Extrinsic muscles of the hand signal fingertip location more precisely than they signal the angles of individual finger joints.

Studies have demonstrated that muscle spindle organs provide the majority of the proprioceptive information available to the nervous system about limb position. Other studies suggest that a sense of position may be lacking in the fingers, as subjects were unaware of rather large excursions of finger joints if the excursions were made slowly enough. We sought to investigate the basis for this unexpected finding with a biomechanical model of the human long finger and the forearm muscles which actuate it, in order to study potential contributions of spindle organs in the extrinsic muscles of the hand to a sense of position of the finger.

Autologous versus allogeneic transfusion: patients' perceptions and experiences.

Background: Preoperative autologous donation is one way to decrease a patient's exposure to allogeneic blood transfusion. This study was designed to determine patients' perceptions about the autologous blood donation process and their experiences with transfusion.

Methods: To assess patient perception, a questionnaire was administered a few days before surgery to patients undergoing elective cardiac and orthopedic surgery in a Canadian teaching hospital.

Tumonoic acids, novel metabolites from a cyanobacterial assemblage of Lyngbya majuscula and Schizothrix calcicola.

Five new metabolites have been isolated from a lyngbyastatin 1- and dolastatin 12-producing assemblage of Lyngbya majuscula and Schizothrix calcicola collected at Tumon Bay, Guam. Structure elucidation employed 2D NMR techniques and chemical derivatization. These compounds have been assigned the trivial names tumonoic acids A (2), B (1), and C (5); methyl tumonoate A (3), and methyl tumonoate B (4).

A randomised, blinded, placebo-controlled, dose escalation study of the tolerability and efficacy of filgrastim for haemopoietic stem cell mobilisation in patients with severe active rheumatoid arthritis.

Autologous haemopoietic stem cell transplantation (HSCT) represents a potential therapy for severe rheumatoid arthritis (RA). As a prelude to clinical trails, the safety and efficacy of haemopoietic stem cell (HSC) mobilisation required investigation as colony-stimulating factors (CSFs) have been reported to flare RA. A double-blind, randomised placebo-controlled dose escalation study was performed.

Composition and function of peripheral blood stem and progenitor cell harvests from patients with severe active rheumatoid arthritis.

High-dose chemotherapy with autologous stem cell rescue has been proposed as an intensive therapy for severe rheumatoid arthritis (RA). In view of previous observations of abnormal haemopoiesis in RA patients, the composition and function of peripheral blood stem cell harvests (PBSCH) was investigated. Compared with PBSCH from healthy allogeneic donors mobilized with the same dose of G-CSF (filgrastim; 10 microg/kg/d, n = 14), RA PBSCH (n = 9) contained significantly fewer mononuclear cells (375 v 569 x 10(6)/kg, P = 0.

Functional nonequivalence of Drosophila actin isoforms.

We show that different Drosophila actin isoforms are not interchangeable. We sequenced the six genes that encode conventional Drosophila actins and found that they specify amino acid replacements in 27 of 376 positions. To test the significance of these changes we used directed mutagenesis to introduce 10 such conversions, independently, into the Act88F flight muscle-specific actin gene.

Isolation, structure determination, and biological activity of dolastatin 12 and lyngbyastatin 1 from Lyngbya majuscula/Schizothrix calcicola cyanobacterial assemblages.

Lyngbyastatin 1 (1a), a new cytotoxic analogue of dolastatins 12 (2a) and 11 (4), was isolated as an inseparable mixture with its C-15 epimer (1b) from extracts of a Lyngbya majuscula/Schizothrix calcicola assemblage and a L. majuscula strain collected near Guam. Dolastatin 12 (2a) was also encountered as an inseparable mixture with its C-15 epimer (2b) in L.

The sequence alteration associated with a mutational hotspot in p53 protects cells from lysis by cytotoxic T lymphocytes specific for a flanking peptide epitope.

A high proportion of tumors arise due to mutation of the p53 tumor suppressor protein. A p53 hotspot mutation at amino acid position 273 from R to H, flanking a peptide epitope that spans residues 264-272, renders cells resistant to killing by human histocompatibility leukocyte antigen (HLA)-A*0201-restricted cytotoxic T lymphocytes (CTLs) specific for this epitope. Acquisition of the R to H mutation at residue 273 of the human p53 protein promotes tumor growth in vivo by selective escape from recognition by p53.

Activation of the mitogen-activated protein kinase pathway in U937 leukemic cells induces phosphorylation of the amino terminus of the TATA-binding protein.

Phorbol ester treatment of U937 leukemic cells results in the activation of numerous protein kinase pathways, followed by cell cycle arrest and differentiation into macrophage-like cells. Because major changes in gene transcription are associated with this process, the role of general transcription factors in the cell response to phorbol esters was examined. Experiments demonstrate that phorbol ester treatment of U937 cells stimulates the phosphorylation of the TATA-binding protein (TBP); this phosphorylation occurs within 30 min and is still apparent, although greatly reduced, at 4 h.

Rapid colorimetric assay for the detection of the bcr-abl rearrangement.

