by experienced surgeons and be observed for 24 hours. The placement of a Uratape (Porges-Mentor) via a transobturator approach should also be considered in such cases.

Differences by race, sex and age in the clinical and immunologic features of recently diagnosed systemic lupus erythematosus patients in the southeastern United States.

We examined the prevalence of clinical and immunologic features of systemic lupus erythematosus (SLE) by race, sex and age in a population-based study of 265 SLE patients. Patients fulfilled the American College of Rheumatology classification criteria. The median time between diagnosis and study enrollment was 13 months. The clinical and hematologic data were limited to occurrences up to 6 months after the diagnosis date, as documented in medical records. We used sera collected at study enrollment from 244 (92%) patients for serologic testing of autoantibodies. The associations between clinical and immunological features of SLE and age, sex and race were examined using logistic regression. The effect of each of these variables was examined adjusting for the other two demographic factors. Mean age at diagnosis was 6 years younger among African-Americans and other minorities compared with white patients (P < 0.01). Discoid lupus, proteinuria, anti-Sm and anti-RNP autoantibodies were more commonly seen in African-American patients, with odds ratios higher than 3.0. Photosensitivity and mucosal ulcers were noted less often in African-American patients. Proteinuria, leukopenia, lymphopenia and thrombocytopenia were approximately three times more common in men compared with women. The prevalence of oral or nasal ulcers and anti-DNA autoantibodies declined with age. The extent to which the differences we observed reflect genetic or environmental influences on the disease process should be investigated.

Fas, ceramide and serum withdrawal induce apoptosis via a common pathway in a type II Jurkat cell line.

Ceramide is a key mediator of apoptosis, yet its role in Fas-mediated apoptosis is controversial. Some reports have indicated that ceramide is either a primary signaling molecule in Fas-induced cell death, or that it functions upstream of Fas by increasing FasL expression. Other studies have suggested that ceramide is not relevant to Fas-induced cell death. We have approached this problem by studying ceramide-induced apoptosis in unique Jurkat cell clones selected for resistance to membrane-bound FasL-induced death. Resistance of the mutant Jurkat cells was specific for FasL killing, since the mutant clones were sensitive to other apoptotic stimuli such as cycloheximide and staurosporine. We tested the effects of serum withdrawal, one of the strongest inducers of ceramide, and of exogenous ceramide on apoptosis of both wild-type and FasL-resistant clones. Wild-type Jurkat cells were remarkably sensitive to serum withdrawal and to exogenous ceramide. In contrast all FasL-resistant mutant clones were resistant to these apoptosis-inducing conditions. In contrast to previous work, we did not detect an increase in FasL in either wild-type or mutant clones. Moreover activation of stress-activated protein kinases (JNK/SAPKs) after serum withdrawal and exogenous ceramide treatment was detected only in the wild-type and not in the resistant clones. Because of the parallel resistance of the mutant clones to Fas and to ceramide-induced apoptosis, our data support the notion that ceramide is a second messenger for the Fas/FasL pathway and that serum withdrawal, through production of ceramide, shares a common step with the Fas-mediated apoptotic pathway. Finally, our data suggest that activation of JNK/SAPKs is a common mediator of the three pathways tested.

The one-piece orbitozygomatic approach: the MacCarty burr hole and the inferior orbital fissure as keys to technique and application.

OBJECTIVE: Use of the MacCarty keyhole burr hole and the inferior orbital fissure provides simplicity and safety to perform the one-piece frontotemporal orbitozygomatic (FTOZ1) approach. METHODS: We performed the FTOZ1 approach with its three subtypes (i.e., total, temporal, and frontal) in cadaveric head specimens in the Goodyear Laboratory and subsequently in surgical cases. RESULTS: The orbitozygomatic osteotomy, when added to a frontotemporal craniotomy, comprises the frontotemporal orbitozygomatic (FTOZ) approach, provides an expanded exposure to the anterior and middle cranial fossae, and enables the surgeon to create a window to the posterior cranial fossa. The MacCarty burr hole is used to facilitate orbital cuts, and the anterolateral portion of the inferior orbital fissure connects the orbital cuts to the zygomatic cuts. This allows the FTOZ1 craniotomy flap to be "out-fractured" with ease. The three types of FTOZ1 approach, i.e., the total, the temporal, and the frontal, are described step by step. CONCLUSIONS: Understanding the MacCarty keyhole burr hole and the microsurgical anatomy of the inferior orbital fissure is essential to performing the FTOZ1 approach. The three types of FTOZ1 approach enable the surgeon to tailor the approach according to the surgical exposure needed for each lesion.

