We report the specific induction of B cell plasma membrane depolarization with the use of thymus-dependent and -independent antigens. We have utilized various trinitrophenol-carrier conjugates for ...the stimulation of isolated trinitrophenol-binding mouse B cells. Membrane depolarization was assessed by flow cytometric analysis of 3-3'-pentyloxacarbocyanine iodide (DiOC53)-stained cells. Entry into the cell cycle was determined by flow cytometric analysis of acridine orange-stained cells. The results indicate that polyvalent antigens, but not free hapten, induce B cell membrane depolarization by a large proportion of antigen-binding cells within 2 hr of stimulation. Although all polyvalent antigens induce membrane depolarization, only thymus-independent antigens induce the subsequent G0 to G1 transition, suggesting that the membrane Ig cross-linking signal alone, although sufficient to induce membrane depolarization and subsequent increased IA expression, is insufficient to drive the entry of B cells into the cell cycle. The G0 to G1 transition appears to be dependent on a second signal, perhaps mediated by the thymus-independent carrier or antigen-specific, Ia-restricted T cell helper.
To assess safety, tolerance, and the clinical and laboratory effects of oral ribavirin in patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-related complex.
Three uncontrolled ...phase I trials of increasing duration: 14 days, 8 weeks, and 12 months.
Outpatient clinic of a university-referral hospital.
All patients were antibody-positive for the human immunodeficiency virus (HIV) by radioimmunoprecipitation assay, all had recovered from Pneumocystis carinii pneumonia, and none had Kaposi sarcoma at entry. Nine of ten patients with AIDS had less than 100 CD4+ lymphocytes/mm3 at entry and all patients with the AIDS-related complex had fewer than 200 CD4+ lymphocytes/mm3. Five patients with AIDS and five with the AIDS-related complex entered the 14-day trial. All but two patients with AIDS went on to the 8-week trial, along with seven additional patients with AIDS. Five surviving patients with AIDS and 3 patients with the AIDS-related complex went on to the 1-year study.
Oral ribavirin, 1200 mg twice daily for 3 days was given, followed by 300 mg twice daily for 11 days. During an 8-week trial, a loading dose of oral ribavirin was administered for 3 days, followed by a dose of 300 mg twice daily for 8 weeks. Prolonged regimen of a 3-day loading dose was given, followed by a dose of 300 mg twice daily for 1 year.
Ribavirin treatment was well tolerated, with anemia requiring transfusion in one of the ten patients with AIDS receiving the drug for 8 weeks; no other significant toxicity occurred. Six of nine patients initially positive for HIV-1 in blood became negative during ribavirin treatment. Six of nine patients with AIDS had a twofold improvement in lymphoproliferative response to at least one lectin with ribavirin treatment. Mean survival from first episode of P. carinii pneumonia was 17.3 months in patients with AIDS receiving 8 weeks of ribavirin and 21.2 months in patients with AIDS receiving prolonged treatment.
Oral ribavirin, 600 mg daily, was well tolerated and safe in the patients with severe AIDS and the AIDS-related complex. Ribavirin therapy merits extensive evaluation in a multicenter controlled trial to assess its efficacy.
The function of the surface antigen receptor of B cells (BCR) has been extensively studied with respect to the activation of mature B lymphocytes. B cells at other points of development (e.g., pre-B ...cells, immature B cells, and germinal center B cells) also express forms of the BCR, and for cells at these developmental timepoints, signaling through the BCR in some cases may lead to outcomes other than B-cell activation. Understanding the molecular events that are initiated by BCR crosslinking would enhance our understanding of the regulation and functional results of BCR signaling throughout B-cell development. In this article we review the current understanding of BCR signal transduction from initiation of the signal through changes in expression of genes that regulate the activation state. Costimulatory and modulatory molecules are considered with regard to their ability to affect the sensitivity or outcome of the BCR signal. Finally, we discuss how BCR signal transduction and the results of BCR signaling may differ at distinct stages in B-cell development.
