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Biomedical subjects

A C Smith

Publications and source records attributed to A C Smith.

At least 127 records · Page 7Linked to original sources
PubMed1991

Gallbladder sepsis after stent insertion for bile duct obstruction: management by percutaneous cholecystostomy.

Of 364 patients undergoing insertion of a biliary endoprosthesis in 1989, six (1.6 per cent) developed gallbladder sepsis. Three patients had cholangiocarcinoma, two had carcinoma of the pancreas and one had a benign biliary stricture. Two of the five patients with malignancy had gallbladder stones, and the patient with a benign stricture developed stones after 3 years of stenting. Three patients developed gallbladder sepsis early after endoprosthesis insertion (less than 6 days), while in the other three it occurred late (greater than 6 months). All six patients failed to respond to antibiotics and were successfully managed by percutaneous cholecystostomy; the patient with a benign biliary stricture also had cholecystolithotomy. The gallbladder drainage tubes were removed or became dislodged at intervals varying from 2 weeks to 6 months without complications. Percutaneous cholecystostomy is the treatment of choice for gallbladder sepsis unresponsive to antibiotics in patients with a biliary endoprosthesis in situ.

Adenoma, Bile Duct↗
PubMed1991

Multidrug resistance phenotype associated with selection of an aminopterin resistant dog kidney cell line.

A determination of the mechanisms of drug resistance in tumour cells is important for developing strategies to combat such resistance in persons receiving chemotherapy. This report describes a combined cellular, biochemical, and molecular analysis of a dog kidney cell line selected for resistance to increasing levels of the hydrophilic antifolate, aminopterin. Three distinct drug resistance phenotypes were observed in cells exhibiting high levels of aminopterin resistance. Two of these phenotypes were decreased aminopterin accumulation and increased levels of dihydrofolate reductase specific activity. The third drug resistance phenotype was noted initially as cross resistance to a variety of hydrophobic drugs indicating multidrug resistance. Biochemical assays demonstrated reduced accumulation of the hydrophobic fluorescent drug daunorubicin and of 3H-colchicine in the aminopterin resistant cells. These results were then correlated with increased levels of the multidrug resistance (mdr) gene product, P-glycoprotein, and mdr mRNA levels in the aminopterin resistant cells. However, experiments designed to prove a role for expression of the mdr gene in providing a degree of aminopterin resistance were unsuccessful. It is concluded that aminopterin selection in these dog kidney cells resulted in expression of at least three distinct drug resistance phenotypes and that one of these phenotypes, multidrug resistance, represented a secondary response to the aminopterin selection.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Anesthetic and postoperative protocols for a canine model of reversible left ventricular volume overload.

The purpose of this study was to develop anesthetic and postoperative methods that could be used in a canine model of reversible left ventricular volume overload (LVVO). LVVO was created by inducing mitral regurgitation (MR) in adult conditioned dogs. Using fluoroscopy, MR was induced by passing urologic grasping forceps into the left ventricle through a carotid artery and rupturing one or more chordae tendinea. Cardiac catheterization was performed after significant cardiac dysfunction developed (3 months after creation of MR) in order to collect data to confirm reduced contractile function. The MR was repaired by replacing the damaged valve with a bovine pericardial xenograft. Dogs were followed with sequential cardiac catheterizations to determine if the valvular replacement reversed the cardiac dysfunction. To develop this model, unique anesthetic and post-operative care protocols had to be instituted. In order not to exacerbate the existing cardiac dysfunction, a high dose narcotic anesthetic regimen using a sufentanil infusion at 9-13 microgram/kg h-1 was developed in association with cardiopulmonary bypass and hypothermia for the mitral valve replacement surgery. Intensive postoperative care protocols that involved major personnel and pharmaceutic interventions were necessary. Using our methods 11/17 dogs survived the procedure and were included in the protocol for study of mechanisms involved in reversal of cardiac dysfunction.

Anesthesia↗
PubMed1991

Sedative and cardiovascular effects of midazolam in swine.

