Biomedical subjects

D B Williams

Publications and source records attributed to D B Williams.

At least 73 records · Page 4Linked to original sources

PubMed1995

Determinants of operative mortality in octogenarians undergoing coronary bypass.

BACKGROUND: The elderly segment of the population is increasing rapidly, and surgeons are being asked to consider patients more than 80 years old as candidates for coronary bypass. The objective of this study was to identify risk factors that may adversely affect mortality as well as analyze functional outcomes and survival in octogenarians undergoing coronary bypass. METHODS: From July 1989 through February 1994, 300 consecutive patients 80 years of age and older underwent coronary artery bypass grafting. There were 176 men (58.7%) and 124 women (41.3%) with a mean age of 80.9 years (range, 80 to 99 years). Preoperatively, 274 patients (91.3%) had disabling angina, 76 (25.3%) had left main coronary stenosis greater than 50%, and 293 patients (98.3%) were in New York Heart Association class III or IV. RESULTS: The overall hospital mortality was 11.0% (33/300) with an elective mortality of 9.6% (23/240), urgent mortality of 11% (5/45), and emergent mortality of 33.3% (5/15). Significant independent predictors of operative mortality were preoperative renal dysfunction, postoperative pulmonary insufficiency, postoperative renal dysfunction, use of intraaortic balloon pumping, and sternal wound infection. The actuarial survival for patients discharged from the hospital was 74.6% +/- 5.6% (standard error of the mean) at 54 months. CONCLUSIONS: A favorable outcome may be expected when coronary artery bypass grafting is performed in patients 80 years of age or older with severe angina.

Aged↗

PubMed1995

Benzodiazepine binding varies with stage of estrous cycle in unwashed membranes from mouse brain.

The influence of the stage of the estrous cycle on binding of [3H]diazepam was examined in membranes from brains of female mice. In order to conserve endogenous factors such as progesterone, other steroids, or GABA, the assay was performed without the extensive washing procedures typically employed in measurements of benzodiazepine binding. Significant variations in the apparent maximal numbers of binding sites (Bmax) were noted during the estrous cycle in both hypothalamus and cortex. The Bmax measured in membranes from proestrus female mice was significantly higher than in membranes from mice at other stages in the estrous cycle. Variations in apparent equilibrium binding dissociation constants (Kd) were not statistically significant by stage of the estrous cycle. The demonstrated variations in binding suggest the existence of a factor which varies with the estrous cycle in female mice and modulates the activity of the GABAA receptor complex.

Animals↗

PubMed1995

Molecular chaperones in antigen presentation.

As is the case with most proteins of the secretory pathway, the biogenesis of MHC class I and class II molecules occurs in association with molecular chaperones. Considerable progress has been made in identifying the chaperones involved and recent studies on two of these, calnexin and invariant chain, have shown that they influence multiple processes including protein stability, folding, assembly and intercellular retention.

Animals↗

PubMed1995

Does intrauterine insemination offer an advantage to cervical cap insemination in a donor insemination program?

OBJECTIVE: To compare pregnancy outcome after IUI versus cervical cap insemination in a donor insemination program. DESIGN: A randomized prospective clinical trial in which patients were alternately inseminated with cryopreserved human semen using either IUI or cervical cap insemination methods. SETTING: The donor insemination program at Washington University School of Medicine. PATIENTS: Forty-two women with either isolated male factor or male factor plus corrected ovulatory dysfunction using clomiphene citrate underwent 141 cycles of donor insemination. MAIN OUTCOME MEASURES: Clinical pregnancy rates (PRs) defined as a viable intrauterine gestation > 12 weeks or delivered were compared between groups using the chi 2 test. RESULTS: Clinical PRs were significantly higher in the IUI group (16.4%) compared with the cervical cap insemination group (5.9%). The spontaneous abortion rates were similar between the IUI (1.4%) and cervical cap insemination groups (4.4%). CONCLUSIONS: These findings suggest an advantage to IUI over cervical cap insemination in a donor insemination program.