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Background: Chimeric transcription factors are ideal anti-cancer targets since they are only present in tumor cells, however they are often considered ‘undruggable’ proteins. The ...EWS-FLI1 fusion protein of Ewings sarcoma (ES) has been validated as an anticancer target both alone and as a partner of RNA Helicase A (RHA). Our prior work identified (S)-YK-4-279 as an enantiospecific inhibitor of EWS-FLI1 by blocking the interaction with RHA leading to apoptosis. Methods: Pharmacokinetic (PK) models of YK-4-279 for both IP and IV administration were developed in SD rats and BL6 mice using drug concentrations determined by a validated LC-MS/MS assay. Xenograft ES mice validated PK models with apoptosis measured by TUNEL. A novel nude rat ES orthotopic xenograft was created give (S)-YK-4-279 by continuous IV infusion. Results: SD rat and BL6 mouse PK modeling demonstrated an elimination half-life t1/2 of 30 minutes following IV administration; SCID/bg mice demonstrated 50% faster clearance. A survival curve showed maximal killing of ES cells between 1 and 3 microM YK-4-279 over a 40-hour time course. Clonogenic replating assays demonstrated 3 microM exposure for 72 hours would reduce replating efficiency of ES cells to less than 0.01%. SCID/bg ES xenografts treated with IP YK-4-279 BID for 6 doses showed a 25-35% enantiospecific tumor regression with an average 3.5-fold increase in apoptosis. A nude rat xenograft, with continuous infusion (S)-YK-4-279 maintained an average level of 4.9 microM in plasma for 26 days. The ES1 xenograft tumor responded in 4 of 5 animals, with complete regression in 2 of 5, without toxicity. Conclusions: A combination of PK modeling and cell culture studies confirmed that (S)-YK-4-279 is required to be present at low microM levels for optimal tumor response. These levels were achieved in a novel rat xenograft of ES in order to demonstrate an important proof of efficacy. These PK-driven xenograft therapy studies are useful for development of PK models to compare YK-4-279 levels with functional activity. Targeting ‘undruggable’ protein-protein interactions with small molecules is novel and the ES model shows that continuous IV infusion may be required for optimal clinical translation.
Using correlated flow cytometric analysis of cell surface Ia antigen expression (immunofluorescence) and cell cycle phase (pulse-width of axial light extinction), we have quantitated changes in ...expression of mIa antigen on murine B cells during progression through cell cycle. Our results indicate that density of mIa expressed on mitogen-stimulated B cells increases fourfold to fivefold during the transition from G0 to G1. By early S phase, mIa density has decreased by fourfold to fivefold relative to peak expression. This decrease becomes more evident by late S, G2, and M phases, when an eightfold decrease in mIa antigen density is observed relative to peak levels. This decrease results in mIa antigen expression lower than that of resting, unstimulated B cells. Therefore, maximum mIa antigen expression occurs during G0 to G1 transition and in early G1, when a requirement for I region-restricted, antigen-driven T cell help for thymus-dependent, antigen-driven B cell activation has been demonstrated.
Abstract Hip arthroscopy has become the standard treatment for symptomatic femoroacetabular impingement as patients have shown good outcomes and high satisfaction with this intervention. However, ...capsular management to gain access for intra-articular procedures remains greatly debated. Capsular closure is advocated particularly in the setting of interportal or T-capsulotomy to avoid complications of instability or nonhealing capsule. We introduce a technique for capsular management through a limited periportal capsulotomy during arthroscopic treatment of femoroacetabular impingement. In using dilation of the anterolateral and mid-anterior portals without completion of a full interportal capsulotomy, the stabilizing iliofemoral ligament is preserved. We have found that periportal capsulotomy provides safe and sufficient access to the hip joint without necessitating capsular closure.