Early carotid endarterectomy for critical carotid artery stenosis after thrombolysis therapy in acute ischemic stroke in the middle cerebral artery.

BACKGROUND AND PURPOSE: Tissue plasminogen activator (tPA) has been shown to be effective for acute ischemic stroke. However, if a high-grade cervical carotid stenosis remains despite tPA therapy, patients are at risk for recurrent stroke. Carotid endarterectomy (CEA) has been shown to be effective in symptomatic patients with high-grade cervical carotid stenosis in reducing the risk of stroke, but it is unknown whether CEA can be performed safely after tPA thrombolysis. We describe our experience with 5 patients who underwent early (<48 hours) CEA for residual high-grade cervical carotid stenosis after thrombolytic therapy for acute ischemic stroke in the middle cerebral artery territory. METHODS: All patients had a critical (>99%) carotid artery stenosis on the symptomatic side after tPA therapy. All patients received intravenous tPA; 3 patients also received intra-aortic tPA. Three patients received intravenous heparin infusion immediately after administration of tPA. All patients showed marked improvement in their National Institutes for Health Stroke Scale scores after treatment with tPA. CEA was then performed within 45 hours (6 hours in 1 patient, 23 hours in 2, 26 hours in 1, and 45 hours in 1). RESULTS: All 5 patients underwent successful CEA. There were no complications related to surgery. At discharge, 2 patients had a normal examination, and the remaining patients had mild deficits. In a long-term follow-up of 5 to 22 months, no patient had a recurrent cerebrovascular event. CONCLUSIONS: Early CEA can be performed safely and successfully in patients after tPA treatment for acute ischemic stroke in appropriately selected patients.

Phagocytosis and clearance of apoptotic cells is mediated by MER.

Apoptosis is fundamental to the development and maintenance of animal tissues and the immune system. Rapid clearance of apoptotic cells by macrophages is important to inhibit inflammation and autoimmune responses against intracellular antigens. Here we report a new function for Mer, a member of the Axl/Mer/Tyro3 receptor tyrosine kinase family. mer(kd) mice with a cytoplasmic truncation of Mer had macrophages deficient in the clearance of apoptotic thymocytes. This was corrected in chimaeric mice reconstituted with bone marrow from wild-type animals. Primary macrophages isolated from mer(kd) mice showed that the phagocytic deficiency was restricted to apoptotic cells and was independent of Fc receptor-mediated phagocytosis or ingestion of other particles. The inability to clear apoptotic cells adequately may be linked to an increased number of nuclear autoantibodies in mer(kd) mice. Thus, the Mer receptor tyrosine kinase seems to be critical for the engulfment and efficient clearance of apoptotic cells. This has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus.

B and T cell responses to the spliceosomal heterogeneous nuclear ribonucleoproteins A2 and B1 in normal and lupus mice.

Autoantibodies directed against spliceosomal heterogeneous nuclear ribonucleoproteins (hnRNPs) are a typical feature of rheumatoid arthritis, systemic lupus erythematosus, and mixed-connective tissue disease. With the aim of investigating a potential pathogenic role of these Abs, we have studied the Ab response to A2/B1 hnRNPs in different murine models of lupus. The specificity of anti-A2/B1 Abs was tested with a series of 14 overlapping synthetic peptides covering the region 1-206 of A2 that contains most of the epitopes recognized by patients' Abs. A major epitope recognized very early during the course of the disease by Abs from most of MRL lpr/lpr mice but not from other lupus mice and from mice of different MHC haplotypes immunized against B1 was identified in residues 50-70. This peptide contains a highly conserved sequence RGFGFVTF also present in other hnRNPs and small nuclear ribonucleoproteins. Abs reacting with a second A2 epitope identified in residues 35-55 were detectable several weeks later, suggesting an intramolecular B cell epitope spreading during the course of the disease. We identified several T cell epitopes within the region 35-175 that generated an effective Th cell response with IL-2 and IFN-gamma secretion in nonautoimmune CBA/J mice sharing the same MHC haplotype H-2k as MRL/lpr mice. None of the peptides stimulated T cells primed in vivo with B1. Because Abs to peptide 50-70 were detected significantly earlier than Abs reacting with other A2 peptides and the protein itself, it is possible that within the protein, this segment contains residues playing an initiator role in the induction of the anti-A2/B1 and antispliceosome Ab response.

