Research, audit and postgraduate education.
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Education, Medical, Graduate↗
Biomedical subjects
B A Smith
Publications and source records attributed to B A Smith.
Experience with three different third-generation cardioverter-defibrillators in patients with coronary artery disease or cardiomyopathy.
Clinical investigations are being performed in multiprogrammable devices whose therapeutic options include antitachycardia pacing, cardioversion, defibrillation and bradycardia pacing. Three different third-generation devices were implanted in 46 research patients at 1 clinical center to document their safety and efficacy for the treatment of malignant ventricular arrhythmias. Additionally, the purpose of the study was to determine if antitachycardia pacing is a desirable and frequently used feature of tiered devices. The Medtronic PCD was implanted in 15 patients (12 men, mean age 60 +/- 13 years, mean ejection fraction 40 +/- 15%), the Ventritex Cadence in 21 patients (17 men, mean age 65 +/- 10 years, mean ejection fraction 38 +/- 12%), and the CPI VENTAK PRx in 10 patients (8 men, mean age 63 +/- 14 years, mean ejection fraction 31 +/- 8%). All patients presented with cardiac arrest or ventricular tachycardia. During follow-up of 10 +/- 6 months (range 1 to 19), 70% of the 20 patients with antitachycardia pacing activated used the feature for spontaneous ventricular tachycardia. The antitachycardia pacing parameters were reprogrammed 20 times in 15 patients. Two thousand six hundred thirty-eight of 2,675 (98%) antitachycardia pacing attempts successfully terminated spontaneous tachyarrhythmias. Low-energy cardioversion or defibrillation terminated tachyarrhythmias in patients where pacing was unsuccessful. One hundred forty-eight episodes of tachycardia were successfully treated directly by shocks in 16 of 46 patients (35%). There were no deaths due to device failure. This initial single-center clinical experience suggests that the PCD, Cadence and VENTAK PRx are all safe and effective tiered therapy devices for the treatment of malignant ventricular arrhythmias. Antitachycardia pacing successfully terminated most episodes of ventricular tachycardia; in patients with this feature activated, it was used frequently but required reprogramming to achieve high levels of success.
Aged↗
Genetic events in tumour initiation and progression in multiple endocrine neoplasia type 2.
Multiple endocrine neoplasia type 2 (MEN 2) is a familial cancer syndrome arising from mutation at a locus or loci in chromosome region 10p11.2-q11.2. The disease is characterized by medullary thyroid carcinoma (MTC) and pheochromocytoma (Pheo). To assess the genetic events in tumour initiation and progression in this disease, we have compiled an allelotype for MTC and Pheo tumours using polymorphic marker loci from each chromosome arm. Using a panel of 58 tumours, we found frequent allele losses on chromosome arms 1p (42%), 3p (30%), 3q (38%), 11p (11%), 13q (10%), 17p (8%), and 22q (29%). Loss of heterozygosity (LOH) for loci on chromosome 10 was detected in a single tumour where one whole chromosome copy was lost. We used a panel of polymorphic markers for each of chromosomes 1, 3, 11, and 17 to define a shortest region of overlap for these regions. The most frequent allele losses were on chromosome 1, spanning the entire short arm of the chromosome but not loci on 1q. LOH on chromosome 3 encompassed a minimal common region of 3q12-qter. The regions of allelic deletion on chromosome 11 (11pter-p13), 17 (17pter-p11.2), and 13 (13q) encompass known tumour suppressor loci (WTI, TP53, RBI) which must therefore be candidates for genes contributing to MTC and Pheo development. Our data suggest allele loss on chromosome 11, 13, or 17 occurs predominantly in tumours with losses on chromosome 3, potentially reflecting the accumulation of genetic change in tumour progression. These events may be associated with more advanced disease in MTC. We suggest that at least 7 genes contribute to tumour development in MEN 2, including an initiating locus on chromosome 10 and loci on chromosomes 1, 3, 11, 13, 17, and 22 which have a progressional role in these tumours.
Adrenal Gland Neoplasms↗
Thrombin and albumin adsorption to PVA and heparin-PVA hydrogels. 2: Competition and displacement.
