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Biomedical subjects

D B Williams

Publications and source records attributed to D B Williams.

At least 91 records · Page 5Linked to original sources
PubMed1992

Efficient dissociation of the p88 chaperone from major histocompatibility complex class I molecules requires both beta 2-microglobulin and peptide.

Previously, we showed that an 88-kD protein (p88) associates rapidly and quantitatively with newly synthesized murine major histocompatibility complex class I molecules within the endoplasmic reticulum (ER). This interaction is transient and dissociation of p88 appears to be rate limiting for transport of class I molecules from the ER to the Golgi apparatus. In this report, we examine the relationship between p88 interaction and assembly of the ternary complex of class I heavy chain beta 2-microglobulin (beta 2m), and peptide ligand. In both murine and human beta 2m-deficient cells, in which little or no transport of class I heavy chains is observed, p88 remained associated with intracellular heavy chains throughout their lifetime. In murine RMA-S cells, which are apparently defective in accumulating peptide ligands for class I within the ER, prolonged association of p88 with "empty" heavy chain-beta 2m heterodimers was also observed. However, p88 dissociated slowly in parallel with the slow rate of ER to Golgi transport of empty class I molecules in these cells. The close correlation between p88 association and impaired class I transport suggests that p88 functions to retain incompletely assembled class I molecules in the ER. We propose that conformational changes in class I heavy chains induced by the binding of both beta 2m and peptide are required for efficient p88 dissociation and subsequent class I transport.

Antigens, Neoplasm↗
PubMed1992

The p88 molecular chaperone is identical to the endoplasmic reticulum membrane protein, calnexin.

We previously described a novel molecular chaperone (designated p88) that participates in the assembly of murine class I histocompatibility molecules (Degen, E., and Williams, D. B. (1991) J. Cell Biol. 112, 1099-1115). Our findings suggest that p88 may either promote proper assembly of class I molecules or retain them, probably within the endoplasmic reticulum (ER), until assembly of the ternary complex of heavy chain, beta 2-microglobulin, and peptide ligand is complete. In this report, we compare p88 to calnexin, a calcium-binding 90-kDa phosphoprotein of the ER membrane (Wada, I., Rindress, D., Cameron, P. H., Ou, W.-J., Doherty, J.-J., II, Louvard, D., Bell, A.W., Dignard, D., Thomas, D. Y., and Bergeron, J. J. M. (1991) J. Biol. Chem. 266, 19599-19610). We show that p88 and calnexin share antigenic epitopes defined by a polyclonal anti-calnexin antiserum. Furthermore, both proteins were immunoprecipitated in association with an intracellularly retained variant of the class I H-2Kb molecule. Since p88 and calnexin were also indistinguishable by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, were resistant to digestion with endoglycosidase H, and exhibited virtually identical patterns of peptide fragments following digestion with either V8 protease or trypsin, we conclude that p88 and calnexin represent the same protein. The identification of the p88 chaperone as a phosphorylated, calcium-binding protein of the ER membrane suggests possible means whereby its interaction with class I molecules may be regulated.

Animals↗
PubMed1992

Membrane region of surface IgM is not sufficient for transducing growth inhibitory signals in an immature B cell line WEHI-231.

The murine B lymphoma line WEHI-231 is representative of immature B cells. Like normal immature B cells, WEHI-231 is susceptible to growth arrest following cross-linking of surface IgM (sIgM). Previously, we have shown using a WEHI-231 immunoglobulin (Ig) delta-transfectant that sIgD cross-linking failed to initiate growth arrest, in contrast to sIgM. In this report, we extend our research to investigate the structural requirement of Ig mu chain for regulating growth inhibition. Recombinant, chimeric Ig molecules delta/mu m and mu/delta m consisting of exons encoding extracellular delta and mu domains and membrane regions of different isotypes were constructed and introduced into WEHI-231 cells. A similar approach was used for sIgG2b-expressing transfectants. Our findings indicate that the mu m region is not sufficient for regulation of growth inhibition in WEHI-231 cells and suggest that additional extracellular region(s) of mu chain may be required for this response.

Animals↗
PubMed1992

Egr-1 mRNA expression is independent of regulatory proliferative responses in the immature B cell line WEHI-231.

