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Biomedical subjects

E R Smith

Publications and source records attributed to E R Smith.

At least 91 records · Page 5Linked to original sources
PubMed1997

The ontogeny of canine small intestinal submucosa regenerated bladder.

PURPOSE: Small intestinal submucosa has previously been shown to promote regeneration of transitional epithelium, smooth muscle and peripheral nerves in rat and dog bladders. The origin of these regenerated components is presently unknown. This study attempts to define the origin of vascular, smooth muscle and peripheral nerve regeneration. MATERIALS AND METHODS: A total of 22 adult male dogs weighing 25 to 30 kg. underwent partial cystectomy and immediate augmentation with a small intestinal submucosa patch graft. The small intestinal submucosa graft-native bladder interface was marked with permanent marking sutures for future reference. Small intestinal submucosa regenerated bladders were harvested at 2, 3, 4, 6, 8 and 10 weeks after augmentation. The tissue was then studied with routine histology and immunohistochemistry using factor VIII, smooth muscle specific actin (1A4) and neurofilament staining. RESULTS: Results demonstrated that epithelialization of the graft surface was complete by 3 to 4 weeks with normal transitional histology. In the early periods neovascularization was prominent throughout the entire graft, as shown by factor VIII staining. Later more mature vessels were noted. Early in muscle formation sheets of elongated spindle cells extended into the graft from the incised native bladder at both surgical margins and ran parallel to the mucosal surface. At 4 weeks this spindle cell proliferation completely traversed the graft. Trichrome stained sections of the 4-week-old grafts showed no evidence of muscle differentiation and the spindle cells appeared to be fibroblasts. However, these cells stained positive for smooth muscle specific actin (1A4), indicating myogenic potential. Between weeks 4 and 6 the spindle cells became more haphazardly arranged and were separated by loose interstitium. By weeks 8 to 10 there was distinct smooth muscle bundle formation within these areas of proliferating myocytes. Neural regeneration appeared to coincide with smooth muscle development. Early neurofilament positive cells were noted predominantly at the graft-native bladder interface. At 4 weeks neurofilament positive cells were present throughout the graft and by 10 weeks nerve trunks composed of several nerve fibers were identified in association with newly formed smooth muscle bundles. CONCLUSIONS: Small intestinal submucosa serves as a platform for bladder regeneration. Neovascularization smooth muscle and neural regeneration appear to occur through pannus ingrowth from the graft-native bladder interface. Smooth muscle regeneration seems to begin with the maturation of myofibroblasts, which migrate into the graft as early as 2 weeks after augmentation, and it progresses to the formation of distinct smooth muscle bundles by 10 weeks.

Animals↗
PubMed1997

Reconstruction of the high urogenital sinus: early perineal prone approach without division of the rectum.

PURPOSE: Reconstruction of the vagina and external genitalia in the infant is quite challenging, particularly when a urogenital sinus is associated with high confluence of the vagina and urethra. Many surgeons believe that children with such a malformation should undergo staged or delayed reconstruction, so that vaginoplasty is done when the child is older and larger. Vaginoplasty early in life is thought to be difficult due to patient size and poor visualization. The posterior sagittal approach has been beneficial for acquiring exposure to high urogenital sinus anomalies but it has been thought to require splitting of the rectum and temporary colostomy. We report a modification of this technique. MATERIALS AND METHODS: In the last 5 years all patients with urogenital sinus anomalies underwent reconstruction using a single stage approach regardless of the level of confluence. In 8 patients with a high level of confluence reconstruction was performed using a perineal prone approach. Exposure was achieved without division of the rectum. The operative technique is presented in detail. RESULTS: This midline perineal prone approach has allowed excellent exposure of the high vagina even in infants. In all 8 patients reconstruction was done without difficulty and no patient required incision of the rectum or colostomy. This procedure did not preclude the use of a posteriorly based flap for vaginal reconstruction. CONCLUSIONS: While patients with low confluence can be treated with single posteriorly based flap vaginoplasty, those with higher confluence may benefit from a perineal prone approach to achieve adequate exposure for pull-through vaginoplasty. This prone approach to the high urogenital sinus anomaly can be performed without division of the rectum, provides excellent exposure of the high confluence even in small children and does not preclude the use of posterior flaps for vaginal reconstruction.

Abnormalities, Multiple↗
PubMed1997

Biological activity and therapeutic potential of homologs of an Ii peptide which regulates antigenic peptide binding to cell surface MHC class II molecules.