Thrombin adsorption to polyvinyl alcohol (PVA) was different from its adsorption to polyethylene (PE)--not so much in amount, but in its affinity. Thrombin was more easily displaced from polyethylene and its adsorption was more readily prevented by prior or simultaneous exposure to albumin. From PVA (or heparin-PVA), only approximately 30% of the adsorbed protein could be removed by a series of eluents, including even harsh ones such as 2.5M NaOH and 6M guanidine; > 85% could be removed from PE. Thrombin adsorption to PVA was not affected by the presence of BSA in solution or at the surface, but was virtually prevented on PE by preexposure to or adsorption with BSA. Heparin-PVA was not much different than PVA in most of these experiments, but did exhibit a "Vroman effect". In the absence of fibrinogen or antithrombin III, there was a maximum in thrombin adsorption from plasma at a plasma concentration of 1%. The behavior on this surface was dependent on both exposure time and protein concentration. These studies highlight the complexity of the interaction between plasma proteins and polymer surfaces (particularly hydrogel surfaces) and the difficulty of obtaining a clear picture of what happens when a single protein interacts with a polymer in the presence of other proteins.
Adsorption↗
Dinitropyrene metabolism, DNA adduct formation, and DNA amplification in an SV40-transformed Chinese hamster embryo cell line.
The environmental pollutants 1,6-dinitropyrene (1,6-DNP) and 1,8-dinitropyrene (1,8-DNP) are strongly carcinogenic in a number of animal models. These DNPs are metabolized by nitroreduction to N-hydroxy arylamine derivatives that either directly or after acetylation bind to cellular DNA. In the experiments reported here, we examined whether DNA adduct formation by 1,6-DNP and 1,8-DNP was associated with amplification of specific DNA sequences, a process that may be causally related to tumorigenesis. CO60 cells, an SV40-transformed Chinese hamster embryo cell line, were incubated with 2.5 or 50 ng/mL [4,5,9,10(-3)H]1,6-DNP for 5 h. High-pressure liquid chromatographic analysis of organic extracts of the medium indicated the presence of 1-acetylamino-6-nitropyrene, suggesting that these cells are capable of nitroreduction and acetylation. 32P-Postlabeling analysis of DNA isolated from cells exposed to 1.0 or 2.5 ng/mL 1,6-DNP revealed dose-related formation of N-(deoxyguanosin-8-yl)-1-amino-6-nitropyrene. A similar adduct, presumably N-(deoxyguanosin-8-yl)-1-amino-8-nitropyrene, was detected after incubations with 1,8-DNP. DNA isolated from analogous experiments was slot-blotted onto nylon membranes and hybridized with 32P-labeled SV40, c-fos, or beta-actin DNA probes. beta-Actin was not amplified and c-fos was amplified only a small amount; however, there was dose-related amplification of SV40 sequences, whose levels were in some instances approximately 20 times that observed in solvent-treated controls. These data indicate that DNA adduct formation by 1,6-DNP and 1,8-DNP is associated with the amplification of certain DNA sequences, a response that may be related to the tumorigenic potential of these compounds.
Actins↗
Sudden death in a young adult: sequelae of childhood Kawasaki disease.
A case of sudden cardiac death in a young adult secondary to sequelae of childhood Kawasaki disease is presented. At autopsy, proximal coronary artery aneurysms typical of Kawasaki disease with recent and remote myocardial infarction was found. Although the acute diagnosis and management of Kawasaki disease has received attention in recent literature, little has been written about the implications of the disease in long-term survivors. Serious morbidity and mortality many years after the acute phase of the disease can occur. Because of the relatively recent recognition of the disease, an undetermined population of patients with previously unrecognized Kawasaki disease exists. Young patients with previous Kawasaki disease may have severe stenotic coronary disease that may be asymptomatic and present with sudden cardiovascular symptoms or death. Acute care physicians should be cognizant of these issues and should seek specific information regarding childhood illnesses when evaluating the young patient with acute cardiovascular symptoms.
Adolescent↗
Interferon production by and leukocyte phenotyping of rhesus monkey lymph node and peripheral blood cells.