The ability to reliably produce sedation in swine is hampered by the paucity of agents available. This project examined the use of a new water soluble benzodiazepine, midazolam, as a sedative in swine. Echocardiographic studies were performed on thirty 23 to 30 kg Yorkshire swine before and 20 minutes after each animal received a single intramuscular dose of 100 micrograms/kg midazolam. Heart rate and respiratory rate decreased significantly compared to nonsedated values (93 +/- 7 versus 117 +/- 2 bpm and 10 +/- 1 versus 20 +/- 1 breaths/min, respectively [p less than 0.05]). However, there was no effect on left ventricular fractional shortening (29.9 greater than 0.05 versus 29.5 +/- 0.05% [p greater than 0.05]). An additional five pigs were instrumented for a dose response study in order to collect hemodynamic data and blood gas values at baseline, and 15 min after the intravenous administration of incremental doses of midazolam (100 to 1,000 micrograms/kg). Despite a significant decrease in heart rate and respiratory rate, cardiac output, blood gases, and pH remained within normal ranges at all dosage levels. Both routes of administration produced sedation for 20 min in all animals. Midazolam is an effective swine sedative that is associated with stable cardiac function.

Animals↗
PubMed1991

Molecular analysis of the Smith-Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2).

We undertook clinical evaluation (32 cases) and molecular evaluation (31 cases) of unrelated patients affected with Smith-Magenis syndrome (SMS) associated with an interstitial deletion of band p11.2 of chromosome 17. Patients were evaluated both clinically and electrophysiologically for peripheral neuropathy, since markers showing close linkage to one form of Charcot-Marie-Tooth disease (CMT1A) map to this chromosomal region. The common clinical findings were broad flat midface with brachycephaly, broad nasal bridge, brachydactyly, speech delay, and hoarse, deep voice. Fifty-five percent of the patients showed clinical signs (e.g., decreased or absent deep tendon reflexes, pes planus or pes cavus, decreased sensitivity to pain, and decreased leg muscle mass) suggestive of peripheral neuropathy. However, unlike patients with CMT1A, these patients demonstrated normal nerve conduction velocities. Self-destructive behaviors, primarily onychotillomania and polyembolokoilamania, were observed in 67% of the patients, and significant symptoms of sleep disturbance were observed in 62%. The absence of REM sleep was demonstrated by polysomnography in two patients. Southern analysis indicated that most patients were deleted for five 17p11.2 markers--FG1 (D17S446), 1516 (D17S258), pYNM67-R5 (D17S29), pA10-41 (D17S71), and pS6.1-HB2 (D17S445)--thus defining a region which appears to be critical to SMS. The deletion was determined to be of paternal origin in nine patients and of maternal origin in six patients. The apparent random parental origin of deletion documented in 15 patients suggests that genomic imprinting does not play a role in the expression of the SMS clinical phenotype. Our findings suggest that SMS is likely a contiguous-gene deletion syndrome which comprises characteristic clinical features, developmental delay, clinical signs of peripheral neuropathy, abnormal sleep function, and specific behavioral anomalies.

Adolescent↗
PubMed1991

Diagnosis and indications for surgical treatment.

Dupuytren's disease is a common problem in most hand surgery practices. It is usually easily diagnosed by the presence of its primary palmar manifestations: the nodule, the cord, and the digital flexion contracture. The isolated nodule may occasionally require biopsy to rule out the possibility of malignancy, but this is unusual. The nodule is typically the first lesion to appear and is the site of active biologic activity. The cord is the pathologically thickened and shortened normal longitudinal fascial structure of the palm and digit. Its insertion distal to the MPJ or PIP accounts for the progressive flexion contracture of these joints. Secondary findings include knuckle pads, plantar fascial nodules, and penile fascial contracture, which may signal the presence of Dupuytren's diathesis, a particularly aggressive form of the disease. The need and advisability of surgical intervention should be determined in close consultation with the patient after becoming thoroughly familiar with functional deficits and specific functional goals. A flexion contracture of more than 30 degrees at the MPJ or any contracture at the PIP is generally thought to be an indication for palmar fasciectomy. Patients should be aware of potential complications, those in higher risk categories should be identified preoperatively. Details of the operative procedure and variations in technique are discussed in subsequent articles in this issue.

