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Biomedical subjects

A C Smith

Publications and source records attributed to A C Smith.

At least 19 recordsLinked to original sources
PubMed1992

Monozygotic twin girls with congenital malformations resembling fanconi anemia.

Monozygotic (MZ) twin girls, diagnosed at birth to have Fanconi anemia (FA) on the basis of multiple anomalies and an apparently increased baseline chromosomal breakage frequency in one twin, have been followed prospectively for 13 years. They have not developed aplastic anemia or other hematologic manifestations of FA. There was no evidence for increased baseline or diepoxybutane (DEB)-induced chromosomal breakage in either twin when the studies were repeated in Denver as well as in New York. Since the cellular phenotype must be considered in establishing the diagnosis of FA, these MZ twins should not be classified as affected with FA. Using the scoring system for FA diagnosis developed by Auerbach et al. [1989], the probability coefficients of their having FA based solely on clinical findings, prior to DEB testing, were .75 and .92, respectively. When the combination of their anomalies are taken together, their FA probability coefficient is .98. Through the International FA Registry, 15 additional patients have been identified with an FA probability score of .75 or greater, but who have not developed aplastic anemia and who are DEB negative. These patients, as well as the twins described in this report, are most likely a heterogeneous group and may represent other syndromes like Holt-Oram, VATER, VACTERL and IVIC, with genetic as well as nongenetic etiologies. These cases demonstrate the importance of testing with DEB or other DNA crosslinking agent in order to discriminate between FA and other syndromes with a similar phenotype.

Abnormalities, Multiple↗
PubMed1992

Overexpression of amyloid precursor protein alters its normal processing and is associated with neurotoxicity.

The recent discovery that point mutations in the beta/A4 amyloid precursor protein may be the cause of certain forms of familial Alzheimer's disease provides strong support for the view that a thorough understanding of the metabolism of this protein may elucidate the pathogenesis of most forms of the disease and thus serve as a basis for rational prevention and therapy. Here we show that overexpression of a portion of the amyloid precursor protein molecule produces at least four distinct fragments of the COOH-terminus of amyloid precursor protein, suggesting altered proteolysis of amyloid precursor protein, and that such overexpression is associated with cytotoxicity. The degree of toxicity in the P19 cell culture model (differentiating mouse embryonal carcinoma cells) is shown to be related to the two larger novel COOH-terminal protein fragments (16 and 14 kilodalton), as well as to levels of expression of these two fragments. The toxicity is manifested in several differentiated cell lineages, including neuronal cells.

Amyloid beta-Protein Precursor↗
PubMed1992

Expression of a carboxy-terminal region of the beta-amyloid precursor protein in a heterogeneous culture of neuroblastoma cells: evidence for altered processing and selective neurotoxicity.

Six independent clonal isolates from a morphologically heterogeneous human neuroblastoma cell line stably expressed several products of the human amyloid precursor protein (APP) from an introduced DNA construct; the "substrate-adherent" phenotype (fibroblast-like cells) predominated in all 6; these displayed immunoreactivity of vimentin, but little to no reactivity of neuron-specific enolase. A stably transfected isolate which did not show any expression from the identical construct (presumably because of a position effect) exhibited the predominantly neuronal phenotype of the parental cells (neuron-specific enolase positive). These results suggest selective neurotoxicity of the expressed products. Two of the 6 stably expressing cell lines showed a decrease of native mRNA for APP to levels that were 1/4-1/3 that of the parental cells and a decrease of their growth rates to half that of the parental cells; these decreased growth rates were improved by conditioned medium from the parental cell line. Western blot analysis revealed at least four distinct fragments of the COOH-terminus of APP in the isolate which expressed protein and mRNA in greatest abundance, suggesting that overexpression of APP in a human neural cell line leads to aberrant cleavage of APP.

Amyloid beta-Protein Precursor↗
PubMed1992

Desmoplastic malignant melanoma: rare and difficult to diagnose.

BACKGROUND: We review our experience with a recent cluster of three cases of rare desmoplastic malignant melanoma (DMM). OBJECTIVE: Our purpose is to alert clinicians to this rare tumor and the difficulty in clinical and histopathologic diagnosis. METHODS: The clinical presentation and steps necessary to establish diagnosis are outlined. A literature review on diagnosis, treatment, and prognosis is presented. RESULTS: Two thirds of DMM are amelanotic and may appear only as a dermal nodule or thickening. Diagnosis can be made with the combination of light microscopy and immunopathology. Treatment consists of surgical excision. Lymph node dissection should be considered only when histologically positive regional nodes are present. CONCLUSION: The diagnosis of DMM may be difficult when based only on clinical expectation of melanoma and light microscopy findings. A strong clinical suspicion of DMM coupled with immunologic studies will establish the diagnosis.

Aged↗
PubMed1992

Paraneoplastic pemphigus, cicatricial conjunctivitis, and acanthosis nigricans with pachydermatoglyphy in a patient with bronchogenic squamous cell carcinoma.

A 77-year-old man with chronic conjunctivitis, acanthosis nigricans with pachydermatoglyphy, and pemphigus-like mucocutaneous lesions was found to have a well-differentiated bronchogenic squamous cell carcinoma. Histopathologic and immunofluorescence studies confirmed the diagnosis of paraneoplastic pemphigus. Skin lesions resolved with oral prednisone and azathioprine therapy, but the conjunctivitis and mucous membrane erosions persisted. The conjunctiva later became scarred with foreshortening of the fornices and development of symblepharon. External beam irradiation arrested the growth of the tumor but did not have any effect on the diseased conjunctiva and other mucous membranes. This case demonstrates that cicatrizing conjunctivitis with bullous mucocutaneous lesions may be a clinical sign associated with an occult neoplasm.

Acanthosis Nigricans↗
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↗