Abortion, Spontaneous↗

PubMed1995

Evaluation of the intestinal absorption of erythromycin in man: absolute bioavailability and comparison with enteric coated erythromycin.

To determine the role of acid hydrolysis on the gastrointestinal absorption of erythromycin, six healthy subjects received erythromycin as a 240 mg intravenous dose, a 250 mg oral solution administered via endoscope directly into the duodenum and bypassing the stomach, and an enteric-coated 250 mg capsule. Blood samples were collected for 6 hours and serum erythromycin quantified by a microbiological method. The time to achieve maximum serum concentrations for the solution was 0.25 +/- 0.08 (mean +/- SD) hours and for the capsule was 2.92 +/- 0.55 hours. The absolute bioavailability of erythromycin from the capsule was 32 +/- 7% and for the duodenal solution 43 +/- 14%. The ratio of the areas under the serum erythromycin concentration-time curve of capsule to solution was 80 +/- 28% (range 38 to 110%). There is substantial loss of erythromycin apart from gastric acid hydrolysis, which cannot be accounted for by hepatic first-pass metabolism. Attempts to further improve the oral bioavailability of erythromycin beyond 50% by manipulation of formulation are likely to be futile.

Administration, Oral↗

PubMed1994

Persistence of glucose residues on core oligosaccharides prevents association of TCR alpha and TCR beta proteins with calnexin and results specifically in accelerated degradation of nascent TCR alpha proteins within the endoplasmic reticulum.

The alpha beta T-cell antigen receptor (TCR) is a multisubunit transmembrane complex composed of at least six different proteins (alpha, beta, gamma, delta, epsilon and zeta) that are assembled in the endoplasmic reticulum (ER). In this report we have examined the role of oligosaccharide processing on survival and assembly of nascent TCR proteins within the ER and their associations with molecular chaperone proteins important in TCR assembly. We found that treatment of BW5147 T cells with the glucosidase inhibitor castanospermine resulted in markedly accelerated degradation of nascent TCR alpha proteins with a half-life of approximately 20 min. Accelerated degradation was unique to TCR alpha proteins, as the stability of nascent TCR beta and CD3 gamma,epsilon chains was unaltered. Consistent with a requirement for glucose (Glc) trimming for survival of nascent TCR alpha proteins within the ER, we found that newly synthesized TCR alpha chains were innately unstable in the glucosidase II-deficient BW5147 mutant cell line PHAR2.7. In addition to destabilizing nascent TCR alpha proteins we found that persistence of Glc residues on core oligosaccharides markedly interfered with association of both TCR alpha and TCR beta glycoproteins with the molecular chaperone calnexin. Finally, using 2B4 T hybridoma cells in which TCR complexes are efficiently assembled, we found that rapid degradation of nascent TCR alpha proteins induced by impaired Glc trimming severely limits assembly of TCR alpha proteins with TCR beta proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Interaction of MHC class I molecules with the transporter associated with antigen processing.

The transporter associated with antigen processing (TAP) delivers cytosolic peptides into the endoplasmic reticulum (ER) where they bind to nascent class 1 histocompatibility molecules. Class 1-peptide complexes are then displayed at the cell surface for recognition by cytotoxic T lymphocytes. Immunoprecipitation of either TAP or class 1 molecules revealed an association between the transporter and diverse class 1 products. TAP bound preferentially to heterodimers of the class 1 heavy chain and beta 2-microglobulin, and the complex subsequently dissociated in parallel with transport of class 1 molecules from the ER to the Golgi apparatus. The TAP-class 1 complexes could also be dissociated in vitro by the addition of class 1-binding peptides. The association of class 1 molecules with TAP likely promotes efficient capture of peptides before their exposure to the lumen of the ER.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1994

Participation of the endoplasmic reticulum chaperone calnexin (p88, IP90) in the biogenesis of the cystic fibrosis transmembrane conductance regulator.

