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Biomedical subjects

J M Smith

Publications and source records attributed to J M Smith.

At least 181 records · Page 10Linked to original sources
PubMed1994

Cloning and characterization of a new purine biosynthetic enzyme: a non-folate glycinamide ribonucleotide transformylase from E. coli.

A novel GAR transformylase has been isolated and characterized from E. coli. The protein, a product of the purT gene, is a monomer of molecular weight 42 kDa and catalyzes the production of beta-formyl GAR from formate, ATP, and beta-GAR. As such it is an alternative to the formyl-folate utilizing purN GAR transformylase. No significant homology exists between the two transformylases. However, the purT protein shows significant homology to the purK protein, also involved in purine biosynthesis. Two different purT reactions have been characterized: one producing fGAR from ATP, beta-GAR, and formate and the other producing acetyl phosphate and ADP from acetate and ATP. The purT GAR transformylase is the first unknown de novo purine biosynthetic enzyme to be discovered in the last 30 years and represents another step forward in understanding cellular control of purine levels.

Acyltransferases↗
PubMed1994

Electrical alternans and vulnerability to ventricular arrhythmias.

BACKGROUND: Although electrical alternans (alternating amplitude from beat to beat on the electrocardiogram) has been associated with ventricular arrhythmias in many clinical settings, its physiologic importance and prognostic implications remain unknown. METHODS: To test the hypothesis that electrical alternans is a marker of vulnerability to ventricular arrhythmias, we developed a technique to detect subtle alternation in the morphologic features of the electrocardiogram (which would not be detectable by visual inspection of the electrocardiogram). In a group of 83 patients referred for diagnostic electrophysiologic testing, we prospectively examined whether levels of alternans predicted vulnerability to arrhythmias as defined by the outcome of electrophysiologic testing and arrhythmia-free survival. RESULTS: Sustained ventricular arrhythmias were induced during electrophysiologic testing in 32 of the patients (39 percent). In this group, low-level electrical alternans (a beat-to-beat change in amplitude of < 15 microV) was detected over a broad range of physiologic heart rates (from 95 to 150 beats per minute) and primarily involved the ST segment and the T wave (i.e., the phase of repolarization). Alternans during repolarization was a significant and independent predictor of inducible arrhythmias on electrophysiologic testing (sensitivity, 81 percent; specificity, 84 percent; relative risk, 5.2). Of 66 patients followed for up to 20 months, 13 had arrhythmic events. Alternans affecting the T wave and inducibility of ventricular arrhythmias were significant and essentially equivalent predictors of survival without arrhythmia (P < 0.001). Actuarial survival without arrhythmia at 20 months was significantly lower among the patients with T-wave alternans (19 percent) than among the patients without T-wave alternans (94 percent). CONCLUSIONS: Electrical alternans affecting the ST segment and T wave is common among patients at increased risk for ventricular arrhythmias. Subtle electrical alternans on the electrocardiogram may serve as a noninvasive marker of vulnerability to ventricular arrhythmias.

Actuarial Analysis↗
PubMed1994

Estimating selection by comparing synonymous and substitutional changes.

A higher ratio of substitutional to synonymous changes in between-species than in within-species comparisons has been taken as evidence for positive selection changing amino acids. A model is presented in which a difference of this kind arises as a result of purely neutral mutations, provided that the "species" compared are sufficiently different to approach a steady state between forward and backward mutation. In Neisseria, substitutions are twice as frequent, relative to synonymous changes, in between-species comparisons: it is shown that the data are consistent with the neutral model. The argument does not invalidate evidence for positive selection, for example in Drosophila, when the species compared are fairly similar.

Animals↗
PubMed1994

Molecular genetics of Aspergillus pathogenicity.

Aspergillus fumigatus is the most frequent cause of Invasive Pulmonary Aspergillosis (IPA), a life-threatening disease of immunosuppressed patients. In addition to a number of general physiological attributes of this fungus, it has been suggested that extracellular elastase and toxins might facilitate its growth in lung tissue. We have investigated the roles of two extracellular proteins, an alkaline protease with elastase activity (AFAlp), and the ribotoxin restrictocin in murine models of IPA. Gene disruption was used to create stable null mutant strains of the fungus lacking one or other protein, and their virulence and histopathological features were compared with an isogenic parental strain in steroid-treated and neutropenic mice. We have been unable to demonstrate any significant differences between the three strains, which shows that, considered independently, these proteins are not important virulence determinants. We are also interested in identifying fungal-specific gene products involved in general metabolism and which are required for growth in the lung, because these could represent new targets for antifungal drugs. For this work a model of murine IPA involving Aspergillus nidulans was established, to take advantage of the many well characterised mutations affecting metabolic pathways. Pathogenicity tests with strains carrying one of two auxotrophic mutations, lysA2 and pabaA1, have shown while lysine biosynthesis is not essential for the fungus to cause pulmonary disease, biosynthesis of p-aminobenzoic acid is essential. We are now in the process of cloning the A. fumigatus pabaA homologue to determine its function and whether this gene is required for growth of the clinically important species in the lung.