An invariant chain peptide (murine Ii76-92; Ii-Key) is known to produce a 10 to 50 times baseline enhancement of the presentation of specific antigenic peptides to murine T cell hybridomas by cell surface MHC class II molecules. In order to define structure-activity relationships in Ii-key, homologs were synthesized with the following systematic variations: 1) N- and C-terminal truncations, 2) N-terminal acetylation and C-terminal amidation, 3) substitutions with 13 natural amino acids in each position of the shortest, fully active peptide, and then with an additional 12 nonnatural amino acids at certain 'pharmacophore' positions, 4) substitutions with D-amino acids and N-methyl-leucine, and 5) cyclical forms. More than 160 homologs were tested for effects on antigen presentation by the murine MHC class II alleles: A(d), Ak, E(d), or Ek. For some compounds, allele specificity between E(d) and Ek exceeded 1:20. D-Amino acid and/or N-methyl-leucine substitutions were accepted at some residue positions, leading to peptides with relatively long half-lives in mouse serum and low toxicities in mice. An Ii-Key homolog inhibited in vitro presentation of an internally processed hen egg lysozyme determinant to a specific T hybridoma. The best compounds can be tested in vivo for therapeutic applications: 1) immunosuppression upon release of antigenic peptide, and 2) vaccination or immunomodulation upon co-administration of a second antigenic peptide.

Amino Acid Sequence↗
PubMed1996

Evidence for disruption of sphingolipid metabolism as a contributing factor in the toxicity and carcinogenicity of fumonisins.

Fumonisins are inhibitors of the biosynthesis of sphingosine and more complex sphingolipids. In eucaryotic cells, fumonisin inhibition of sphingolipid biosynthesis is a result of inhibition of the enzyme ceramide synthase. Large increase in free sphinganine concentration in plant and animal cells are observed within a few hours after exposure to fumonisins and/or Alternaria toxins (AAL-toxins). Some of the sphinganine is metabolized to other bioactive intermediates, and some is released from cells. In animals, free sphinganine accumulates in tissues and quickly appears in blood and urine. Free sphingoid bases are toxic to most cells, and complex sphingolipids are essential for normal cell growth. Fumonisin B1 stimulates sphinganine-dependent DNA synthesis in Swiss 3T3 cells, but is mitoinhibitory in other cell types. In cultured cells the accumulation of bioactive long-chain sphingoid bases and depletion of complex sphingolipids are clearly contributing factors in growth inhibition, increased cell death, and (in Swiss 3T3 cells) mitogenicity of fumonisins. While disruption of sphingolipid metabolism directly affects cells, it may indirectly affect some tissues. For example, fumonisin B1 impairs the barrier function of endothelial cells in vitro. Adverse effects on endothelial cells could indirectly contribute to the neurotoxicity and pulmonary edema caused by fumonisins. It is hypothesized that fumonisin-induced changes in the sphingolipid composition of target tissues could directly or indirectly contribute to all Fusarium moniliforme-associated diseases.

Alternaria↗
PubMed1996

Fumonisin toxicity and sphingolipid biosynthesis.

Fumonisins are inhibitors of sphinganine (sphingosine) N-acyltransferase (ceramide synthase) in vitro, and exhibit competitive-type inhibition with respect to both substrates of this enzyme (sphinganine and fatty acyl-CoA). Removal of the tricarballylic acids from fumonisin B1 reduces the potency by at least 10 fold; and fumonisin A1 (which is acetylated on the amino group) is essentially inactive. Studies with diverse types of cells (hepatocytes, neurons, kidney cells, fibroblasts, macrophages, and plant cells) have established that fumonisin B1 not only blocks the biosynthesis of complex sphingolipids; but also, causes sphinganine to accumulate. Some of the sphinganine is metabolized to the 1-phosphate and degraded to hexadecanal and ethanolamine phosphate, which is incorporated into phosphatidylethanolamine. Sphinganine is also released from cells and, because it appears in blood and urine, can be used as a biomarker for exposure. The accumulation of these bioactive compounds, as well as the depletion of complex sphingolipids, may account for the toxicity, and perhaps the carcinogenicity, of fumonisins.

Amidohydrolases↗
PubMed1996

Tumor angiogenesis as a predictor of recurrence in stage Ib squamous cell carcinoma of the cervix.