Deletion of phenylalanine at position 508 (delta F508) in the first nucleotide-binding fold of the cystic fibrosis transmembrane conductance regulator (CFTR) is the most common mutation in patients with cystic fibrosis. Although retaining functional Cl- channel activity, this mutant is recognized as abnormal by the cellular "quality control" machinery and is retained within the endoplasmic reticulum (ER). We have used human epithelial cells and recombinant Chinese hamster ovary cells to identify molecular interactions that may contribute to this intracellular retention. Based upon coimmunoprecipitation and cosedimentation through glycerol density gradients, newly synthesized wild-type and delta F508 mutant CFTRs associated specifically with calnexin, the calcium-binding transmembrane chaperone of the ER. This association was restricted to the immature (or ER-associated) forms of the CFTR proteins. Although the bulk of wild-type and delta F508 CFTRs were present initially in complexes containing calnexin, only wild-type CFTR was able to escape from this association and exit the ER. Calnexin retains misfolded or incompletely assembled proteins in the ER and thus is likely to contribute to the mislocalization of mutant CFTR.

Animals↗

PubMed1994

Regulation of MHC class I transport by the molecular chaperone, calnexin (p88, IP90).

Assembled class I histocompatibility molecules, consisting of heavy chain, beta 2-microglobulin, and peptide ligand, are transported rapidly to the cell surface. In contrast, the intracellular transport of free heavy chains or peptide-deficient heavy chain-beta 2-microglobulin heterodimers is impaired. A 90-kilodalton membrane-bound chaperone of the endoplasmic reticulum (ER), termed calnexin, associates quantitatively with newly synthesized class I heavy chains, but the functions of calnexin in this interaction are unknown. Class I subunits were expressed alone or in combination with calnexin in Drosophila melanogaster cells. Calnexin retarded the intracellular transport of both peptide-deficient heavy chain-beta 2-microglobulin heterodimers and free heavy chains. Calnexin also impeded the rapid intracellular degradation of free heavy chains. The ability of calnexin to protect and retain class I assembly intermediates is likely to contribute to the efficient intracellular formation of class I-peptide complexes.

Amino Acid Sequence↗

PubMed1994

Analysis of bovine immunoglobulin G by capillary gel electrophoresis.

A method for the analysis of bovine immunoglobulin G (IgG) using sodium dodecyl sulphate capillary gel electrophoresis (SDS-CGE) has been described. Under the electrophoretic conditions employed, monomeric and dimeric IgG were readily resolved, as were light chain and heavy chain subunits, and heavy chain dimers in reduced samples. Molecular weights determined by SDS-CGE compared favourably with those measured by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and published values. Reproducibility of protein quantitation was achieved resulting in a relative standard deviation of approximately 13% and calibration was linear in the range of 0.2-3.5 mg ml-1 protein under the conditions used.

Animals↗

PubMed1994

Calnexin: a membrane-bound chaperone of the endoplasmic reticulum.

Calnexin is a new type of molecular chaperone that interacts with many nascent membrane and soluble proteins of the secretory pathway. Calnexin is unrelated to molecular chaperones of the Hsp60, Hsp70 and Hsp90 families, and is further distinguished from them in that it is an integral membrane protein. One of its demonstrated functions is the retention of incorrectly or incompletely folded proteins, suggesting that calnexin is a component of the quality control system of the endoplasmic reticulum.

Calcium-Binding Proteins↗

PubMed1994

Using pharmacist clinical intervention data for quality improvement of medication use and physician assessment.