Dupuytren Contracture↗
PubMed1990

Spin-lattice relaxation time measurements using hybrid CSI--phantom study.

The spin-lattice relaxation time T1 of multicomponent tissues is often determined by fitting relaxation data to monoexponential functions. This process can lead to large errors in the relaxation time. We describe a procedure using chemical-shift imaging (CSI) which separates the NMR signal into water and lipid components thus allowing the two signals to be individually analyzed for relaxation times. This procedure yields more representative relaxation times than those obtained by both monoexponential and biexponential fitting schemes.

Body Water↗
PubMed1990

Inhibition of tissue prostaglandin synthesis during third molar surgery: use of preoperative fenbufen.

Preoperative administration of a non-steroidal anti-inflammatory drug (fenbufen) reduced immediate postoperative pain in a group of 38 patients undergoing removal of mandibular third molars, compared to placebo. However, overall pain experience and morbidity were not significantly improved suggesting that there was no clinical benefit derived from interference with tissue prostaglandin synthesis at the time of surgery.

Adult↗
PubMed1990

Relationship of bioimpedance to thermodilution and echocardiographic measurements of cardiac function.

Bioimpedance cardiography has been suggested as a noninvasive means to monitor cardiac function. However, this method has not been compared to more conventional techniques such as echocardiography. This study compared simultaneously obtained thermodilution cardiac output and right ventricular ejection fraction (RVEF), and echocardiographic left ventricular fractional shortening (LVFS), to bioimpedance cardiac output and the maximum first derivative of the bioimpedance signal (dZ/dtmax) during positive inotropic stimulation and preload reduction. Eight pigs were instrumented with a rapid response thermistor (positioned in the pulmonary artery) and bioimpedance electrodes. Simultaneous thermodilution, echocardiographic, and bioimpedance measurements were performed at baseline and after 5, 10, and 15 min of isoproterenol infusion (0.5 microgram/kg.min). In six pigs, measurements were also performed after balloon occlusion of the inferior vena cava. A significant correlation was observed between LVFS and dZ/dtmax (r = .88, n = 35) over all time points. Thermodilution and bioimpedance cardiac output were in close agreement (r = .92, n = 35). However, bioimpedance overestimated cardiac output in the very low and high output states. The mean difference between thermodilution and bioimpedance cardiac outputs was -0.02 +/- 0.37 L/min. There was a positive relationship between RVEF and dZ/dtmax (r = .54, n = 35). In summary, bioimpedance was significantly correlated with thermodilution cardiac output over a wide hemodynamic range. The peak first derivative of the bioimpedance signal dZ/dtmax may provide a noninvasive index of ventricular pump performance. Further studies are required to evaluate the diagnostic value of bioimpedance cardiography in the clinical setting.

Animals↗
PubMed1990

Chronic supraventricular tachycardia causes ventricular dysfunction and subendocardial injury in swine.

Chronic supraventricular tachycardia has been associated with ventricular dysfunction in humans and animals. However, this ventricular failure is poorly characterized, and the ultrastructural consequences of supraventricular tachycardia are unknown. We serially examined right and left ventricular function, endomyocardial ultrastructure, and creatine kinase activity in eight pigs at base line and again at 1, 2, and 3 wk following rapid atrial pacing. Left and right ventricular ejection fractions fell significantly from base line after 1 wk of chronic tachycardia. Three weeks of chronic pacing resulted in further deterioration in ejection fractions. Significant biventricular chamber dilatation developed and was associated with a reduction in end-diastolic wall thickness after 2 wk of tachycardia. Mitochondrial injury and diminished mitochondrial cytochrome oxidase staining of subendocardial myocytes were observed after 2 wk of tachycardia. Endomyocardial creatine kinase activity fell from control levels following 2 wk of pacing. Postmortem examination revealed a reduction in left ventricular wall thickness compared with 14 control animals. Fibrosis occurred along the subendocardial layer in paced animals, and glycogen content was also reduced. In summary, chronic supraventricular tachycardia resulted in severe biventricular pump dysfunction and chamber dilatation that were associated with ultrastructural alterations and reduced enzyme activity of the subendocardial myocytes. These ultrastructural and metabolic changes may be potential mechanisms responsible for the ventricular dysfunction and dilatation observed in this model.