4-Aminobenzoic Acid↗
PubMed1994

Direct operation versus ICD therapy for ischemic ventricular tachycardia.

Now that the implantable cardioverter defibrillator is available as a therapeutic option for the management of ventricular tachycardia (VT), some argue that there no longer should be a role for direct surgical intervention for this malignant arrhythmia. Rebuttal of this argument is difficult for the following reasons: (1) there are many patients who are candidates for implantable cardioverter defibrillator therapy but not for direct VT operation, and thus direct comparisons of the two therapies is difficult; (2) implantable cardioverter defibrillator therapy by definition is palliative, but a VT operation is curative in most instances; (3) in many electrophysiologic triage algorithms, implantation of a cardioverter defibrillator and VT operation are employed as alternative, not competitive, therapies, again making direct comparisons difficult; and (4) probably most importantly, there are misconceptions in the literature regarding the risks and benefits of direct VT surgical procedures as they are currently performed. In this brief review, we examine the currently available data on both sides of this argument.

Catheter Ablation↗
PubMed1994

Proliferating cell nuclear antigen: a new prognostic indicator in renal cell carcinoma.

Renal cell carcinoma is a tumor, the prognosis and behavior of which remain poorly understood. Proliferating cell nuclear antigen levels have been shown to act as an independent prognostic variable in a variety of malignancies. Proliferating cell nuclear antigen was evaluated in 59 cases of renal cell carcinoma, and the results were correlated with existing clinicopathological variables and survival. Proliferating cell nuclear antigen index (percentage of tumor cells positive for proliferating cell nuclear antigen) did not correlate with stage, grade or ploidy. To assess survival, tumors with proliferating cell nuclear antigen indexes of greater than and less than 60% were compared. The 24 patients with a high index (greater than 60%) had a significantly worse survival than did 35 with a low index (less than 60%, p < 0.001). Therefore, the prognostic potential of proliferating cell nuclear antigen in renal cell carcinoma is promising and may be of clinical value in the management of patients with renal cell carcinoma.

Adult↗
PubMed1994

Reduction in tissue egg load and maintenance of resistance to challenge in mice infected with Schistosoma mansoni, following combined treatment with praziquantel and an antifibrotic agent.

Antifibrotic therapy with beta-aminoproprionitrile (BAPN), when combined with praziquantel (PZQ) treatment of mice infected with Schistosoma mansoni, led to a marked change in the temporal pattern of parasite egg excretion. The rate of egg excretion was higher and terminated sooner and the tissue egg load was smaller in mice treated with BAPN and PZQ than in mice treated with PZQ alone. Some of the mice that received the combined treatment were challenged 2 or 5 weeks after PZQ treatment; they retained a high level of resistance to challenge, similar to that observed in untreated, infected mice. In contrast, mice given only PZQ were as susceptible to challenge as the uninfected control mice. The activity of peritoneal macrophages, as measured by their production of hydrogen peroxide, nitric oxide and tumour necrosis factor alpha in vitro, was only elevated in cells obtained from untreated, infected mice. These results demonstrate that modulation of granuloma formation by combined antifibrotic/PZQ therapy significantly changes the dynamics of egg granuloma formation and attenuates the host's resistance to challenge infection.

Aminopropionitrile↗
PubMed1994

Metabolic consequences of increasing energy intake by adding lipid to parenteral nutrition in full-term infants.