BACKGROUND: Patient-specific intervention data are often used for drug usage evaluation (DUE), but their use in physician assessment is less often discussed. In response to the quality assurance department's request, the pharmacy department at the Medical College of Georgia (Augusta) developed a database and a reporting system that supports quality assessment of the medical staff, identifies housestaff education needs, and directs efforts for improvement in medication use. THE REPORTING SYSTEM: In 1991 the comprehensive, concurrent screening of drug therapy by pharmacists formed the foundation of the hospital's DUE program. Each month information from the pharmacy database is sorted with use of a spreadsheet software program to generate medical department-level reports and for use in physician reappointment. Identified performance deficiencies can be used to educate individual prescribers and to develop educational programs for the department or specialty areas. Feedback from the medical staff assessment is useful for pharmacist education, such as identifying newly reported indications and dosage regimens. RESULTS: During the first six months after all pharmacists began participating in the reporting program, a mean of 224 interventions were recorded monthly. For the period January through June 1994, 400-550 interventions were recorded monthly. System improvements in medication during the first year of implementation included hospitalwide guidelines for parenteral potassium and phosphate dosing and administration and a renewed focus on patient allergies. CONCLUSION: Emphasis for use of intervention data has shifted from identifying "problem" persons to improving performance by identifying topics for corrective education and redesigning systems to promote positive patient outcomes.

Adverse Drug Reaction Reporting Systems↗

PubMed1994

Assessment of less than monthly progestin therapy in postmenopausal women given estrogen replacement.

OBJECTIVE: To study progestin administration at less than monthly intervals in postmenopausal women given continuous estrogen replacement. METHODS: Eighty postmenopausal women received 0.625 mg/day of conjugated equine estrogens for 48 weeks. Using a double-masked design, the subjects were randomized to medroxyprogesterone acetate 10 mg/day for 14 days every 28 or 84 days, or the same dosage for 28 of 84 days. Bleeding patterns, endometrial histology, and serum lipids were assessed. RESULTS: The total days of bleeding during the 48-week study were significantly reduced (P < .05) in the women given the progestin for 14 days every 3 months (mean +/- standard deviation 29 +/- 16 days) than with the other two regimens. In all groups, secretory endometrium was reported in 17-39%. At 24 but not 48 weeks, simple hyperplasia was observed in one subject in each of the less than monthly progestin groups. Significant increases (P < .05) of high-density lipoprotein cholesterol were observed before but not after medroxyprogesterone acetate in the women receiving it less than monthly. No change was seen with monthly progestin. CONCLUSIONS: In this direct comparison, medroxyprogesterone acetate given for 14 days every 3 months elicited less vaginal bleeding than standard monthly administration. Only a single woman had simple hyperplasia with each regimen of progestin given every 84 days. Medroxyprogesterone acetate given for 14 days every 3 months represents a possible alternative to standard monthly therapy if coupled with regular assessment of the endometrium.

Adult↗

PubMed1994

Progestin replacement in the menopause: effects on the endometrium and serum lipids.

The benefits of estrogen replacement therapy (ERT) in the menopause have been well demonstrated and are of significant importance, particularly with regard to prevention of osteoporosis and reduction in cardiovascular morbidity and mortality. The addition of a progestin to ERT is advocated in patients with a uterus to minimize the risk of endometrial hyperplasia and cancer. Although progestins can have adverse effects on serum lipids, it is unclear whether or not these effects negate the cardioprotective effects of estrogen. Progestins are an important part of hormone replacement therapy (HRT) regimen in patients with an intact uterus. The minimum dose and duration should be given to offset potential adverse effects on serum lipids while affording adequate protection of the endometrium. Both continuous and sequential progestin regimens appear to be efficacious. The newer progestins may offer increased flexibility in minimizing progestin side-effects while protecting the endometrium. Other regimens, such as less than monthly progestin administration, may offer another alternative to achieve these goals. Future studies in these areas are warranted.

Cardiovascular Diseases↗

PubMed1993

Characterization of the insulin A-chain major immunogenic determinant presented by MHC class II I-Ad molecules.

Data are presented which demonstrate the minimal insulin peptide required to activate a large group of insulin-specific T hybrids following presentation by either live or fixed APC, is the N-terminal insulin-A(1-13) peptide. Functional activation and competition assays using both live and fixed APC with 19 synthesized variants of the N-terminal bovine insulin A-chain molecule permitted classification of peptide residues into MHC agretope and T cell epitope regions. Our findings indicate insulin A-chain peptide occupies the Ag binding groove of class II MHC in an extended conformation as a result of intracellular reduction of A-loop disulfide bonds. Insulin A-chain Cys7 and Cys11 residues represent two independent T cell epitopes N- and C-terminal to the A-loop region. Data are presented that demonstrate the unique residues associated with several insulin isoform molecules contribute to the peptide agretope region. Our findings may suggest peptide agretopes may subtly modify the peptide/MHC conformation presented to TCR.

