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Biomedical subjects

C Watts

Publications and source records attributed to C Watts.

At least 19 recordsLinked to original sources
PubMed1992

Irreversible association of peptides with class II MHC molecules in living cells.

Functional, morphological and biochemical evidence indicates that class II major histocompatibility complex (MHC) molecules associate with processed peptides during biosynthesis. Peptide/MHC complexes in living cells have been reported to be less stable than similar complexes generated in vitro, which has led to the suggestion that there may be a peptide exchange mechanism operating in vivo. Although this could increase the capacity for binding incoming antigens, it would reduce the efficacy of processed antigenic peptides by exchanging these for self peptides. Here we measure the half-life of peptide/class II complexes in human antigen-presenting cells and find that it is very similar to the half-life of class II molecules themselves, indicating that peptides are bound irreversibly under physiological conditions. Thus class II MHC retains long-term 'memory' of past encounters with antigen to maximize the opportunity for T cell/antigen-presenting cell interaction.

Antigen-Presenting Cells↗
PubMed1992

Osmotic blood-brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: patient series and literature review.

In the past, chemotherapeutic treatment of patients with high grade malignant gliomas following surgery and radiation has not added significantly to the 12-14 month median survival rate. Over four years, 37 patients with high grade malignant gliomas underwent 246 treatment procedures with a combination of methotrexate, cyclophosphamide, and procarbazine given in association with hyperosmolar mannitol-induced transient breakdown of the blood-brain barrier. These patients have demonstrated a median survivorship of 22 months after considering age, Karnofsky Performance Score, and necrosis by the Cox Proportional Hazards model. The study group had a mean age of 43 years, and mean Karnofsky Performance Score of 67%. Sixty-five percent of the procedures had well-documented barrier disruption. Sixteen percent remained in complete remission while 24 patients (65%) had partial or temporary remission. Progression-free intervals after blood-brain barrier disruption/chemotherapy ranged from 1-47 (mean 15) months. Neurotoxicity has been minimal with one peri-procedural mortality and five patients suffering an increase in neurologic deficit after a procedure. The results of this study are consistent with and further extend the reported literature on this method of brain tumor therapy as described in other centers. Chemotherapy in conjunction with osmotic disruption of the blood-brain barrier may provide the pharmacokinetic advantage sufficient to significantly improve survival in patients with high grade malignant glioma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Constitutive endocytosis and recycling of major histocompatibility complex class II glycoproteins in human B-lymphoblastoid cells.

Cleavable cell surface radiolabelling reagents were used to measure the endocytosis and recycling of class II major histocompatibility complex (MHC) glycoproteins in human B-lymphoblastoid cells. It is shown that mature class II alpha beta dimers on the cell surface are constitutively endocytosed and that recycling can be demonstrated even from small endosomal pools. Endocytosis was blocked when cellular ATP levels were depleted or when clathrin polymerization was inhibited, implicating clathrin-coated pits in the endocytic process. Taken together with earlier studies, these results suggest that mature class II MHC molecules are constitutively endocytosed and recycled from acidic peripheral endosomes which may enhance their capacity to bind and present T cell epitopes which do not require processing.

Adenosine Triphosphate↗
PubMed1992

Primary prevention of catastrophic injury.

Motor vehicle crashes are a leading cause of injury and death until age 45. Efforts to prevent these injuries have largely followed the dictates of the public health movement focusing on interventions for entire communities or regulatory statutes. Individual interventions, more congruent with traditional psychological approaches, have been rare. This article argues that a blending of these two approaches is warranted. Evaluation of prevention programs should focus on multiple levels including the individual, the community, and regulatory processes. Identification of subgroups of adolescents and young adults with unique psychological and behavioral dispositions regarding injury must be paired with realistic interventions of adequate duration.

Accidents, Traffic↗
PubMed1992

National Head and Spinal Cord Injury Prevention Program of the American Association of Neurological Surgeons and the Congress of Neurological Surgeons.

Organized neurosurgery has developed and promoted a national educational program for adolescents to reduce the number of head and spinal cord injuries sustained by this group of young people. The program has been adopted widely, with over 1,000,000 teenagers exposed to it since its inception in 1986. Preliminary data suggest that the program has had a favorable impact on the knowledge and attitudes of young people regarding head and spinal cord injuries, risk-taking behavior, and incidence of injuries.

Child↗
PubMed1991

Processed antigen binds to newly synthesized MHC class II molecules in antigen-specific B lymphocytes.