The value of the polymerase chain reaction (PCR) in the diagnosis of malignant disorders is well established. However, several factors such as sample type, storage conditions and extraction methodology affect the ability of the PCR to provide a diagnosis. We describe the use of a PCR-product-specific 'capture' oligo to overcome these potential problems.

Preclinical antitumor activity of an antibody against the leukocyte antigen CD48.

We have evaluated the antitumor activity of a murine antibody (IgG2a) against the leukocyte antigen CD48. CD48 is expressed on T and B lymphocytes, monocytes, and a wide range of lymphoid malignancies. To assess the therapeutic potential of an anti-CD48 antibody, we established a reproducible model of human B-cell (Raji) leukemia/lymphoma in C.

Ex vivo effects associated with the expression of a bcr-abl-specific ribozyme in a CML cell line.

The bcr-abl chimeric gene is found in 95% of chronic myeloid leukemia (CML) patients and is thought to be seminal to the etiology of the disease. The possibility of using ribozymes to suppress bcr-abl gene expression and subsequently alter the malignant phenotype of hematopoietic cells may provide an alternative therapeutic approach to current regimens. A series of hammerhead ribozymes targeted to a b3a2 bcr-abl transcript has been developed and previously shown to be capable of cleaving the desired sequence with varying degrees of specificity.

Long-term outcome of autoimmune disease following allogeneic bone marrow transplantation.

Objective: To investigate the long-term outcome of autoimmune disease following allogeneic bone marrow transplantation (BMT), and its relationship to hemopoietic chimerism.

Methods: Three previously described patients with rheumatoid arthritis (RA) who underwent allogeneic BMT for therapy-related severe aplastic anemia and 1 new patient with psoriasis who received BMT for chronic myeloid leukemia (CML) were followed up. Molecular studies were performed to assess hemopoietic and immune reconstitution in 3 cases.

Strategies for tumor elimination by cytotoxic T lymphocytes.

Despite differences in their tissue of origin, many tumors share high level expression of certain tumor-associated proteins. Our laboratory has focused on the possibility of utilizing antigenic components of these proteins as a focus for T-cell immunotherapy of cancer. The advantage of targeting such commonly expressed proteins is the fact that such therapy could be of value in eliminating many different types of tumors.

Detection of a soluble form of the leukocyte surface antigen CD48 in plasma and its elevation in patients with lymphoid leukemias and arthritis.

Proteins with glycosylphosphatidylinositol (GPI) anchors exhibit a range of activities and some of these proteins exist in both a membrane-associated and a soluble form. CD48 is a 47-kd GPI-linked glycoprotein which is expressed on T and B lymphocytes, monocytes, and many lymphoid malignancies. The biological function of CD48 is unknown.

Complex regulation of CDK2 during phorbol ester-induced hematopoietic differentiation.

Phorbol myristate acetate (PMA) treatment of U937 human leukemic cells results in late G1 cell cycle arrest and terminal monocyte/macrophage-like differentiation. The PMA-induced G1 arrest involves a marked decrease in cdk2 activity, which correlates with total cdk2 dephosphorylation. Here, we show that the levels of cyclin A mRNA and protein markedly decrease during PMA-induced differentiation of U937 cells.

The temperature-sensitive (ts) phenotype of a cold-passaged (cp) live attenuated respiratory syncytial virus vaccine candidate, designated cpts530, results from a single amino acid substitution in the L protein.

cpts530, a candidate live-virus vaccine, is an attenuated strain of human respiratory syncytial virus (RSV). It was derived by subjecting a cold-passaged (cp) strain of RSV to a single round of chemical mutagenesis. cpts530 is a temperature-sensitive (ts) mutant that is attenuated in mice and chimpanzees, and its ts phenotype exhibits a high level of stability during replication in both species.

Bone marrow transplantation for severe aplastic anemia: has outcome improved?

Bone marrow transplants for severe aplastic anemia were first performed in the 1970s. Transplant regimens, supportive care, and patient selection have changed substantially since then. Our objective was to determine the impact of these changes on transplant outcome.

Allogeneic bone marrow transplantation from a donor with severe active rheumatoid arthritis not resulting in adoptive transfer of disease to recipient.

We report a patient who underwent allogeneic bone marrow transplantation from a sibling with longstanding untreated severe active rheumatoid arthritis. After 4 years of follow-up there is no evidence of adoptive transfer of rheumatoid arthritis to the recipient. This case, along with another recently reported case, provides reassurance that haemopoietic stem cell transplantation from a donor with systemic autoimmune disease may not necessarily result in adoptive transfer of the disease.

A recombinant GM-CSF-PE40 ligand toxin is functionally active but not cytotoxic to cells.

A granulocyte/macrophage colony-stimulating factor (GM-CSF)-Pseudomonas exotoxin (PE) 40 fusion protein was constructed for potential use in the treatment of myeloid leukaemias, as a conditioning agent prior to allogeneic bone marrow transplantation or for ex vivo purging of malignant cells prior to autologous bone marrow transplantation. The GM-CSF-PE40 fusion protein successfully binds to the GM-CSF receptor and is capable of initiating a mitogenic signal similar to native GM-CSF in the GM-CSF-dependent TF1 cell line. The toxin component also appears to be fully functional as determined by an in vitro adenosine diphosphate-ribosylation assay.