OBJECTIVE: To explore the possibility of using histologic microvessel count of sections from the tumor to predict recurrence of stage Ib squamous cell carcinoma of the cervix. METHODS: Tumor sections from 22 patients (11 patients free of disease after 3 years and 11 patients with recurrence) were stained histoimmunochemically for factor VIII-related antigens. Vessel counting in the most active area of angiogenesis was performed by two pathologists on a x 200 microscopic field (0.739 mm2) without knowledge of the patient's' outcome. To predict recurrence, vessel count was compared with age, tumor size, tumor grade, lymph-vascular invasion, duration of follow-up, and type of therapy. RESULTS: Only high microvessel count (mean 19.9, range 7-43, versus mean 30.1, range 17-78; P < .05) and tumor size (mean 2.84 cm, range 1-4.2, versus mean 4.11 cm, range 2.2-6; P < .05) were independent factors predicting recurrence. CONCLUSION: High microvessel count in tumors may be used to predict recurrence in stage Ib squamous cell carcinoma of the cervix.

Adult↗
PubMed1996

Central propranolol and pindolol, but not atenolol nor metoprolol, inhibit sexual behavior in male rats.

Are the anti-sexual effects of propranolol and pindolol due to actions within the brain? To answer this, these agents were administered directly into the brain ventricular system (ICV). Additionally, atenolol and metoprolol were evaluated to see whether differential delivery to the brain contributed to the observed lack of effect of systemically administered beta 1-adrenoceptor antagonists. ICV administration of pindolol (45 or 90 micrograms) was followed by a suppression of copulation. At 45 micrograms, inhibition was limited to performance aspects of copulation, whereas at 90 micrograms, decrements in motivational and performance aspects of copulation were evident. ICV administration of propranolol also suppressed copulatory behavior. At 45 micrograms, no significant effects were observed, whereas at 90 micrograms decrements in motivational and performance aspects of copulation were evident. In contrast, ICV administration of the beta 1-adrenoceptor antagonists, atenolol and metoprolol, was not associated with any major modifications in copulatory behavior. We suggest that the inhibitory effects of propranolol and pindolol may involve interactions with 5-HT1A receptors in the CNS. Alternatively, it may be that the adverse effects of pindolol and propranolol are due to the simultaneous blockade of both beta 1- and beta 2-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1996

What do connectionism and social psychology offer each other?

Social psychologists can benefit from exploring connectionist or parallel distributed processing models of mental representation and process also can contribute much to connectionist theory in return. Connectionist models involve many simple processing units that send activation signals over connections. At an abstract level, the models can be described as representing concepts (as distributed patterns of activation), operating like schemas to fill in typical values for input information, reconstructing memories based on accessible knowledge rather than retrieving static representations, using flexible and context-sensitive concepts, and computing by satisfying numerous constraints in parallel. This article reviews open questions regarding connectionist models and concludes that social psychological contributions to such topics as cognition-motivation interactions may be important for the development of integrative connectionist model.

Cognition↗
PubMed1996

Malignant testicular neoplasms in immunosuppressed patients.

PURPOSE: Testicular cancers were studied in patients on immunosuppression. MATERIALS AND METHODS: A retrospective analysis was done of testicular cancer in patients on immunosuppression reported on between 1975 and 1995. RESULTS: The management schemes adopted in the immunosuppressed population followed the generally accepted management concepts. No patient with low stage (A to B1) disease died of testis cancer. Only 4 of 66 patients (6.1%) with the acquired immunodeficiency syndrome died of testis cancer compared to 5 of 20 (25%) after transplantation, implying significantly higher cause specific mortality in post-transplant patients (Fisher's exact test, p < 0.01). The incidence of adverse effect of therapy did not differ from the expected incidence in other patients. CONCLUSIONS: Patients on immunosuppression with testicular neoplasms should be treated in the standard fashion as indicated by tumor histology and stage of disease, since most will tolerate therapy and benefit from the standard treatment protocols.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Hepatitis B vaccine uptake among surgeons at a London teaching hospital: how well are we doing?

In order to determine the perceptions of surgical staff of the risks of hepatitis B virus (HBV) infection and its prevention through vaccination, and to assess frequency of 'sharps' injuries and compliance with the Department of Health (DoH) recommendations on vaccination, a questionnaire was distributed to surgical staff in the Guy's and St Thomas' Hospital Trust. Only 52 of the 88 surgeons who responded (59%) had documented vaccine-induced immunity to HBV. Eighty-five (97%) had received at least one dose of vaccine but 15 of these (18%) had failed to complete the course. Of the 70 surgeons completing the course, only 56 (80%) had had their immune responses checked and only 44 (63%) admitted sustaining a 'sharps' injury at least once a month, yet only 17% consistently reported these injuries. Those least likely to report were cardiothoracic and obstetric and gynaecology surgeons; these specialties also sustained the highest frequency of 'sharps' injuries. Ophthalmologists, who sustained the lowest rate of injury, were most likely to report. In conclusion, a significant number of surgeons appeared not to have completed a course of hepatitis B vaccine in the presence of a high frequency of 'sharps' injuries. Following the publication of DoH guidelines on protecting workers from HBV, it must be stressed that failure to comply with recommendations may have medicolegal implications.