We describe the direct detection of radiolabeled antigen fragments bound to class II MHC molecules following immunoglobulin-mediated endocytosis and processing of native antigen in B lymphoblastoid cells. Tris-Tricine SDS gels revealed six distinct iodinated processing products that could be detected on class II MHC 1 hr after antigen endocytosis and persisted for at least 20 hr. These physiological processed antigen-class II complexes were remarkably stable, as judged by the fact that class II alpha beta dimers, which remain associated in SDS, became labeled with the same set of processed peptides. Using a lectin-binding assay, we show that these physiological processing products bind to the newly maturing population of MHC molecules rather than binding to the preexisting cell surface population; in contrast, an exogenous peptide binds predominantly to the latter population. A direct T cell-independent assay for processed peptide-MHC complex formation should facilitate additional studies on the exogenous antigen processing pathway.

Antibodies, Monoclonal↗
PubMed1990

Cycling of cell-surface MHC glycoproteins through primaquine-sensitive intracellular compartments.

Class II major histocompatibility complex (MHC) glycoproteins associate with peptides derived from material endocytosed by antigen-presenting cells and processed along the endocytotic pathway. No consensus exists as to what extent class II molecules themselves are endocytosed and it is not known whether endocytosed MHC class II molecules can be recycled again to the cell surface--an itinerary which might allow a single cell-surface MHC molecule to associate with different peptides during its lifetime. We now show by using new cleavable labelling reagents that class II and class I MHC on B lymphoblastoid cells are continually endocytosed and recycled to the cell surface. The intracellular pool size is normally kept small by efficient recycling, but in the presence of primaquine the rate of recycling is slowed, thereby increasing the size of this pool substantially. On removal of the amine, the intracellular population recycles rapidly to restore the original distribution. These results reveal a cycle that might explain the rapid binding and turnover of some peptide/class II MHC complexes and the exchange of pre-existing for new peptides observed in living cells.

Antibodies, Monoclonal↗
PubMed1990

Endocytosis, intracellular trafficking, and processing of membrane IgG and monovalent antigen/membrane IgG complexes in B lymphocytes.

Human B lymphoblastoid cell lines specific for tetanus toxin/toxoid were used in our earlier studies to demonstrate the rapid endocytosis of monovalent Ag and its processing, as a complex with mIgG. Here we show that the mIgGR for Ag is endocytosed in the presence or absence of Ag and that at any given time about 60% of this recycling pool of membrane (m) Ig is inside the cell. During the earliest detectable stages of Ag processing a high proportion of Ag fragments resolved on SDS gels were bound to intact mIg. However, at later times, as fragmented Ag accumulated, the fragments were precipitable only with antibodies against the Fab region of mIgG indicating proteolytic fragmentation of this receptor. Fractionation of cell homogenates on self-forming Percoll gradients revealed that at least two compartments are involved in Ag processing: a low density endosome compartment and a dense "late endosome"/lysosomal compartment. The spectrum of Ag fragments observed in each fraction differed: fragments produced at later times during processing were detected only in the late endosome/lysomal fraction whereas the earliest observed fragments were found both in this fraction and in the low density fractions. Monovalent Ag/mIgG complexes appear to have an increased probability, compared to unoccupied mIgG, of targeting to proteolytically active compartments leading to processing of the Ag/mIg complex and to accelerated degradation of the mIgG.

Antigen-Antibody Complex↗
PubMed1990

The antigen processing pathway in B lymphocytes.

Monovalent antigen bound to membrane immunoglobulin on human B lymphoblastoid cells is endocytosed through coated pits and passes sequentially from a site which actively recycles membrane to the cell surface and then to a proteolytically active processing site. A high affinity of immunoglobulin for antigen precludes antigen dissociation following endocytosis and results in the processing of an antigen/Ig complex yielding an epitope-specific pattern of processing. Processing of the immunoglobulin also occurs and is enhanced by occupancy with monovalent antigen.

Antigens↗
PubMed1990

Use of traction in cervical spine fractures during interhospital transfer by aircraft.

Despite significant improvement in the organization and function of the nation's emergency medical services and the increasing sophistication of initial providers of critical care, there has apparently been no reduction in the incidence of neurological deficits suffered by patients with unstable cervical spine injuries during management prior to intervention by the spine surgeon. In analyzing the techniques used to stabilize patients with suspected unstable cervical spine injuries during this phase, we conclude that present standard techniques are either insufficient or potentially destabilizing. We have developed a system that will permit the use of cervical traction, applied with a halter or the standard Gardner-Wells tongs, during the prehospital phase of management of patients with cervical spine injuries. Based on our experience with the system, we recommend that patients with such injuries be stabilized with skeletal traction when transferred between hospitals by air ambulance. Logic permits consideration of the concept even earlier in the prehospital phase of management and in ground ambulances.

Adult↗