MHC class II-bound self peptides from autoimmune MRL/lpr mice reveal potential T cell epitopes for autoantibody production in murine systemic lupus erythematosus.

The systemic lupus erythematosus-like syndrome in MRL/lpr mice involves high-titered IgG autoantibodies, particularly antinuclear Abs that target histones, DNA, and RNA particles. Although T cell help is required for the generation of antinuclear Abs, the epitopes recognized by such helper T cells are unknown. To address this question, we isolated and sequenced self peptides bound by MHC class II molecules from MRL/lpr mice. We identified a number of peptides that are not seen in similar preparations from nonautoimmune C3H animals. The "abnormal" peptide donors include histone, a protein component of a small nuclear ribonucleoprotein, ribosomal proteins, and RNA processing enzymes. We postulate that the peptides from these donors are T cell epitopes required for the generation of the most frequent antinuclear Abs specificities seen in MRL/lpr mice.

Spontaneous and induced apoptosis in systemic lupus erythematosus: multiple assays fail to reveal consistent abnormalities.

The immunologic basis of systemic lupus erythematosus (SLE) is multifactorial and still elusive. Recent advances in the field of apoptosis have suggested new paradigms for the development of lupus autoimmunity. In the present studies we examined the possibility that individual populations of T and B cells are abnormally resistant to apoptosis or that they stand out in over- or underexpressing Fas. Fas was generally overexpressed in cells freshly isolated from SLE patients but the apoptotic response to FasL was normal. We did not find increased spontaneous ongoing apoptosis in SLE lymphocytes. Normal cleavage of PARP similarly implied that the final biochemical pathway of apoptosis is relatively intact in SLE. Finally we placed special emphasis on the response of SLE patient cells to UV irradiation, especially cells from photosensitive patients, and found no difference in Fas expression. In conclusion our results indicate that SLE patients do not suffer from a major apoptotic abnormality. The results also raise questions concerning the dynamic expression of Fas and the significance of ongoing apoptosis as a risk for autoimmune disease.

Apoptosis provoked by the oxidative stress inducer menadione (Vitamin K(3)) is mediated by the Fas/Fas ligand system.

Menadione, or vitamin K(3) (VK(3)), a potent oxidative stress inducer, has been recently used as an effective and remarkably safe cytotoxic drug for treatment of several human tumors. VK(3) induces apoptotic cell death through a poorly understood mechanism. Here we show for the first time that VK(3)-induced apoptosis requires the Fas/FasL system. Spleen cells from both Fas- and FasL-deficient mice (C57BL/6-lpr and C57BL/6-gld, respectively) had much lower levels of VK(3) apoptosis in vitro compared to cells from control C57BL/6 mice. VK(3) cytotoxicity toward mouse splenocytes was also blocked with a Fas-Fc fusion protein. VK(3) induced apoptosis in Jurkat cells, coincident with an increase in both Fas and FasL expression. A FasL-resistant variant of these Jurkat cells was also resistant to VK(3)-induced apoptosis. Furthermore, because VK(3) effects were inhibited by glutathione, a potent antioxidant, oxidative stress was linked to the Fas/FasL system. Moreover, since the Jurkat cell lines were p53 null, the activation of Fas/FasL system after oxidative stress apparently acted through a p53-independent pathway. The therapeutic relevance of the K vitamins has been growing in recent years; our findings offer new insight for improving and expanding their applications.

Differential control of autoantibodies and lymphoproliferation by Fas ligand expression on CD4+ and CD8+ T cells in vivo.

We have previously shown that the gld autoimmune syndrome is suppressed in lethally irradiated gld mice reconstituted with a mixture of normal and gld bone marrow (BM). Furthermore, in vivo depletion of normal Thy-1+ cells restores lymphoproliferation and autoantibody production in such chimeras, suggesting that T cells bearing Fas ligand are responsible for correcting the gld defect. In this study, mixed-BM chimeras lacking either normal CD4+ (B6CD4KO-B6gld) or normal CD8+ T cells (B6CD8KO-B6gld) were generated to determine the contribution of the normal T cell subsets to disease suppression. Lymphoproliferation was completely suppressed in B6CD4KO-B6gld chimeras but only modestly in B6CD8KO-B6gld chimeras. On the other hand, both types of mixed-BM chimeras had incomplete effects on the suppression of serum autoantibodies when compared with B6gld reconstituted with isologous BM. These results suggest that both T cell subsets provide Fas ligand to suppress immune cells responsible for autoantibody production; however, CD8+ T cells are mainly responsible for preventing lymphoproliferation.