The effect on energy metabolism and fuel utilization of increasing energy intake by adding intravenous lipid to a glucose and amino acid regimen was examined. Twenty fullterm, appropriate-for-gestational-age, intravenously fed neonates were entered into one of two groups: total energy intake was 261 kJ.kg-1 x d-1 (62 kcal.kg-1 x d-1) in group 1 and 355 kJ.kg-1 x d-1 (85 kcal.kg-1 x d-1) in group 2. Both groups received 2.8 g protein.kg-1 x d-1 and 14 g glucose.kg-1 x d-1. Group 2 received an additional 2 g lipid.kg-1 x d-1. Metabolic rate, respiratory gas exchange, and nonprotein substrate oxidation were similar in both groups. The addition of energy as lipid enhanced nitrogen retention (230 vs 306 mg.kg-1 x d-1; P < 0.02) and utilization (52.8% vs 66.5%; P < 0.03). Our data suggest that nitrogen utilization is improved in parenterally fed neonates by adding fat and increasing energy intake without change in metabolic rate, carbon dioxide production, oxygen consumption, and nonprotein substrate utilization. Energy expenditure does not necessarily increase with increasing energy intake independently of diet composition.

Calorimetry↗
PubMed1994

Spatial and temporal inhomogeneity of adenosine's effect on atrial refractoriness in humans: using atrial fibrillation to probe atrial refractoriness.

INTRODUCTION: Adenosine is an antiarrhythmic agent widely used for the diagnosis and treatment of supraventricular tachyarrhythmias. Bolus administration of adenosine has been associated with transient atrial fibrillation, but the underlying mechanisms have not yet been delineated, due in part to the technical limitations resulting from adenosine's short half-life. In this study, the rapid, repetitive activation of atrial tissue during atrial fibrillation was exploited to yield a nearly continuous estimate of atrial refractoriness, enabling a description of adenosine's action on atrial refractoriness in humans. METHODS AND RESULTS: Simultaneous right and left atrial, narrow-spaced, bipolar electrograms were recorded in 15 patients before, during, and after bolus administration of 12 mg of adenosine during atrial fibrillation. By estimating the local cycle length of excitation from the atrial activation frequency, a refractory period index (RPI) of local tissue was obtained. Adenosine dramatically increased the activation frequency from 6.4 +/- 0.7 to 12.2 +/- 12.2 Hz in the right atrium and from 6.1 +/- 0.6 to 8.7 +/- 1.2 Hz in the left atrium, corresponding to a decrease in the RPI from 156 to 82 msec (P < 0.0001) and from 163 to 116 msec (P < 0.0001), respectively. The magnitude of adenosine's effect was greater (47% vs 29% shortening) (P < 0.001) and the duration of adenosine's effect longer (28 vs 19 sec) (P < 0.05) in the right compared to the left atrium. CONCLUSION: Adenosine, at doses routinely used clinically, produces a transient, but spatially and temporally inhomogeneous, shortening of atrial refractoriness, which may explain the increased propensity toward atrial fibrillation associated with its use.

Adenosine↗
PubMed1994

Virulence of Aspergillus fumigatus double mutants lacking restriction and an alkaline protease in a low-dose model of invasive pulmonary aspergillosis.

To investigate the pathogenicity of Aspergillus fumigatus mutants lacking putative virulence factors, we have developed a new murine model of invasive pulmonary aspergillosis based on neutropenia, the major factor predisposing patients to this infection. Mice were treated with cyclophosphamide and inoculated by the intranasal route with 5 x 10(3) conidia, a significant reduction from inoculum levels used in previous models. Evidence for the production of the extracellular alkaline protease (Alp) in lung tissue was obtained by using a fungal transformant harboring an alp::lacZ reporter gene fusion. The pathogenicities of single mutant strains lacking either Alp or the ribotoxin restrictocin and of a double mutant strain lacking both proteins were assessed in this infection model. There were no significant differences between the mutant and the wild-type strains in terms of mortality or histological-features. Inoculations with mixtures of conidia showed that the double mutant strain is slightly less virulent than the wild-type strain. We conclude that Alp and restrictocin are not important virulence determinants in pulmonary infection.

Allergens↗
PubMed1994

Virulence studies of Aspergillus nidulans mutants requiring lysine or p-aminobenzoic acid in invasive pulmonary aspergillosis.

To identify steps in fungal intermediary metabolism required by Aspergillus spp. during invasive pulmonary aspergillosis, we have developed murine models involving Aspergillus nidulans as the inoculum. The advantages of using A. nidulans over Aspergillus fumigatus or Aspergillus flavus, which are the most common agents of clinical disease, are the well-understood genetics of A. nidulans and a large range of mutants of this species which are affected in a variety of metabolic pathways. Comparison of the virulence of A. nidulans strains carrying mutations which block the biosynthesis of lysine (lysA2) and p-aminobenzoic acid (pabaA1) shows that lysA2 strains have reduced virulence while pabaA1 strains are entirely nonpathogenic. The pathogenicity of pabaA1 strains can be restored by supplementing the drinking water of animals with p-aminobenzoic acid. The results indicate that the availability of lysine in the lung is limited, and p-aminobenzoic acid is probably not available at all. Thus, models of invasive pulmonary aspergillosis involving A. nidulans can be used to identify metabolic pathways that may be essential for the pathogenicity of A. fumigatus, the predominant pathogenic species, suggesting potential new targets for antifungal therapy.