Animals↗
PubMed1990

Cardiac function and morphology of Hanford miniature swine and Yucatan miniature and micro swine.

The use of miniature swine in biomedical research is increasing; however, a comparison of cardiac function and morphology between strains has yet to be characterized. The purpose of this project was to examine comprehensive hemodynamics and cardiac morphology of three groups of ten normal, 4 months old, age-matched Yucatan miniature (MINI) pigs, Yucatan micropigs (MICRO) and Hanford (HAN) miniature pigs, 5 males and five females per group. Closed chest cardiac catheterization under equivalent conditions was performed followed by post mortem cardiac morphometry. Mean arterial pressure was significantly greater in the Hanford group when compared to both the minipig and micropig pigs (HAN: 89 +/- 4; MINI: 48 +/- 3; MICRO: 53 +/- 2 mmHg). Pulmonary vascular resistance was significantly different between the three groups (HAN: 9 +/- 1; MINI: 60 +/- 12; MICRO: 111 +/- 29 dyne x sec/cm x m2). The Hanford strain had a significantly smaller heart weight to body weight ratio than the other two groups (HAN: 4.6 +/- 1.0; MINI: 5.7 +/- 0.1; MICRO: 5.5 +/- 1.0). Variations in cardiovascular parameters occur among these strains and should be considered when constructing experimental designs.

Animals↗
PubMed1990

Heritable ventricular septal defect in Yucatan miniature swine.

A heritable ventricular septal defect (VSD) was found in a strain of Yucatan miniature swine. The defect was determined to be a high membranous VSD analogous in anatomic location to the most common from of VSD in humans. Eighteen animals were studied clinically, hemodynamically and at necropsy to characterize the defect. Three mature animals developed pulmonary hypertension. Three animals were found to have a patent foramen ovale (PFO) in addition to the VSD. VSD is heritable probably due to polygenic factors. VSD in Yucatan miniature swine may be a suitable model of the human disease syndrome.

Animals↗
PubMed1990

The pig as a model of tachycardia and dilated cardiomyopathy.

Chronic Supraventricular Tachycardia (SVT) can produce a dilated cardiomyopathy which has a poorly understood association with ventricular dysfunction in humans and animals. The purpose of this study was to produce a model of chronic SVT and dilated cardiomyopathy using swine, which have a cardiac anatomy similar to man. Eight pigs were implanted with chronic atrial catheters and a pacemaker, with four additional sham-operated pigs serving as controls. We examined ventricular function and morphology at baseline (120 +/- 3 bpm), pacing baseline (240 bpm), and at 1, 2 and 3 weeks of rapid atrial pacing (240 bpm). Ventricular ejection fractions fell significantly from baseline following 1 week (left: 38 +/- 3% vs baseline 61 +/- 1%; right: 31 +/- 5% vs baseline 56 +/- 1%; p less than 0.05) and deteriorated further by 3 weeks of SVT (left: 26 +/- 4%, right: 19 +/- 3%; p less than 0.05). Significant biventricular chamber dilation developed by 2 weeks of SVT (left: 50 +/- 5 cc vs paced baseline 27 +/- 2 cc; right: 67 +/- 6 cc vs paced baseline 28 +/- 3 cc; p less than 0.05) and continued to increase by week 3 of SVT (left: 66 +/- 11 cc; right: 78 +/- 8 cc; p less than 0.05). Five additional paced pigs, without chronic atrial catheters, were followed using echocardiography.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Right ventricular function computed by thermodilution and ventriculography. A comparison of methods.

