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Biomedical subjects

D L Williams

Publications and source records attributed to D L Williams.

At least 127 records · Page 7Linked to original sources
PubMed1996

Carcinoma of the lung after heart transplantation.

We have recently noted an unexpected high incidence of lung cancer in our population of cardiac allograft recipients. We conducted a retrospective review of cardiac transplantation at our institution to investigate the incidence, clinical course, and outcome of patients who developed lung cancer following heart transplantation. Nine patients--each with a history of smoking at 30 pack-years--developed lung cancer following heart transplantation, for an incidence of 1.56% of patients at risk. Eight of the patients were male > or = 50 years of age, representing 3.3% of the male transplant recipients in this age group. The interval from transplantation to diagnosis clustered around 3-5 years after transplantation, but in two instances (22%), a neoplasm was discovered within 6 months of transplantation. Almost half of the cancers were discovered incidentally, despite routine radiographic surveillance. Seven of 9 (78%) patients had stage IV disease at presentation. Median survival after diagnosis was 3 months, and five of the seven patients who died survived less than 4 months after diagnosis. We conclude that cardiac transplant recipients are at increased risk for development of lung cancer. Patients with a moderate to heavy smoking history might well be advised to undergo chest CT scanning in an aggressive search for occult lung cancer before cardiac transplantation is considered further. Finally, despite frequent radiologic examinations, these lung cancers are often diagnosed incidentally, are far advanced at the time of diagnosis, are not surgically resectable, and are poorly responsive to adjuvant therapy.

Adolescent↗
PubMed1996

Apolipoprotein A-I is required for cholesteryl ester accumulation in steroidogenic cells and for normal adrenal steroid production.

In addition to its ability to remove cholesterol from cells, HDL also delivers cholesterol to cells through a poorly defined process in which cholesteryl esters are selectively transferred from HDL particles into the cell without the uptake and degradation of the lipoprotein particle. The HDL-cholesteryl ester selective uptake pathway is known to occur in human, rabbit, and rodent hepatocytes where it may contribute to the clearance of plasma cholesteryl ester. The selective uptake pathway has been studied most extensively in steroidogenic cells of rodents in which it accounts for 90% or more of the cholesterol destined for steroid production or cholesteryl ester accumulation. In this study we have used apo A-I-, apo A-II-, and apo E-deficient mice created by gene targeting in embryonic stem cells to test the importance of the three major HDL proteins in determining cholesteryl ester accumulation in steroidogenic cells of the adrenal gland, ovary, and testis. apo E and apo A-II deficiencies were found to have only modest effects on cholesteryl ester accumulation. In contrast, apo A-I deficiency caused an almost complete failure to accumulate cholesteryl ester in steroidogenic cells. These results suggest that apo A-I is essential for the selective uptake of HDL-cholesteryl esters. The lack of apo A-I has a major impact on adrenal gland physiology causing diminished basal corticosteroid production, a blunted steroidogenic response to stress, and increased expression of compensatory pathways to provide cholesterol substrate for steroid production.

Adrenal Cortex Hormones↗
PubMed1996

Receptor binding and internalization of a water-soluble (1-->3)-beta-D-glucan biologic response modifier in two monocyte/macrophage cell lines.

Glucan phosphate, a water-soluble, chemically defined (1-->3)-beta-D-glucan biologic response modifier, has been reported to exert antisepsis activity and accelerate wound healing. In this study we describe the specific binding of glucan phosphate to human and murine monocyte/macrophage cell lines, U937 and J774A.1, respectively. At 37 degrees C, equilibrium binding was rapidly achieved, i.e., within 1 min. In U937 cells, binding occurred with an affinity (Kd) of 37 microM and a Bmax of 65 x 106 binding sites/cell at 37 degrees C. In J774A.1 cells, glucan phosphate bound with an affinity (Kd) of 24 microM and a Bmax of 53 x 106 binding sites/cell at 37 degrees C. In both cases there was insignificant nonspecific binding. We further demonstrated that bound glucan phosphate cannot be displaced by a 50-fold excess of unlabeled ligand, suggesting internalization of glucan phosphate. Transmission electron microscopy showed significantly increased cytoplasmic vacuolization and significantly decreased mitotic activity in glucan phosphate-treated U937 cells compared with that in untreated cells. Pullulan, a random coil alpha-(1-->4)-(1-->6)-linked glucose polymer that served as a control, did not compete for the same binding site as glucan phosphate in either cell line, indicating the specificity of the binding site for (1-->3)-beta-D-glucans. We conclude that water-soluble pharmaceutical grade (1-->3)-beta-D-glucan phosphate specifically binds to and is internalized by U937 and J774A.1 cells.