4-Aminobenzoic Acid↗
PubMed1994

Time course of postnatal changes in rat heart action potential and in transient outward current is different.

The rat ventricular action potential shortens after birth. The contribution of increases in the transient outward current (Ito) to postnatal action potential shortening was assessed by measuring Ito in isolated cells and by determining the effect of 2 mM 4-aminopyridine (4-AP) on the action potentials of papillary muscles. 4-AP had no effect on 1-day action potential duration at 25% repolarization (APD25), and 1-day cells had little Ito. In 8- to 10-day muscles, 4-AP caused a small, but significant, increase in APD25. Ito increased slightly between day 1 and days 8-10, but this increase was not significant. Most of the increase in Ito (79%) and in the response to 4-AP (64%) occurred between days 8-10 and adult; however, approximately 75% of the APD25 shortening took place by days 8-10. Thus, while Ito may contribute to repolarization in late neonatal and adult cells, the different time courses of action potential shortening and increases in Ito suggest that changes in Ito are unlikely to be responsible for most of the postnatal action potential shortening.

4-Aminopyridine↗
PubMed1994

Serum lipids and apolipoproteins in liver transplant recipients: a comparative study of cyclosporin A and FK 506.

The immunosuppressive agent cyclosporin A (CsA) is reportedly associated with clinically adverse effects on circulating lipid and apolipoprotein concentrations. To date few data have been reported concerning the effects on lipid metabolism of the new macrolide immunosuppressive agent FK 506, and no comparative studies of the effects of these drugs have been performed. In consideration of the pivotal role of the liver in lipid metabolism, we measured fasting serum lipids and apolipoproteins a median of 8 (range 5 to 9) months after the operation in 20 clinically stable liver transplant recipients randomly allocated to maintenance immunosuppression with CsA +/- azathioprine (n = 10) or FK 506 (n = 10). To avoid the confounding effects of corticosteroids on lipid metabolism, prednisolone was withdrawn at least 6 weeks beforehand in each case. Ten healthy volunteers matched for age and body mass index served as control subjects. Serum total cholesterol concentration was significantly lower in both the CsA (p < 0.001) and FK 506 (p < 0.05) treatment groups when compared with the healthy control subjects. Serum high-density lipoprotein (HDL) cholesterol concentration was also significantly lower in both the CsA (p < 0.005) and FK 506 (p < 0.01) treatment groups. Neither the ratio of serum total cholesterol to HDL cholesterol nor the fasting triglyceride concentrations were significantly different (p > 0.1) from those of the healthy control subjects for either transplant group. Serum apolipoprotein B level was lower than that of the control group in both the CsA (p < 0.005) and FK 506 groups (p = 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)

Apolipoproteins↗
PubMed1994

Compulsive buying: a report of 20 cases.

BACKGROUND: Compulsive buying is a probably common but little studied disorder. To further characterize this syndrome, the authors assessed 20 compulsive buyers. METHOD: Twenty consecutive psychiatric patients with problematic buying behavior characterized as (1) uncontrollable; (2) markedly distressing, time-consuming, and/or resulting in family, social, vocational, and/or financial difficulties; and (3) not occurring only in the context of hypomanic or manic symptoms were evaluated with structured diagnostic interviews. Family histories of psychiatric disorders and patients' responses to psychological and biological treatments were also assessed. RESULTS: Nineteen (95%) of the compulsive buyers studied had lifetime diagnoses of major mood disorders. Sixteen (80%) had lifetime diagnoses of anxiety disorders, 8 (40%) had impulse control disorders, and 7 (35%) had eating disorders. First-degree relatives displayed a high prevalence of mood disorders. Nine (69%) of 13 patients receiving thymoleptics at the time of compulsive buying episodes reported reduction or remission of their buying symptoms. CONCLUSION: Compulsive buying may cause significant psychological, interpersonal, and financial difficulties; may co-occur with other psychiatric disorders; may be treatable; and, thus, should be further studied as a mental disorder in its own right. To this end, preliminary operational criteria for its diagnosis are proposed.

Adult↗