Right ventricular ejection fractions have been difficult to estimate clinically. It has been recently suggested that right ventricular ejection fractions can be calculated by thermodilution techniques with a fast-response thermistor and computer. These studies were performed to compare right ventricular ejection fractions obtained from thermodilution and biplane ventriculography. Ten pigs were instrumented with a right ventricular angiographic, thermodilution, and systemic arterial catheter. Right ventricular ejection fractions were determined by thermodilution and ventriculography at four times: (1) baseline, (2) infusion of isoporterenol (5 micrograms/min), (3) 50% of baseline mean arterial pressure produced by hemorrhage, and (4) reinfusion of isoproterenol during hypovolemia. A significant correlation existed between thermodilution and ventriculographic ejection fractions (r = 0.74, p = 0.004). However, during hypovolemia, thermodilution measurements of right ventricular ejection fraction were significantly lower than ventriculographic measurements (p less than 0.05). To determine if the position of the thermistor had a significant effect on thermodilution computations, right ventricular ejection fractions were computed by thermodilution in 10 additional pigs by means of a jugular and femoral insertion, as well as by ventriculography in each pig. Femoral insertion resulted in a greater distance from pulmonic valve to thermistor as compared with jugular placement (p = 0.005). Right ventricular ejection fractions obtained from femoral placement were significantly less than those obtained by jugular insertion (p = 0.008) and ventriculography (p = 0.006). There was no significant difference between jugular and ventriculographic ejection fractions (p = 0.35). Results from these studies demonstrates that thermodilution right ventricular ejection fraction measurements are strongly correlated to ventriculographic methods over a wide hemodynamic range and that improved accuracy is obtained when the pulmonic valve to thermistor distance is minimized. Thus thermodilution may provide a simple and repeatable means to monitor right ventricular function in the critical care setting.

Animals↗
PubMed1989

Pharmacokinetics of buthionine sulfoximine (NSC 326231) and its effect on melphalan-induced toxicity in mice.

Intravenous doses of buthionine sulfoximine (BSO, NSC 326231), an inhibitor of glutathione synthesis, were eliminated rapidly from mouse plasma in a biexponential manner. The initial phase of the plasma concentration versus time curve had a half-life of 4.9 min and accounted for 94% of the total area under the curve. The half-life of the terminal phase of the curve was 36.7 min and the area accounted for only 6% of the total area under the curve. Plasma clearance of BSO was 28.1 ml/min/kg and the steady state volume of distribution was 280 ml/kg. The oral bioavailability of BSO, based on plasma BSO levels, was extremely low. However, comparable glutathione depletion was apparent after i.v. and p.o. doses of BSO, suggesting a rapid tissue uptake and/or metabolism of BSO. Therefore, due to the rapid elimination of BSO from mouse plasma, plasma drug levels do not directly correlate with BSO-induced tissue glutathione depletion. Administration of multiple i.v. doses of BSO to male and female mice resulted in a marked 88% depletion of liver glutathione at doses of 400-1600 mg/kg/dose. Toxicity of i.v. administered BSO was limited to a transient depression of peripheral WBC levels in female mice given six doses of 1600 mg/kg. Multiple i.v. doses of BSO of up to 800 mg/kg/dose (every 4 h for a total of six doses) did not alter the toxicity of i.v. administered melphalan. However, multiple doses of 1600 mg/kg/dose of BSO did potentiate histopathological evidence of melphalan-induced bone marrow toxicity in 30% of the mice and, additionally, the combination of BSO and melphalan produced renal tubular necrosis in 80% of the male mice. The potentiation of melphalan induced toxicity did not appear to be related to GSH depletion, since: quantitatively similar amount of GSH depletion occurred at lower dose of BSO without any increase in melphalan toxicity.

Administration, Oral↗
PubMed1989

4-Ipomeanol: a novel investigational new drug for lung cancer.

4-Ipomeanol (IPO) is the first agent to undergo preclinical development at the National Cancer Institute (NCI) based principally on a specific biochemical-biological rationale for clinical investigation as an antineoplastic agent targeted against lung cancer. This disease-specific development of IPO was initially stimulated by observations that the compound was activated by metabolism, preferentially within the mammalian lung, specifically within bronchiolar Clara cells, and that its predominant toxicity was to the lung in most species. IPO is inactive or only minimally active against most conventional antitumor test systems. However, some human lung cancer cell lines, as well as a variety of fresh human lung tumor biopsy specimens, have been shown to be capable of mediating the in situ biotransformation of IPO to a potentially cytotoxic intermediate. In this report, the biochemistry, metabolism, preclinical pharmacology, and toxicology of IPO are reviewed and the clinical development plans for this unique and challenging new agent are presented.

Animals↗