Attitude of Health Personnel↗
PubMed1996

Accessible attitudes influence categorization of multiply categorizable objects.

Every person or object can be categorized in multiple ways. For example, a person can be categorized (and hence stereotyped) by gender, age, race, or occupation. Earlier research demonstrated that objects toward which people have highly accessible attitudes attract attention when they are present in the visual field. On the basis of that work, the authors hypothesized that categories toward which people have highly accessible attitudes are preferentially applied to multiply categorizable objects. Three experiments, with cued recall and categorization response time as dependent variables, support the hypothesis. Categories toward which people's attitudes had been rendered accessible by an earlier task were more readily produced in response to multiply categorizable objects serving as a cue, or could more quickly be verified as fitting the object. These results demonstrate the power and functional value of accessible attitudes in shaping basic categorization and judgmental processes.

Adult↗
PubMed1996

Ventricular interaction and venous capacitance modulate left ventricular preload.

The concept of left ventricular (LV) 'preload' has seemed simple and straightforward. Similarly, the capacitance function of the veins seemed to be defined, in spite of the fact that 'venous return' might be said to be increased in heart failure when it was obvious that cardiac output was substantially decreased. In studies during the past several years, we have demonstrated that pericardial pressure, as a major modulator of ventricular interaction, must be accounted for before preload, myocardial compliance or contractility can be assessed reliably. Also, using a new conceptual model based on venous pressure-volume relations that explains how changes in venous capacitance modulate ventricular preload, we have defined the comparative capacitance-conductance effects of various vasodilators in a model of heart failure. We conclude that left ventricular preload is significantly modulated by both changes in ventricular interaction and venous capacitance. To optimize the care of patients with heart disease, it is important to understand both these mechanisms.

Heart Failure↗
PubMed1995

Spatial features in body-surface potential maps can identify patients with a history of sustained ventricular tachycardia.

BACKGROUND: Regional disparities of ventricular primary-repolarization properties contribute to an electrophysiological substrate for arrhythmias. Such disparities can be assessed from body-surface distributions of ECG QRST areas. Our objective was to isolate and test those features of QRST-area distributions that would be suitable for identifying patients at risk for life-threatening ventricular arrhythmias. METHODS AND RESULTS: We recorded ECGs simultaneously from 120 leads during sinus rhythm for 204 patients taking no antiarrhythmic drugs: half had had sustained ventricular tachycardia (VT); the other half, a myocardial infarction but no history of VT. For each patient, we calculated the QRST area in each lead and, using Karhunen-Loeve (K-L) expansion, reduced these data to 16 coefficients (each relating to one spatial feature, an eigenvector, derived from the total set of 204 QRST-area maps). Using stepwise discriminant analysis, we selected feature subsets that best discriminated between the two groups, and we estimated by a bootstrap procedure using 1000 trials how these subsets would perform on a prospective patient population. The mean diagnostic performance of the classifier for 1000 randomly selected training sets (n = 102 in each, with both groups equally represented) increased monotonically with the number of features used for classification. The initial trend for the corresponding test sets (n = 102 in each) was the same but reversed when the number of features exceeded eight. For an optimal set of eight spatial features, the sensitivity and specificity of the classifier for detecting patients with VT in 1000 test sets were (mean +/- SD) 90.3 +/- 4.3% and 78.0 +/- 6.1%, and its positive and negative predictive accuracies were 80.7 +/- 4.2% and 89.2 +/- 4.2%, respectively. Use of QRS duration as a supplementary feature to eight K-L coefficients can, in the test sets, increase specificity to 80.9 +/- 5.4% and positive predictive accuracy to 82.8 +/- 3.9% compared with the results for the optimal number of eight K-L features alone. CONCLUSIONS: Multiple body-surface ECGs contain valuable spatial features that can identify the presence of an arrhythmogenic substrate in the myocardium of patients at risk for ventricular arrhythmias. Our results compare very favorably with those achieved by any other known test, invasive or noninvasive, for arrhythmogenicity.

Body Surface Potential Mapping↗
PubMed1995

Differential roles of de novo sphingolipid biosynthesis and turnover in the "burst" of free sphingosine and sphinganine, and their 1-phosphates and N-acyl-derivatives, that occurs upon changing the medium of cells in culture.