B‐cell development is a highly ordered multistep process dependent upon signals generated by the pre‐B and B‐cell antigen receptor (BCR). BCR signals drive maturation of the B cell by integrating a ...number of parallel and sequential biological processes that result in generation of fully immunocompetent B cells. Among these biological processes are positive selection through several developmental checkpoints, negative selection of potentially self‐reactive B cells, and activation of the mature B cell. In addition, recent studies have shown that developing and mature B cells rely on the constant activity of the BCR for their continued survival. Ligand (antigen)‐dependent and ‐independent mechanisms of BCR signaling have been proposed, but their specific contributions to B‐cell maturation and differentiation in the bone marrow and periphery are not completely clear. We discuss here a model, whereby ligand‐independent basal BCR activity would be sufficient to trigger B‐cell development through to the mature stage. However, long‐term survival and formation of specific mature B‐cell populations may be dependent on ligand–receptor interactions.
Recent literature suggests that many online patient resources are poor in quality and lack important clinical information. The purpose of this study was to investigate the value of online resources ...available to patients considering shoulder arthroplasty. A total of 84 websites were discovered with the terms "total shoulder replacement" (TSR) and "reverse shoulder replacement" (RSR), they were reviewed and graded for quality and accuracy. Overall quality scores were low for TSR and RSR websites, 22.8/45 (95% confidence interval (CI): 19.9-25.6) and 24.2/45 (95% CI: 21.6-26.9), respectively. The authorship of a website significantly influenced the quality for both TSR (p = 0.013) and RSR (p = 0.048). When comparing search rank to quality scores, websites that appeared earlier demonstrated significantly higher quality scores, TSR (p = 0.017) and RSR (p = 0.018). Overall, most websites were accurate but provided incomplete information. Websites authored by professional societies have higher quality scores than websites authored by medical providers or commercial entities. (Journal of Surgical Orthopaedic Advances 28(4):290-294, 2019).
A superfusion system employed to measure the K+-stimulated release of 3H5-hydroxytryptamine (3H5-HT, 3Hserotonin) from a synaptosomal-rich spinal cord tissue preparation was carefully characterized, ...then used to examine the regulation of spinal 5-HT release. Spinal 5-HT release is apparently modulated by an autoreceptor. Exogenous 5-HT depressed, in a concentration-dependent manner, the K+-stimulated release of 3H5-HT. Similarly, lysergic acid diethylamide (LSD) produced a concentration-dependent decrease in 3H5-HT release. Methiothepin and quipazine blocked the inhibition of release induced by exogenous 5-HT. The 5-HT2 receptor antagonists spiperone and ketanserin failed to alter the action of 5-HT at the spinal 5-HT autoreceptor. Spiperone and ketanserin were shown, however, to alter the storage of 3H5-HT. When used in concentrations greater than 10 nM, the drugs evoked increases in basal 3H5-HT and 3H5-hydroxyindoleacetic acid ( 3H5-HIAA) effluxes which were independent of the presence of calcium ions. A good agreement existed between the potencies of drugs for modifying autoreceptor function and their abilities to compete for high-affinity 3H5-HT binding in the spinal cord (designated 5-HT1). Furthermore quipazine, in concentrations that preferentially interact with the 5-HT1B subtype, antagonized the actions of exogenous 5-HT on K+-stimulated release. Spiperone, in a concentration that approximated the affinity constant of 5-HT1A sites for the drug, was ineffective in altering the ability of exogenous 5-HT to modulate K+-stimulated 3H5-HT release. These results suggest that 5-HT1B sites are associated with serotonergic autoreceptor function in the spinal cord.
Abstract
Transjugular intrahepatic portosystemic shunt (TIPS) creation offers potentially life-saving portal decompression regardless of patient age or size, but has been underutilized in pediatric ...patients to date. Experience has therefore been limited, and the full clinical benefit in this population is yet to be realized. Those wishing to embark on pediatric TIPSs would benefit not only from significant experience in adult TIPSs, but also from an awareness of challenges posed by the unique pediatric population. We herein review the etiologies and manifestations of portal hypertension more common in children, highlight some of the technical nuances of creating TIPSs in smaller anatomy, and summarize the existing literature on the topic. As extrahepatic portal vein occlusion (EHPVO) occurs with greater frequency in pediatric patients, special attention is paid to this condition and its associated challenges.
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