Animals↗
PubMed1996

Current concepts in the management of canine cataract: a survey of techniques used by surgeons in Britain, Europe and the USA and a review of recent literature.

One of the authors (D. L. W.) visited ophthalmologists in Great Britain, Europe and the USA to assess current practice in the surgery of cataracts in dogs. This paper describes the results of these visits and provides a survey of the literature. The success rates in canine cataract surgery have increased markedly in the last 10 years, particularly as a result of the introduction of phacoemulsification techniques and the reduction in the use of extracapsular cataract extraction; these new techniques and the problems they seek to overcome are discussed. The paper also considers the developing field of intraocular lens implantation, the rationale behind such developments and the benefits and potential problems which may occur after the extraction of a cataract and the implantation of a lens.

Animals↗
PubMed1996

Estrogen induces the assembly of a multiprotein messenger ribonucleoprotein complex on the 3'-untranslated region of chicken apolipoprotein II mRNA.

UV cross-linking was used to identify estrogen-induced hepatocyte proteins that bind to apoII mRNA. Probes spanning the entire message revealed the presence of eight estrogen-induced proteins cross-linked to the 3'-untranslated region (UTR), but not to the coding region or the 5'-UTR. Two estrogen-induced proteins of 132 and 50 kDa were either absent or barely detectable in control animals, whereas six additional proteins of 93, 83, 74, 65, 58, and 45 kDa were clearly present in control animals and increased 2-5-fold by estrogen. A similar profile of estrogen-induced proteins was seen with the 3'-UTRs of the estrogen-regulated mRNAs for apoB and vitellogenin II, but not with the 3'-UTRs of the non-estrogen-regulated mRNAs for apoA-I and glyceraldehyde-phosphate dehydrogenase. These findings indicate that the estrogen-induced proteins discriminate among mRNAs and suggest that they interact selectively with the family of estrogen-regulated mRNAs. The estrogen-induced proteins are found in the cytoplasmic fraction of liver extracts, and a subset of them are also found in adrenal glands, testes, heart, brain, and kidneys, but they are estrogen-induced only in the liver. Deletion analysis defined a 150-nucleotide region of the apoII 3'-UTR that is necessary for maximal binding of the estrogen-induced proteins. An internal deletion of endonucleolytic cleavage sites previously identified within the apoII 3'-UTR selectively reduced the binding of the 58-kDa protein. These findings reveal remarkable complexity in estrogen-stimulated protein-RNA interactions within the 3'-UTRs of estrogen-regulated mRNAs. These proteins may participate in the mRNA degradation process or in other aspects of cytoplasmic mRNA metabolism that accompany estrogen-stimulated vitellogenesis.

Animals↗
PubMed1996

Pharmacology of L-744,453, a novel nonpeptidyl endothelin antagonist.