We have recently reported cellular growth arrest induced following crosslinking of surface IgM (sIgM) but not surface IgD (sIgD) in the WEHI-231 cell line, representative of the immature B cell stage, and its delta heavy chain (delta) transfectant. An initial report has indicated WEHI-231.7, a subclone of WEHI-231, failed to express Egr-1 mRNA following sIgM crosslinking, in contrast to significant up-regulation found in mature B lymphocytes. The implication for linkage between selective surface immunoglobulin (sIg) signal transduction, expression of immediate/early genes and control of cellular growth imposes an attractive model for induction of immature B cell tolerance. Our investigations examined the relationships between Egr-1 mRNA expression and growth regulation in WEHI-231, WEHI-231.7 and their respective delta-transfectants (WEHI-delta, WEHI-delta 7). We report sIgM and sIgD crosslinking leads to a rapid increase of Egr-1 mRNA expression in WEHI-231 and WEHI-delta but not in the subclone WEHI-231.7 and WEHI-delta 7. Nevertheless, both WEHI-231, WEHI-231.7 and their delta-transfectants demonstrate the ability to induce growth arrest following sIgM but not sIgD crosslinking. Furthermore, we found Egr-1 expression could be achieved by direct activation of protein kinase C (PKC) by phorbol 12-myristate 13-acetate (PMA) circumventing the classical sIg activated phosphatidylinositol signal transduction pathway. Our results suggest Egr-1 expression does not directly participate in growth regulation of immature B cell clones but rather is a consequence of signal transduction through sIg.

Animals↗
PubMed1992

Falloposcopic classification and treatment of fallopian tube lumen disease.

OBJECTIVE: To devise a diagnostic classification and scoring system for tubal lumen disease based on falloposcopy and to evaluate it against tuboplasty procedures and pregnancy outcomes. DESIGN: Prospective study approved by the hospital Institutional Review Board. SETTING: Academic tertiary infertility center. PATIENTS: Seventy-five women with hysterosalpingographic and laparoscopic evidence of endotubal disease had 112 tubes available for falloposcopic evaluation. INTERVENTION: Diagnostic and operative falloposcopy was performed, when indicated, using aquadissection, flexible wire cannulation, or direct balloon tuboplasty. RESULTS: The endotubal lumens were considered to be falloposcopically normal in 52 tubes (46%), to contain mild to moderate disease in 33 (29%), and severe to obstructive disease in 27 (25%) cases. Within a year of the procedure, 6 of the 28 women (21%) in whom at least 1 tube was normal conceived, in 2 of 22 (9%) with mild to moderate disease, and in 0 of 16 (0%) with severe endotubal disease. CONCLUSIONS: Falloposcopy provides a visual means of scoring endotubal disease and may be intrinsically therapeutic for dislodging intraluminal debris and breaking down filmy adhesions in normal or minimally diseased tubes. The presence of severe disease remains resistant to the use of current endotuboplasty treatments as reflected by poor pregnancy outcome, and such women should be provided the option of microsurgical tubal repair or in vitro fertilization and embryo transfer procedures.

Adult↗
PubMed1991

Peptide binding to class I MHC on living cells and quantitation of complexes required for CTL lysis.

Antigenic peptides are presented to CD8+T lymphocytes by class I major histocompatibility complex (MHC) molecules. Peptides specifically bind to purified class I molecules in vitro, and to class I molecules on cells at nonphysiological temperatures. We report here the kinetic and equilibrium parameters for the binding of radiolabelled influenza nucleoprotein peptides (NP-Y365-380 and shorter homologues) to the murine H-2Db molecule on intact, viable cells at 37 degrees C. In contrast to earlier reports, we show that peptide binding is rapid and reversible, with dissociation constants ranging from nanomolar to micromolar, suggestive of typical ligand-receptor interactions. Only 10% of cell-surface Db molecules can bind these peptides. To address the relationship between peptide binding and T-cell recognition of the antigen-MHC complex, we determined the minimum number of complexes required to sensitize a target cell for lysis by class I-restricted cytotoxic T-lymphocytes. Our data indicate that EL4 thymoma cells (H-2b) can be sensitized for lysis by cytotoxic T-lymphocytes when as few as 200 class I-peptide complexes (less than 0.08% of surface Db molecules) are present per cell.

Amino Acid Sequence↗
PubMed1991

Binding protein BiP is required for translocation of secretory proteins into the endoplasmic reticulum in Saccharomyces cerevisiae.

The endoplasmic reticulum of mammalian cells contains a heat shock protein of approximately 70 kDa (hsp70) termed binding protein BiP that is thought to promote the folding and subunit assembly of newly synthesized proteins. To study BiP function, we placed the BiP-encoding gene from Saccharomyces cerevisiae under the control of a regulated promoter and examined the effects of BiP depletion. Reduction of BiP protein to about 15% of normal levels led to a profound reduction in secretion of alpha factor and invertase. At the same time, unglycosylated precursors of these proteins accumulated intracellularly. The predominant form of the invertase precursor had undergone signal sequence cleavage but accumulated as a soluble species in the cytosol. In contrast, the alpha-factor precursor was exclusively in the signal-uncleaved form. It sedimented with microsomal membranes and was exposed at the cytoplasmic face in a protease-resistant form. These findings suggest that, in yeast, BiP function is required for translocation of soluble proteins into the endoplasmic reticulum at a stage beyond the initial nascent chain-membrane association.