The ability of peripheral blood leukocytes to produce interferon-gamma (IFN-gamma) and be labeled with monoclonal antibodies against cell-surface markers was determined in this study. Both peripheral blood leukocytes and lymph node cells were able to produce IFN-gamma after challenge with mitogens. The rhesus monkey IFN-gamma was detectable by means of a biological assay but not by means of a radioimmunoassay for human IFN-gamma. Peripheral blood leukocytes and lymph node cells from rhesus monkeys (Macaca mulatta) were treated with fluoresceinated antibodies directed primarily against cell-surface antigens of humans. The degree of binding was determined by means of flow cytometry. Several of the anti-human antibodies did bind to the rhesus monkey peripheral blood leukocytes, as expected. In a novel study, the antibodies bound in a similar fashion to rhesus monkey lymph node cells. Binding of the antibodies was equivalent whether the cells came from inguinal or axillary lymph nodes. Rhesus monkey peripheral blood leukocytes incubated with recombinant human IFN-gamma showed enhanced expression of class II major histocompatibility complex antigens, as detected with anti-HLA-DR antibodies.
Animals↗
Conversion rates of induced versus spontaneous ventricular tachycardia by a third generation cardioverter defibrillator. The VENTAK PRx Phase I Investigators.
Seventy consecutive patients received the first VENTAK PRx pulse generators (Cardiac Pacemakers, Inc.) implanted in the United States. This multiprogrammable device has therapeutic options that include: (1) antitachycardia pacing; (2) low energy cardioversion; (3) defibrillation shocks; and (4) bradycardia pacing. There were 60 males and 10 females with a mean age of 65.3 +/- 9.4 years. The anatomical diagnoses were coronary artery disease in 55 patients, cardiomyopathy in 7 patients, congenital heart disease in 2 patients, and miscellaneous disease in the remaining 6 patients. Thirty-six percent had a history of sudden cardiac death and 90% had documented monomorphic ventricular tachycardia. The mean ejection fraction was 32.7% +/- 12.2%. Thirty-three (49.3%) had an ejection fraction < or = 30%. Electrophysiological testing was done preimplant, predischarge, and 1 to 2 months postimplant to define a specific electrical therapy and evaluate the efficacy of the device. Two hundred ninety-three of 367 (80%) episodes of induced ventricular tachycardia were successfully terminated by the VENTAK PRx programmed for antitachycardia pacing. There were 1,794 total therapy episodes for spontaneous ventricular tachycardia; 91% (1,641 episodes) were terminated by antitachycardia pacing and 153 episodes were converted by shocks during a minimal 6-month follow-up per patient. We conclude that documentation of a successful antitachycardia pacing modality in the electrophysiology laboratory predicts conversion of spontaneous episodes of ventricular tachycardia. Furthermore, antitachycardia pacing by the VENTAK PRx can terminate the majority of episodes of ventricular tachycardia.
Aged↗
Mathematical modeling of ligaments and tendons.
Ligaments and tendons serve a variety of important functions in maintaining the structure of the human body. Although abundant literature exists describing experimental investigations of these tissues, mathematical modeling of ligaments and tendons also contributes significantly to understanding their behavior. This paper presents a survey of developments in mathematical modeling of ligaments and tendons over the past 20 years. Mathematical descriptions of ligaments and tendons are identified as either elastic or viscoelastic, and are discussed in chronological order. Elastic models assume that ligaments and tendons do not display time dependent behavior and thus, they focus on describing the nonlinear aspects of their mechanical response. On the other hand, viscoelastic models incorporate time dependent effects into their mathematical description. In particular, two viscoelastic models are discussed in detail; quasi-linear viscoelasticity (QLV), which has been widely used in the past 20 years, and the recently proposed single integral finite strain (SIFS) model.
Animals↗
DNA adduct formation in relation to lymphocyte mutations and lung tumor induction in F344 rats treated with the environmental pollutant 1,6-dinitropyrene.