Ectopic expression of B7-1 (CD80) on T lymphocytes in autoimmune lpr and gld mice.

Defective Fas-mediated apoptosis in mice, caused by the gld mutation in the fas ligand gene, results in the development of lupus-like autoantibodies and severe lymphoproliferation. We previously demonstrated ectopic expression of the costimulatory molecule B7-1 (CD80) on T lymphocytes in B6/gld mice. This report extends these observations by demonstrating similar results in B6/lpr mice, which possess a mutation in the gene encoding Fas. Additionally, we demonstrate that this phenomenon is age-dependent and occurs on multiple subsets of B6/gld T lymphocytes. B7-1 upregulation is observed on T cells from both conventionally housed and specific-pathogen-free B6/gld mice, suggesting that this is not a consequence of infection by pathogen. T cells from lpr and gld mice show increased binding of CTLA4-Ig fusion protein, suggesting that the upregulated B7-1 is functional. CD28, a receptor for B7-1 which activates T cells, is upregulated in B6/lpr and B6/gld mice, while CTLA4, a negative regulator of T cells which binds B7-1, is not. Our results suggest that ectopic expression of B7-1 on T cells of lpr and gld mice may be playing a role in exacerbation of lymphoproliferation and/or autoimmunity.

The role of environmental antigens in the spontaneous development of autoimmunity in MRL-lpr mice.

It has been proposed that the "normal" stimulation of the immune system that occurs from interactions with environmental stimuli, whether infectious or dietary, is necessary for the initiation and/or continuation of autoimmunity. We tested this hypothesis by deriving a group of MRL-lpr mice into a germfree (GF) environment. At 5 mo of age, no differences between GF and conventional MRL-lpr mice were noted in lymphoproliferation, flow cytometric analysis of lymph node cells (LN), or histologic analysis of the kidneys. Autoantibody levels were comparably elevated in both groups. A second experiment tested the role of residual environmental stimuli by contrasting GF mice fed either a low m.w., ultrafiltered Ag-free (GF-AF) diet or an autoclaved natural ingredient diet (GF-NI). At 4 mo of age, both groups showed extensive lymphoproliferation and aberrant T cell formation, although the GF-AF mice had approximately 50% smaller LNs compared with sex-matched GF-NI controls. Autoantibody formation was present in both groups. Histologic analysis of the kidneys revealed that GF-AF mice had much lower levels of nephritis, while immunofluorescence analysis demonstrated no difference in Ig deposits but did reveal a paucity of C3 deposition in the kidneys of GF-AF mice. These data do not support a role for infectious agents in the induction of lymphoproliferation and B cell autoimmunity in MRL-lpr mice. Furthermore, they suggest that autoantibodies do not originate from B cells that were initially committed to exogenous Ags. They do suggest a possible contributory role for dietary exposure in the extent of lymphoproliferation and development of nephritis in this strain.

Expression and function of Fas on cells damaged by gamma-irradiation in B6 and B6/lpr mice.

Fas (CD95) is a cell surface protein that mediates apoptosis. lpr is a mutation of the Fas gene caused by a retroviral insertion resulting in premature termination of transcription and aberrant splicing of Fas mRNA. Mice homozygous for the lpr gene develop lymphoproliferation and produce autoantibodies closely resembling those of human systemic lupus erythematosus. While lpr mice have been reported to express low levels of normally spliced Fas mRNA, it is unknown whether they express functional Fas protein. Here we show that splenocytes from lpr mice that have been damaged by gamma-irradiation expressed Fas protein. Fas was up-regulated on irradiated B6 cells and could be detected on B6/lpr cells undergoing apoptosis following in vitro culture. Detection of Fas on live lpr cells was demonstrable when apoptosis was blocked by zinc. In a short term chimera system, Fas was shown to play a role, in vivo, in the disposition of radiation-injured cells from both normal and lpr mice. The addition of anti-Fas Ab to in vitro cultures resulted in an increase in apoptosis in both B6 and B6/lpr cells. Detection of intact Fas message and low levels of Fas protein in lpr mice has led to the consideration of lpr as a leaky mutation. This study demonstrates that lpr mice can produce functional Fas protein. This system is also appropriate for identifying the in vivo role of Fas/FasL in apoptosis following other cell manipulations.