Endoplasmic Reticulum↗
PubMed1991

Transmission electron microscope in situ fatigue experiments: a computer-control approach.

A computer-control procedure was developed to facilitate in situ fatigue experiments within an intermediate voltage transmission electron microscope using a goniometer-type straining holder. The procedure was designed to allow sine-wave tension-tension cyclic loading of a microfatigue specimen similar in geometry to a center-crack panel fatigue specimen. Computer control allows greater freedom for the operator to control the experiments while providing better reproducibility from one test to another. Further development of this procedure is possible by coupling this computer-control technique with computer-controlled stage motion and digitized TV imaging.

Electronic Data Processing↗
PubMed1991

Cerebral angiotropic large cell lymphoma (neoplastic angioendotheliosis): therapeutic considerations.

Cerebral angiotropic large cell lymphoma (neoplastic angioendotheliosis) is a rare disease with a particular propensity to affect the central nervous system by vascular occlusion. Because the disease is rare and there are no specific diagnostic procedures apart from cerebral biopsy, it is difficult to diagnose in life. Accordingly, chemotherapy or radiotherapy has only rarely been attempted and their effectiveness is uncertain. We established the diagnosis in a 62-year-old patient by cerebral biopsy and observed remission following institution of combination chemotherapy. Unfortunately, neurologic deterioration recurred during maintenance chemotherapy. We identified 30 patients in the literature who initially presented with definite central nervous system manifestations and whose clinical conditions were described sufficiently enough for comparison with our case. Eleven patients had the diagnosis made in life, but only 5 received chemotherapy other than corticosteroid hormones. Our patient's survival for 16 months exceeded that in the majority of the 30 reported cases. Intense anti-lymphoma chemotherapy, and possibly radiotherapy, may be beneficial and should be studied in this otherwise rapidly fatal disease. It seems certain that early diagnosis is essential if therapeutic intervention is to be successful.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Motor neuron disease (amyotrophic lateral sclerosis).

Amyotrophic lateral sclerosis is an insidiously developing, adult-onset, progressive anterior horn cell degeneration with associated degeneration of descending motor pathways. It has been recognized as an important clinical syndrome since the middle of the 19th century. Despite increasing clinical and research interest in this condition, its cause remains obscure, even in the broadest terms. Epidemiologic characteristics of the disease have been interpreted as evidence of both genetic and environmental causes. A major change in the view of this disease is the widely developing perception that it is a disease of elderly persons more than of middle-aged adults as was previously taught. Etiologic hypotheses encompass a broad range of postulated pathophysiologic mechanisms, and we review these in detail. The clinical limits of the disease can now be better defined by using modern diagnostic techniques. Although interest in supportive symptomatic therapy is growing, no intervention has yet been shown to modify the biologically determined motor system degeneration.

Amyotrophic Lateral Sclerosis↗
PubMed1991

Participation of a novel 88-kD protein in the biogenesis of murine class I histocompatibility molecules.

Chemical cross-linking and gel permeation chromatography were used to examine early events in the biogenesis of class I histocompatibility molecules. We show that newly synthesized class I heavy chains associate rapidly and quantitatively with an 88-kD protein in three murine tumor cell lines. This protein (p88) does not appear to possess Asn-linked glycans and it is not the abundant ER protein, GRP94. The class I-p88 complex exists transiently (t1/2 = 20-45 min depending on the specific class I heavy chain) and several lines of evidence suggest that p88 dissociates from the complex while still in the ER. Dissociation is not triggered upon binding of beta 2-microglobulin to the heavy chain (t1/2 = 2-5 min). However, the rate of dissociation does correlate with the characteristic rate of ER to Golgi transport for the particular class I molecule studied. Consequently, dissociation of p88 may be rate limiting for ER to Golgi transport. Class I molecules bind antigenic peptides, apparently in the ER, for subsequent presentation to cytotoxic T lymphocytes at the cell surface. p88 could promote peptide binding or it may retain class I molecules in the ER during formation of the ternary complex of heavy chain, beta 2-microglobulin, and peptide.

Animals↗
PubMed1991

Falloposcopic observations of endotubal isthmic plugs as a cause of reversible obstruction and their histological characterization.