Epidemiological studies suggest an association between exposure to diesel emissions and an increased incidence of lung and bladder cancer in humans. Of the compounds associated with diesel emissions, 1,6-dinitropyrene is a particularly potent mutagen and carcinogen. In these experiments we administered [4,5,9,10-3H]1,6-dinitropyrene (30 or 100 micrograms) directly to the lungs of F344 rats according to a protocol known to induce lung tumors and characterized the DNA adducts present in the target tissue. In addition, we examined the adducts present in spleen lymphocytes and assayed for the induction of mutations at the hypoxanthine-guanine phosphoribosyltransferase locus in these cells, as measured by the frequency of 6-thioguanine-resistant (TGr) T-lymphocytes. Adduct formation was detected in both lung and spleen lymphocyte DNA, with the extent of binding being dose-dependent in the lymphocytes but not the lung. 32P-Postlabeling analyses indicated the formation of a major DNA adduct, N-(deoxyguanosin-8-yl)-1-amino-6- nitropyrene, in both tissues. 1,6-Dinitropyrene treatment resulted in a dose-dependent increase in TGr T-lymphocytes, with the increase being detected for at least 21 weeks after treatment. These data indicate that 1,6-dinitropyrene is metabolically activated by nitroreduction to form DNA adducts in both the target tissue and spleen lymphocytes and that a tumorigenic dose results in a significant induction of TGr T-lymphocytes.
Animals↗
Effect of verapamil on an accessory pathway manifesting as "fatigue phenomenon" in Wolff-Parkinson-White syndrome.
Electrophysiologic study was performed in a 52-year-old man with type A ventricular preexcitation. An accessory atrioventricular pathway with no ventriculoatrial conduction was localized to the posteroseptal region. "Fatigue phenomenon," defined as suppression of atrioventricular conduction following rapid pacing, was observed to be provoked by atrial pacing in a rate- and duration-dependent manner. Administration of 5 mg of intravenous verapamil during sinus rhythm abolished the delta waves. These observations may indicate that pathologic changes in the accessory pathway are responsible for these phenomena.
Cardiac Pacing, Artificial↗
A TQM model for home care coordination & provider partnering.
Quality Improvement Teams can identify areas of customer dissatisfaction and raise coordinators' and caregivers' awareness of problems. Through home care coordination--whereby an expert home care nurse develops partnerships with key referral sources and facilities--they improved services and built both market share and service excellence into the wellness continuum.
California↗
Effect of root conditioning on periodontal microvascular wound healing with and without guided tissue membrane: a pilot study.
The aim of this study was to determine (1) the influence of root conditioners, i.e., citric acid (CA) and tetracycline (TC), on the vascular response of closed periodontal wounds, and (2) the effect of implantation of nonresorbable membranes on the vascularization process. Thirty-two alveolar fenestrations were created in the maxillae of four healthy dogs. The depth of the fenestrations reached the periodontal ligament, cementum, and dentin. Topical application of CA, TC, or sterile water (SW) was done on the exposed dentin. Nonresorbable membranes were then implanted in half of the created defects between the mucoperiosteal flap and the alveolar bone. The vascular response at the experimental sites was determined by histological evaluation and cleared specimens following observation periods of 3, 7, 14, and 21 days post-operatively. Results from this pilot study indicated that: (1) the coronal aspect of the periodontal ligament contributed the most to the initial vascularization of the defect; (2) there was no definitive advantage of the administration of CA or TC on the vascular response at 14 or 21 days; (3) no differences in vascular response were observed between treatment with or without the implantation of nonresorbable membranes; and (4) at 21 days, the vasculature in the defect area had not returned to its presurgical state.
Animals↗
Effect of root conditioning on periodontal wound healing with and without guided tissue regeneration: a pilot study. 1. Histologic evaluation.
Closed fenestration wounds in four mongrel dogs were used to study the source of fibroblast proliferation and extracellular matrix production during healing; the arrangement and attachment of newly formed collagenous fibers; and the cementogenesis and osteogenesis at healing sites. Fenestration wounds were made through the alveolar bone, periodontal ligament, cementum, and dentin, and citric acid, tetracycline, or sterile water was applied to the dentinal walls for 3 minutes. Nonresorbable membranes were randomly placed over half of the defects. Animals were killed at 1, 3, 7, or 21 days and routine histologic examinations with hematoxylin and eosin staining followed. Results of this pilot study suggest that the periodontal ligament and/or alveolar bone are the main source of fibroblast proliferation and migration as well as extracellular matrix formation at the initial stages of healing, and that at 21 days, citric acid stimulated more cementogenesis than tetracycline or sterile water. Also, while the tetracycline influenced the maximal deposition of alveolar bone, no differences in healing were found between the citric acid, tetracycline, and sterile water with and without the use of membrane barriers.