L-744,453 ((+/-)3-[4-(1-carboxy-1-(3,4-methylenedioxyphenyl)methoxy)-3,5-diprop ylphenyl methyl]-3H-imidazo[4,5-c]pyridine) is an endothelin (ET) receptor antagonist from a new structural class, the dipropyl-alpha-phenoxyphenylacetic acid derivatives. L-744,453 competitively and reversibly inhibits [125I]-ET-1 binding to Chinese Hamster Ovary cells expressing cloned human ET receptors (K(i)s: hET(A)=4.3 nM; hET(B)=232 nM), and is selective for endothelin receptors compared to other peptide receptors. It is an antagonist of ET-1 stimulated phosphatidyl inositol hydrolysis in rat uterine slices (IC50=220 nM) and exhibits no agonist activity. This compound also inhibits ET-1 stimulated contraction of rat aortic rings with a K(b) value of 50 nM. L-744,453 protects against ET-1 induced lethality in mice after i.v. (AD50=13 mg/kg i.v.) or oral administration. This compound also antagonizes ET-1 induced increases in diastolic blood pressure in conscious normotensive rats (AD50=0.67 mg/kg i.v.) and anesthetized ferrets (AD50=1.6 mg/kg i.v.). L-744,453 is a potent, selective, orally active endothelin antagonist which may be useful in elucidating the role of endothelin in normal and pathophysiological states.

Animals↗
PubMed1996

Outpatient left ventricular assist device support: a destination rather than a bridge.

BACKGROUND: To evaluate the feasibility and efficacy of outpatient left ventricular assist devices as a bridge to transplantation, we reviewed the initial clinical experience with this modality at our institution. METHODS: During January 1993 to November 1995, 12 male and 2 female patients with an average age of 47 +/- 17 years were supported for an average of 117 +/- 24 days with the Thermo Cardiosystems VE wearable left ventricular assist device. Seven patients were discharged home an average of 35 +/- 4 days after implantation. RESULTS: No device failures occurred, although 29 controller malfunctions were identified during 1,640 total support days. All patients were able to safely maintain their devices. Outflow graft bleeding and driveline infection were responsible for two readmissions. No long-term anticoagulation treatment was used; one small thromboembolic episode occurred, but without significant long-term sequelae. CONCLUSIONS: None of the 7 patients released from the hospital died, and all were able to successfully maintain their devices at home. Hospital discharge of patients supported with left ventricular assist devices has allowed long-term evaluation of this technology, and the findings should prompt study of their use as a long-term alternative treatment to medical management for congestive heart failure.

Adolescent↗
PubMed1996

Generation of nitric oxide from S-nitrosothiols using protein-bound Cu2+ sources.

BACKGROUND: We have recently shown that S-nitrosothiols (RSNOs) decompose in aqueous buffer to give nitric oxide, an important signalling molecule, and the corresponding disulphides. This occurs by reaction with Cu+ generated from Cu2+ (supplied as hydrated Cu2+) by thiolate reduction. To establish whether these reactions are feasible in vivo, we set out to determine whether Cu2+ bound to an amino acid, a tripeptide or to human serum albumin (HSA) could serve as a Cu+ source for generation of NO from S-nitrosothiols. RESULTS: Experiments with Cu2+ bound to the tripeptide Gly-Gly-His or to two histidine molecules or to HSA showed that Cu+ was released (and trapped with neocuproine) when the copper source was treated with a thiol at pH 7.4. RSNO decomposition was achieved with all three copper sources, although not as rapidly as with added hydrated Cu2+. Decomposition was also catalyzed by ceruloplasmin. CONCLUSIONS: These results show clearly that amino-acid- and protein-bound Cu2+ can be reduced by thiolate ion to Cu+, which will generate NO from RSNO species, thus providing a realistic model for these reactions in vivo.

Copper↗
PubMed1996

Characterization of the catalase-peroxidase gene (katG) and inhA locus in isoniazid-resistant and -susceptible strains of Mycobacterium tuberculosis by automated DNA sequencing: restricted array of mutations associated with drug resistance.