Mice deficient in fas ligand (gld) or fas (lpr) show few alterations in granulopoiesis.

Evidence exists that the life span of mature, circulating neutrophils is influenced by apoptosis induced by interactions between Fas ligand (FasL) and Fas (CD95). However, the role of FasL/Fas-mediated apoptosis in granulopoiesis has not been explored. The present study assessed differences in granulopoiesis between normal (B6) mice and mice carrying mutations in the genes for FasL (B6/gld) or Fas (B6/lpr). Granulopoiesis was examined by quantitating mature granulocytes in the blood, committed myeloid progenitor cells (or colony-forming units; CFU) in the bone marrow (BM), and granulocyte lineage cells in the BM. The present study also characterized through flow cytometry the ability of GR-1(+) granulocyte lineage cells from B6, B6/gld, and B6/lpr mice to undergo spontaneous apoptosis in vitro. In comparison to B6 mice, B6/gld mice (but not B6/lpr mice) showed small, but significant increases in the number and percentage of blood granulocytes and in the number of myeloid CFU. However, the number and percentage of GR-1(+) granulocyte lineage cells in the BM were similar in the three strains. The rate of spontaneous apoptosis of GR-1(+) granulocyte lineage cells also did not differ between B6, B6/gld, and B6/lpr mice. In B6 and B6/gld mice, Fas expression on granulocyte lineage cells was downregulated in conjunction with a decrease in forward-angle light scatter (fsc) and externalization of phosphatidylserine (PS), two measures of apoptosis. These results suggest that FasL-Fas interactions play only a minor role in modulating numbers of committed myeloid progenitor cells and the size of the peripheral pool of mature granulocytes. Interactions between FasL and Fas do not influence the size of the BM pool of granulocyte lineage cells or the ability of those cells to undergo spontaneous apoptosis.

Fas ligand (gld)- and Fas (lpr)-deficient mice do not show alterations in the extravasation or apoptosis of inflammatory neutrophils.

Apoptosis of neutrophils plays a critical role in the resolution of acute inflammation. Neutrophils from human peripheral blood express Fas (CD95) and are sensitive to Fas ligand (FasL)/Fas-mediated apoptosis. Mice carrying spontaneous mutations in the genes for fas ligand (B6/gld) or fas (B6/lpr) were used to assess the role of FasL/Fas in the kinetics and magnitude of neutrophil extravasation to the thioglycolate (TG)-inflamed peritoneum and in the spontaneous apoptosis of TG-elicited neutrophils. The results showed that TG-elicited neutrophils (defined by flow cytometry as GR-1/Ly-6G(hi) cells) from normal (B6) and B6/gld mice, but not from the Fas-deficient B6/lpr mice, express high levels of Fas. The TG-elicited neutrophil response began at 2 h, peaked at 4 h, and subsided by 24-48 h after TG administration in all three strains. However, the response was more prolonged in B6 mice, such that B6/gld and B6/lpr mice had fewer neutrophils at 6 h after TG administration than did B6 mice. Further studies showed that 4 h TG-elicited neutrophils from B6, B6/gld and B6/lpr mice undergo apoptosis in vitro at similar rates (as assessed through flow cytometry by the decrease in forward angle light-scatter and externalization of phosphatidylserine (PS; as detected by Annexin V-FITC) that occur as neutrophils undergo apoptosis). Fas expression was down-regulated on apoptotic neutrophils in conjunction with maximal PS externalization and decreased forward angle light-scatter. Collectively, these findings suggest that FasL/Fas-mediated apoptosis is not essential in regulating the lifespan of neutrophils during an acute inflammatory response. The abbreviated inflammatory response observed in FasL/Fas-deficient mice is likely to be a secondary effect of the gld/lpr autoimmune/lymphoproliferative syndrome, and not a direct effect of FasL/Fas on the ability of inflammatory neutrophils to undergo apoptosis.

bca: an activation-related B-cell gene.

We have identified a novel activation related B-cell gene (bca) through differential hybridization screening of a murine B cell cDNA library. The deduced amino acid sequence predicted a protein of 482 amino acids with strong sequence similarity to the SH2 and SH3 domains present within the non-catalytic regions of several protein tyrosine kinases. Northern analysis of RNA from several murine B-cell lines revealed a transcript of 1.8 kb, which was not detected in T-cell and non-lymphoid cell lines. bca was transcribed at low levels in resting spleen cells from a variety of normal mouse strains and was strongly expressed in kidney RNA. bca expression was markedly increased in RNA prepared from mitogen activated B cells, and in freshly isolated spleen and lymph node cells of MRL/lpr and NZB autoimmune strains. The unique sequence of bca, which bears no obvious similarity to any specific class of proteins containing SH2 and SH3 domains, suggests that this gene encodes a novel protein potentially involved in B-cell signal transduction.