Amino Acid Sequence↗

PubMed1993

Identification of the region on the class I histocompatibility molecule that interacts with the molecular chaperone, p88 (calnexin, IP90).

During early stages in their biogenesis, murine class I histocompatibility molecules interact transiently with a molecular chaperone of the endoplasmic reticulum designated p88. Using a series of mutant class I heavy chains we mapped the region of the heavy chain that interacts with p88. Domain deletion mutants of the H-2Db and H-2Kb molecules revealed that most of the extracellular portion of the heavy chain and the bulk of the cytoplasmic domain were not required for the association. However, replacement of the transmembrane segment and cytoplasmic domain with a glycosyl phosphatidylinositol anchor from Q7b resulted in a heavy chain that was incapable of interaction with p88. These results suggested that the primary site of interaction with p88 is within a region containing the transmembrane segment and several flanking amino acids of the class I heavy chain. This finding was supported by replacing the glycosyl phosphatidylinositol anchor of the noninteracting Q7b protein with segments of the Db heavy chain containing the putative interaction site and showing that the hybrids were capable of associating with p88. The apparent lack of interaction between segments of p88 and the class I heavy chain that are present within the lumen of the endoplasmic reticulum was also observed when the association between p88 and the alpha chain of the T cell receptor was examined. The full-length transmembrane alpha chain formed a complex with p88, whereas a soluble variant consisting of most of the luminal portion of the alpha chain exhibited only minimal interaction. Thus, p88 is capable of associating with nascent integral membrane proteins through transmembrane interactions that are unavailable to the major soluble chaperone of the endoplasmic reticulum, BiP (GRP78).

Amino Acid Sequence↗

PubMed1993

Ultrasonic measurement of canine testes.

The goals of the present study were to determine if ultrasonic measurement of testicular dimensions (length, width, and height) would provide an accurate assessment of canine testicular size (weight) and to determine the relationship of these measurements to animal body weight. The bodies of 30 intact male dogs of unknown health, breed or breeding history were obtained after the dogs were humanely killed at the local animal shelter. Total scrotal width (TSW) was measured by calipers and the length, width and height of each scrotal testis, excluding the epididymis, were measured by sonography. The testes were then excised and weighed, again excluding the epididymis. Multiple regression was used to predict total testicular weight from 1) only sonographic measurements (Model 1), 2) all testicular measurements (Model 2), 3) only total scrotal width (Model 3), and 4) only body weight (Model 4). In addition, stepwise multiple regression was used to identify models (Models 5 and 6) using external measurements of the testes which seemed most useful in predicting total testicular weight. Models 1, 2, 3, 4, and 6 yielded r(2) values 0.90, 0.94, 0.88, 0.48 and 0.95 respectively. Model 5 yielded an r(2) of 0.90, but the additional accuracy achieved by using the testicular height was minimal. Although sonographic testicular measurement accurately predicted testicular weight, the small degree of additional accuracy achieved over TSW measurement by calipers does not justify the use of sonography in each case. However, if a testicular ultrasound scan is being performed, the ultrasonic measurements could be used to predict testicular weight.

Journal Article↗

PubMed1993

Effects of pentoxifylline on sperm motility and hyperactivated motility in vitro: a preliminary report.

Previous reports (2, 3) have suggested that pentoxifylline increases sperm motility. In this preliminary report based on five asthenozoospermic and five normal motility semen samples, we were unable to demonstrate any statistically significant effect of pentoxifylline on percent motility of human spermatozoa. However, in vitro exposure to capacitation medium with pentoxifylline may lead to an increase in total hyperactivated motility in asthenozoospermic samples, an effect not evident in the normal motility samples in this study.

Humans↗