The catalase-peroxidase gene (katG) and a two-gene locus (inhA) containing mutations associated with resistance to isoniazid in Mycobacterium tuberculosis were sequenced in 34 resistant and 12 susceptible strains. Virtually all resistant organisms had amino acid changes in KatG or nucleotide substitutions upstream of inhA. A region of katG encoding two amino acids frequently altered in resistant strains (residues Ser315 and Arg463) and the inhA locus were sequenced in 10 susceptible and 51 isoniazid-resistant isolates from the Netherlands. Most (84%) of the resistant isolates had mutations in katG or the inhA locus or lacked katG. Together, approximately 75% of isoniazid-resistant isolates had replacements at amino acids 315 or 463 in KatG or nucleotide substitutions upstream of inhA. All 16 strains of Mycobacterium bovis and Mycobacterium microti studied had Leu463 rather than Arg463 in KatG, an observation consistent with the hypothesis that Leu463 is the ancestral condition in M. tuberculosis.

Amino Acid Sequence↗
PubMed1996

Characterization of rpsL and rrs mutations in streptomycin-resistant Mycobacterium tuberculosis isolates from diverse geographic localities.

Two genes (rpsL and rrs) with mutations associated with streptomycin resistance in Mycobacterium tuberculosis were characterized in 78 streptomycin-resistant and 61 streptomycin-susceptible isolates recovered from patients living in the United States, South America, Europe, Africa, and Asia. Fifty-four percent of the 78 resistant organisms had missense mutations in codon 43 of rpsL resulting in a K-43-->R substitution. Mutations in codon 88 of rpsL were also identified in four Asian isolates.

Antibiotics, Antitubercular↗
PubMed1995

Psychosocial evaluation and prediction of compliance problems and morbidity after heart transplantation.

We examined prospectively determined psychosocial evaluation data in 125 consecutive adult patients undergoing heart transplantation from January 1992 to April 1994 to determine their associations with morbidity, mortality, and compliance. Prospective ratings included age, sex, weight, education, social support, living arrangements, motivation, knowledge and expectations about transplantation, intercurrent social stressors, substance abuse, personality disorder, cognitive impairment, other psychiatric disorders, and the evaluating psychiatrist's global assessment of psychosocial risk. Additional variables evaluated were support group attendance and waiting list time. We examined outcomes including patient survival, compliance, episodes of rejection and infection, development of transplant coronary artery disease, number of missed appointments, and maintenance of ideal body weight. The posttransplant follow-up period was 13.8 +/- 9.9 months (mean +/- SD). In univariate analyses, compliance problems were associated with substance abuse history (P = .0007), personality disorder (P = .007), living arrangements (P = .02), and global psychosocial risk (P = .001). The number of rejection episodes was associated with global psychosocial risk (P = .029), and transplant coronary artery disease was inversely associated with education (P = .01). Survival was not associated with any of the predictor variables. In stepwise multivariate analyses, the significant predictors of compliance were substance abuse (odds ratio 3.69, confidence limits 1.07-12.71) and global psychosocial risk (odds ratio 3.76, confidence intervals 1.18-11.97). These findings suggest that pretransplant evaluation of psychosocial risk factors can identify patients with increased risk of postoperative noncompliance and morbidity.

Adult↗
PubMed1995

Comparison of topical cyclosporin and dexamethasone for the treatment of chronic superficial keratitis in dogs.

Thirty dogs with chronic superficial keratitis (CSK) were randomly assigned to treatment with 0.2 per cent cyclosporin ointment or 0.1 per cent dexamethasone drops. They were treated for six weeks and examined before and after three and six weeks of treatment, and then every three weeks without treatment until the lesions recurred. The regression of the disease during the treatment and the time to a recurrence after the cessation of treatment were determined. Changes in the size of the corneal lesions were measured by image analysis of photographs taken at each examination, and the severity of adnexal changes such as conjunctival hyperaemia was assessed by means of a scoring system. Clinical evaluations suggested that both drugs were equally effective as treatments for CSK and a statistical analysis showed that they had reduced the size of the lesions to the same extent at each examination. There was a significant increase in tear production, measured by the Schirmer tear test, during the treatment with cyclosporin.

Administration, Topical↗
PubMed1995

Preliminary findings of ophthalmological abnormalities in farmed halibut.