Fas/Fas ligand interactions are involved in ultraviolet-B-induced human lymphocyte apoptosis.

We wondered whether the apoptosis known to occur after UV-B irradiation might involve the Fas/Fas ligand (FasL) signaling pathway. We exposed PBLs from normal individuals, and also the Jurkat (E6-1) and U937 cell lines, to graded doses of UV-B irradiation and observed a prompt and marked increase in Fas expression at doses as low as 0.5 mJ/cm2. Increased Fas expression did not require new protein synthesis, since cycloheximide-treated cells also showed an increase in Fas after UV-B. UV-B-irradiated cells cultured in the presence of zinc showed inhibition of apoptosis coincident with a marked increase in Fas+ cells, apparently indicating the accumulation of Fas-bearing cells unable to undergo apoptosis. After UV-B irradiation, PBLs showed increased expression of Fas ligand; the E6-1 lymphocytic cell line also released soluble FasL. UV-B induced apoptosis could be partially blocked by neutralizing FasL Abs, and a FasL-resistant variant of E6-1 cell line showed reduced apoptosis after UV-B irradiation, implying that the increase in Fas expression signified a role for Fas in UV-induced apoptosis. UV-induced Fas expression may serve to target stress-injured cells for removal by FasL-bearing cells or by FasL produced by the cells themselves in response to the stimuli, and may represent a general function of the Fas/FasL pathway in facilitating the apoptosis and elimination of undesirable or harmful cells.

Anti-CD40L accelerates renal disease and adenopathy in MRL-lpr mice in parallel with decreased thymocyte apoptosis.

The CD40/CD40L (CD40 ligand) axis regulates several interactions between T cells and B cells. Blocking of CD40 engagement by CD40L inhibits Ig class switch by B cells as well as diminishes T cell response to an immunizing Ag. For these reasons, disruption of CD40/CD40L interactions by anti-CD40L administration or by genetic disruption of CD40L has ameliorated a variety of autoimmune conditions. More recent findings suggest that a direct signal can be transmitted to T cells via their expressed CD40L, which can costimulate proliferation with CD3 or promote germinal center formation. It is therefore possible that treatment with anti-CD40L Ab might produce a different outcome than observed in genetically CD40L-deficient mice. In this regard, we observe that in contrast to the genetic deletion of CD40L in MRL-lpr mice, which diminishes autoimmune disease but has little effect on adenopathy, administration of anti-CD40L to MRL-lpr mice accelerates both of these parameters. This difference appears to result from anti-CD40L actively delivering a signal that inhibits T cell apoptosis in lpr mice. This was confirmed by in vitro studies demonstrating that CD40L cross-linking on lpr thymocytes inhibited apoptosis and surface TCR down-modulation induced by CD3 ligation.

Bone marrow and peripheral blood involvement in mantle cell lymphoma.

The peripheral blood smears, bone marrow aspirates and biopsies of 46 patients with mantle cell lymphoma were reviewed. The diagnosis of mantle cell lymphoma was established in all cases on extramedullary tissue samples using standard morphologic, phenotypic and molecular genetic criteria. 27/35 patients (77%) had circulating lymphoma cells (median 200%m of all circulating white blood cells; range 5-90%) identified by morphology at some point during the course of their disease. No statistical difference in survival was detected in patients with or without peripheral blood involvement. Lymphoma was identified in bone marrow aspirate specimens from 33/40 patients (83%) and in bone marrow biopsy specimens from 39/43 patients (91%). The pattern of marrow biopsy involvement was nodular (31 cases; 82%), interstitial (19 cases; 50%), paratrabecular (17 cases, 45%) and diffuse (12 cases; 32%). Although the median survival of patients with > or = 50% bone marrow involvement was 13 months, and the median survival of patients with < or = 50% was 49 months; no statistically significant differences between these small subgroups were observed. Mantle cell lymphoma frequently involves the peripheral blood and bone marrow. Its appearance is distinctive but variable, and immunophenotypic studies as well as morphologic confirmation by a biopsy of tissue other than bone marrow is still required for diagnosis.