Eighty falloposcopies were performed in fallopian tubes of women with suspected tubal disease. In three falloposcopies (4%), isthmic plugs were observed occluding the entire isthmic lumen. In all cases these plugs were mobilized by falloposcopic-directed, selected tubal cannulation and aquadissection techniques. Restoration of tubal patency, verified by concurrent chromopertubation under laparoscopic monitoring was achieved in all cases. On one occasion, the isthmic plug was mobilized and identified on the fimbria, and tubal patency was confirmed. When this plug was retrieved and examined histologically, it was found to consist of a cast of debris containing aggregates of histiocyticlike cells of endometrial stromal or mesothelial origin. The genesis of these plugs is unknown. In another subgroup, white to yellow mucus like fragments were observed within the intramural and isthmic lumen during a further 8 of 80 falloposcopies (10%). Whether these mucus like fragments are of physiological or pathophysiological significance remains to be determined. Objective demonstration that isthmic plugs can cause reversible proximal tubal obstruction (PTO) has been achieved using falloposcopy. Falloposcopy offers the diagnostician the ability to objectively classify the cause of PTO. A useful falloposcopic classification and scoring system of tubal lumen lesions has been utilized and is described.

Adult↗
PubMed1991

Falloposcopic identification of a fimbrio-ovarian mucus connection as a possible mechanism for tubal oocyte capture.

Falloposcopy combined with laparoscopy was performed in 11 women during the late follicular phase of spontaneous menstrual cycles, and a preovular follicle was confirmed to be present in each case. The fimbrial end of the tube and the ipsilateral ovary containing the preovular follicle were suspended in a fluid environment of 200 ml of lactated Ringer's solution which acted as a support medium for visualization of tubal mucus and facilitated the endoscopy procedure. As the falloposcope was passed through the fimbrial opening, it was observed to carry clear, elastic and filamentous strands of mucus material from within the distal tubal lumen in 4 of 11 procedures. As these mucus strands were carried on the tip of the falloposcope to touch the surface of the ovary containing the preovular follicle, they attached, on contact, in all cases. The fimbrio-ovarian mucus bridge created was quite strong and could be stretched for up to 7 mm before it detached from the ovarian surface. The mucus attachment appeared to be equally secure over the preovular follicle and adjacent ovarian surfaces. These fimbrio-ovarian mucus connections, which have a high affinity for ovarian surface attachment about the time of ovulation, may play an important role in securing tubal oocyte capture in humans.

Broad Ligament↗
PubMed1991

Incidence and clinical features of glossopharyngeal neuralgia, Rochester, Minnesota, 1945-1984.

The annual crude incidence rate of glossopharyngeal neuralgia per 100,000 population in Rochester, Minn., for 1945 through 1984, was 0.7 for both sexes combined, suggesting that glossopharyngeal neuralgia is a rare disease. There were no significant differences between the sexes (p greater than 0.10) in the overall age-adjusted (to the total 1980 US population) rates: 1.1 for men and 0.5 for women. Overall age-specific crude rates increased slightly with age. Our results and conclusions, achieved by comparing our data with a large referral study at Mayo Clinic, suggest that glossopharyngeal neuralgia is generally a mild disease, since mild attacks are not uncommon, the average annual recurrence rate for a second episode is low (3.6%), and only one fourth of the cases had to have surgery for relief of symptoms. Bilaterality is not uncommon; it was observed in one fourth of the patients, all of whom had mild disease.

Adult↗
PubMed1991

Epidemiology and clinical features of idiopathic trigeminal neuralgia and glossopharyngeal neuralgia: similarities and differences, Rochester, Minnesota, 1945-1984.

A comparison of epidemiological and clinical features of trigeminal neuralgia (TN) and glossopharyngeal neuralgia (GN) in Rochester, Minn., reveals several differences. The overall age- and sex-adjusted annual incidence rates were significantly higher for TN than for GN (4.7 vs. 0.8 per 100,000 population). The TN:GN ratio was increased for both men and women and was 5.9:1 for both sexes combined. This ratio is greater than reported in previous non-population-based studies. GN is a milder disease than TN, as indicated by the number of episodes, treatment, and characterization of pain. The right side is affected more often with TN than with GN. Bilaterality was noted less often in TN than in GN cases.

Adult↗
PubMed1991

Brain injury and neurologic sequelae: a cohort study of dementia, parkinsonism, and amyotrophic lateral sclerosis.

We reviewed the medical records of 821 Olmsted County residents who had suffered head trauma with presumed brain injury between 1935 and 1974 and were more than 40 years old at the time of their last medical assessment. These patients were followed over 15,000 person-years for dementia and other degenerative neurologic diseases. The standardized morbidity ratio (SMR) for dementia was 1.06, and the SMR for dementia of the Alzheimer type was 1.00. These values are not significantly elevated and are inconsistent with studies that suggest that head trauma is a risk factor for Alzheimer's disease. In addition, the SMRs for parkinsonism (1.04), Parkinson's disease (0.94), and amyotrophic lateral sclerosis (1.05) were not significantly elevated, providing no evidence that head trauma is a risk factor for these disorders. However, these latter results are based on smaller total case numbers.

Alzheimer Disease↗