Long-chain (sphingoid) bases are highly bioactive intermediates for sphingolipid metabolism, yet relatively little is known about how the amounts of these compounds are regulated. This study used J774A.1 cells to characterize the "burst" of sphinganine and sphingosine, or the transient increase of up to 10-fold in long-chain base mass, that occurs when cells in culture are changed to fresh medium. The increase in sphinganine was attributable to de novo sphingolipid biosynthesis because: 1) there is increased incorporation of [3H]serine and [3H]palmitate into sphinganine; 2) the incorporation of [3H]serine was equivalent to the increase in sphinganine mass; 3) beta-F-alanine, an inhibitor of serine palmitoyltransferase, blocked the sphinganine burst; 4) the magnitude of the burst depended on the concentration of serine in the medium, which is known to affect long-chain base biosynthesis; and 5) the appearance of sphinganine was relatively unaffected by lyso-osmotrophic agents (NH4Cl and chloroquine) that blocked sphingolipid hydrolysis in these cells. In contrast, the sphingosine burst arose mainly from turnover of complex sphingolipids because no incorporation of [3H]serine or [3H]palmitate into sphingosine was detected; sphingosine mass was not affected by beta-F-alanine or the serine concentration; and, the burst could be followed by the release of sphingosine and ceramide from complex sphingolipids (especially sphingomyelin) in a process that was inhibited by NH4Cl and chloroquine. Additionally, the fate of these long-chain bases differed: sphinganine was mostly (80-85%) acylated and incorporated into dihydroceramide and complex sphingolipids, whereas most of the sphingosine (70%) was phosphorylated and degraded, with incorporation of the resulting ethanolamine phosphate into phosphatidylethanolamine. Sphinganine, however, could be diverted toward degradation by adding an inhibitor of N-acylation (fumonisin B1). In accounting for the elevation in sphingosine and sphinganine after cells are changed to new medium, these studies have provided fundamental information about long-chain base metabolism. The existence of differential changes in sphinganine and sphingosine, as well as their 1-phosphates and N-acyl-derivatives, should be considered when evaluating the roles of sphingolipid metabolites in cell regulation.

Ammonium Chloride↗
PubMed1995

Effects of aortic constriction during experimental acute right ventricular pressure loading. Further insights into diastolic and systolic ventricular interaction.

BACKGROUND: Acute right ventricular (RV) hypertension may result in hemodynamic collapse. The associated reduction in left ventricular (LV) end-diastolic volume is thought to result from reduced RV output (secondary to RV ischemia) and adverse direct ventricular interaction. Aortic constriction improves cardiac function in these circumstances; this has been attributed to a reversal of the RV ischemia caused by an increased coronary perfusion pressure. We hypothesized that altered ventricular interaction, potentially via altered septal mechanics, may also contribute to the beneficial effects of aortic constriction. METHODS AND RESULTS: We instrumented nine dogs with ultrasonic dimension crystals to measure RV segment length, septum-to-RV free wall and septum-to-LV free wall diameters, and LV anterioposterior diameter. Catheter-tipped manometers were used to measure LV and RV pressures. Pericardial pressure was measured with flat, liquid-containing balloon transducers. Inflatable cuff constrictors were placed on the pulmonary artery (PA) and aorta, and a flow probe was placed on the PA. The right coronary artery (RCA) was perfused independently by a roller pump calibrated for flow. During moderate PA constriction, while RCA pressure was maintained at control level, RCA flow did not change significantly (15.8 +/- 6.2 to 16.9 +/- 11.5 mL/min) and was similar during severe PA constriction (18.6 +/- 9.8 mL/min). During severe PA constriction, RV stroke volume decreased from a control value of 10.3 +/- 4.9 to 2.3 +/- 1.4 mL/beat (P < .05). When aortic constriction was added while RCA pressure was maintained at control level, there was an increase in RV stroke volume to 4.5 +/- 2.0 mL/beat (P < .05) with no associated change in RCA flow (17.8 +/- 9.5 mL/min). However, pressure-dimension loops clearly demonstrated changes in diastolic and systolic ventricular interaction; with aortic constriction, there was a large increase in the transeptal pressure gradient associated with a rightward septal shift. During either isolated severe PA constriction or simultaneous severe PA and aortic constriction, RCA flow was increased until RCA pressure was approximately equal to that in the aorta. This produced an increase in RCA flow of 50% (P < .05); however, this increase in coronary flow was ineffective in improving any measure of RV function. CONCLUSIONS: In this model of acute RV hypertension, aortic constriction improves cardiac function, at least in part, by altering ventricular interaction independent of changes in RCA flow. Changes in RCA flow do not appear to have a significant impact on cardiac function in this model in which coronary artery pressure was maintained at normal or increased levels.

Animals↗