Acid Etching, Dental↗
Biology and biomechanics of the anterior cruciate ligament.
With detailed information concerning the role of the anterior cruciate ligament in the overall kinematic response of the knee during external loading, current clinical management of the orthopedic injuries to this joint may be improved upon and refined. Among the largest challenges to be met will be elucidation of the effects of various levels and types of muscular stabilization concurrent with a precise determination of the roles of passive knee restraints.
Animals↗
Effect of dietary fat and aging on adipose tissue cellularity in mice differing in genetic predisposition to obesity.
A line of mice had been developed which became obese when fed a commercial mouse breeder chow. This obese line was compared to a non-obese line at various ages to determine whether the type or amount of dietary fat would affect adipocyte size and number. Experimental diets containing beef tallow (38% of calories as beef fat and 2% as corn oil), corn oil (40% corn oil) or low fat (2% corn oil) were provided ad libitum at the time of weaning. Dorsoscapular subcutaneous fat pads were removed at 5, 6, 7, and 8 weeks and at 3, 6, 9, 12, 15, 18, and 21 months of age. Adipocyte size and number were determined histologically. Obese mice had enhanced adipocyte hyperplasia compared to the non-obese line. Only when eating the low fat diet did the obese mice have life-long elevated hypertrophy compared with their non-obese counterparts since non-obese mice responded to high fat feeding with a dramatic increase in adipocyte volume, regardless of type of fat. Body weight was greater in the obese line at all ages studied; however, some overlap in body weight was encountered between non-obese mice fed the high fat diets and genetically obese mice. Non-obese mice fed the low fat diet were smaller than mice in all other treatment groups throughout the study. Weight of the dorsoscapular subcutaneous adipose tissue was consistently greater in the obese line; however, high fat feeding greatly increased fat pad weight in non-obese mice.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Loss of NF1 alleles in phaeochromocytomas from patients with type I neurofibromatosis.
Type I neurofibromatosis (NF1) is a common autosomal dominant disorder that affects tissues derived from the neural crest. The manifestations are varied, comprising generalised disorders of growth and development as well as an increased risk of benign and malignant tumours including phaeochromocytomas and neurofibrosarcomas. The NF1 locus has been mapped to chromosome bands 17q11-12, and recently the NF1 gene has been cloned. Deletions identified in the constitutional genotype of some patients have suggested that the NF1 phenotype may arise from loss of function mutations of the NF1 gene, consistent with the hypothesis that it is a tumour suppressor gene. To date, however, analysis of NF1 tumours has not revealed the frequent allele losses encompassing the NF1 locus, implying loss of the wild-type NF1 allele, which would support this hypothesis. We report allele losses with markers flanking the NF1 region in each of 7 NF1 phaeochromocytomas. In each of the 3 tumours for which this could be determined, the loss involved the wild-type chromosome. These results provide strong evidence that, in cells of the adrenal medulla at least, the NFI gene may act as a tumour suppressor.
Adrenal Gland Neoplasms↗
Thrombin and albumin adsorption to PVA and heparin-PVA hydrogels. I. Single protein isotherms.
More radiolabeled thrombin was adsorbed to heparin-polyvinyl alcohol (PVA) than to PVA, consistent with a specific interaction with the immobilized heparin. The maximum surface concentration on heparin-PVA was estimated to be approximately 450 nmol/m2 with an apparent affinity constant (Ka) of 2.5 microM-1; on PVA, the plateau concentration was 10 nmol/m2 with a Ka less than 1 nM-1. There was little difference in bovine serum albumin (BSA) adsorption between PVA and heparin-PVA. Interestingly, thrombin adsorption to polyethylene was indistinguishable from that to PVA despite the large difference in surface chemistry. BSA adsorbed to polyethylene with higher affinity than to the hydrogels, although the plateau concentrations were comparable. The adsorbed thrombin was biologically inactive at least towards chromogenic substrate, with the residual activity on PVA unaffected by subsequent incubations with antithrombin III. PVA and heparin-PVA presented a heterogeneous and complex substrate for interaction with proteins. The adsorbed protein was likely present in multiple states depending on the groups with which it interacted.
Adsorption↗