Ocular abnormalities occurring in farmed halibut at the Sea Fish Industry Authority Marine Farming Unit, Ardtoe, Argyll were investigated clinically and post mortem. A significant number of fish were found to have posterior polar cystic changes either causing scleral ectasia or gross degenerative posterior segment abnormalities with chorioretinal atrophy. Other ocular abnormalities included cataract formation and intraocular inflammation. In a small number of fish gas bubble formation in the anterior chamber was observed during capture and examination. It is possible that the lesions seen in these fish are a form of gas bubble disease although super-saturation, the cause of gas bubble disease previously reported in farmed fish, does not occur in the tanks in which these fish are housed. While this paper provides no answers with regard to the aetiopathogenesis of the lesions, it is hoped that it will stimulate discussion, leading to resolution of these questions through a multidisciplinary approach to the problem.

Animals↗
PubMed1995

Comparison of the carbohydrate biological response modifiers Krestin, schizophyllan and glucan phosphate by aqueous size exclusion chromatography with in-line argon-ion multi-angle laser light scattering photometry and differential viscometry detectors.

A major barrier to the development, preclinical and clinical application of natural carbohydrate biological response modifiers has been the difficulty involved in accurately characterizing carbohydrate polymers with molecular masses ranging from 10(4) to 10(7) g/mol. Herein, we employed size exclusion chromatography with multi-angle laser light scattering and differential viscometry to compare and contrast structural properties of the biological response modifiers Krestin, schizophyllan and glucan phosphate. Krestin, schizophyllan and glucan phosphate exhibit significant differences in molecular mass moments, molecular mass distribution, polymer sizes, intrinsic viscosity and perhaps their solution behaviour. This knowledge of precise physicochemical data is required for a better understanding of the properties and higher structure of complex carbohydrate biological response modifiers.

Chromatography, Gel↗
PubMed1995

De novo solid malignancies after cardiac transplantation.

BACKGROUND: As long-term survival after cardiac transplantation improves, neoplastic complications are increasingly being discovered. Although lymphoproliferative disorders predominate, the incidence and clinical spectrum of solid tumors in a uniform population of heart transplant recipients remains uncertain. METHODS: We reviewed our experience with 712 patients who underwent cardiac transplantation. Clinical charts were reviewed and telephone interviews were conducted, when possible. RESULTS: De novo solid malignancies were identified in 3.3% of patients at risk (21 of 633 patients). Twenty patients were male; mean age was 51.5 +/- 8.6 years. Most patients reported a significant smoking history. Pulmonary, urologic, and Kaposi's sarcoma were the most common malignancies identified. Mean interval from transplantation to diagnosis was 35 months. Six patients were diagnosed within 6 months of transplantation. One-year and 5-year survival after transplantation were 90% and 49%, respectively. One-year and 3-year survival after cancer diagnosis were 60% and 52%, respectively. CONCLUSIONS: De novo solid malignancy after transplantation occurred with about half the frequency of lymphoproliferative disorders. A striking male predominance was noted. The interval from transplantation to the appearance of cancer is variable, and no clustering was identified. A significant smoking history warrants aggressive search for occult malignancy during pretransplantation evaluation of potential heart recipients.

Adolescent↗
PubMed1995

NO, nitrosonium ions, nitroxide ions, nitrosothiols and iron-nitrosyls in biology: a chemist's perspective.

The multiplicity of biological functions thus far attributed to NO has led to suggestions that some effects might be mediated by other, related species instead. The radical nature of NO cannot account for its cytotoxicity, but its reaction with superoxide to form peroxynitite and highly reactive hydroxyl radicals may be important in this context. The ease with which NO can react with and destroy Fe-S clusters is also an important factor. Nitrosonium and nitroxide ions can be produced in vivo and will react under conditions that are physiologically relevant. Both could, in theory, serve in cell signalling or as cytotoxic agents. More direct experimental evidence for their involvement is needed before we can confidently assign them specific biological roles. In this article, Anthony Butler, Frederick Flitney and Lyn Williams discuss the chemistry of NO and related species.

Free Radicals↗