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Biomedical subjects

A Nathan

Publications and source records attributed to A Nathan.

At least 19 recordsLinked to original sources
PubMed2000

Perivascular graft heparin delivery using biodegradable polymer wraps.

Heparin remains the gold-standard inhibitor of the processes involved in the vascular response to injury. Though this compound has profound and wide-reaching effects on vascular cells in culture and animal models, its clinical utility has been questionable at best. It is clear that the mode of heparin delivery is critical to its potential and it may well be that routine forms of administration are insufficient to observe benefit given the heparin's short half-life and complex pharmacokinetics. When ingested orally, heparin is degraded to inactive oligomer fragments while systemic administration is complicated by the need for continuous infusion and the potential for uncontrolled hemorrhage. Thus alternative heparin delivery systems have been proposed to maximize regional effects while limiting systemic toxicity. Yet, as heparin is such a potent antithrombotic compound and since existing local delivery systems lack the ability to precisely regulate release kinetics, even site-specific therapy is prone to bleeding. We now describe the design and development of a novel biodegradable system for the perivascular delivery of heparin to the blood vessel wall with well-defined release kinetics. This system consists of heparin-encapsulated poly(DL lactide-co-glycolide) (pLGA) microspheres sequestered in an alginate gel. Controlled release of heparin from this heterogeneous system could be obtained over a period of 25 days in vitro. The experimental variables affecting heparin release from these matrices were investigated. Gel permeation chromatography (GPC) and scanning electron microscopy (SEM) were used to monitor the degradation process and found to correlate well with the release kinetics. Heparin-releasing gels inhibited growth of bovine vascular smooth muscle cells in tissue culture in a dose-dependent manner. Moreover, gel release controlled vascular injury in denuding and interposition vascular graft animal models of disease even when uncontrolled bleeding was evident with standard matrix-type release. This system may therefore provide an effective means of examining the effects of various compounds in the control of smooth muscle cell proliferation in accelerated arteriopathies and also shed light on the biologic nature of these processes.

Angioplasty, Balloon↗
PubMed2000

Intravenous crocetinate prolongs survival in a rat model of lethal hypoxemia.

OBJECTIVE: To examine whether a carotenoid, trans-sodium crocetinate, has beneficial effects on hemodynamic status and short-term outcome in a rat model of lethal hypoxemia. DESIGN: Randomized, placebo-controlled study. SETTING: Medical school laboratory. SUBJECTS: Eighteen spontaneously breathing, anesthetized Sprague-Dawley rats (six per group). INTERVENTIONS: Rats underwent instrumentation to measure blood pressure, aortic and renal blood flow, arterial blood gases, bladder epithelial oxygen tension (by an intraluminal Clark electrode), and hepatic microvascular oxygen tension (measured by porphyrin phosphorescence). After stabilization, the rats were subjected to breathing 10% inspired oxygen concentration. After 10 mins, they were administered 1.25 mL/kg intravenous boluses of either isotonic saline (control), normal strength crocetinate (40 microg/mL), or a concentrated crocetinate solution (60 microg/mL). These boluses were repeated at 30-min intervals until either death or 3 hrs had elapsed. MEASUREMENTS AND MAIN RESULTS: With the onset of hypoxemia, we observed a rapid reduction in blood pressure and renal blood flow, maintenance of aortic blood flow, an increase in arterial base deficit, and falls in oxygen tensions in arterial blood, bladder epithelium, and hepatic microvasculature. A progressive deterioration in the control rats was noted, with only two of the six animals surviving for 3 hrs. However, all 12 rats in the two crocetinate groups survived for 3 hrs, with hemodynamic stability until 150 mins and a slow decline thereafter. CONCLUSIONS: Trans-sodium crocetinate improved hemodynamic status and prolonged survival in this model of severe acute hypoxic hypoxia. To our knowledge, this is the first demonstration of an intravenous agent having such an effect.

Animals↗
PubMed1999

'Brown bag' medication reviews as a means of optimizing patients' use of medication and of identifying potential clinical problems.

BACKGROUND: 'Brown bag' medication reviews carried out by community pharmacists collaborating with GPs have become established, in the USA and elsewhere, as an effective means of helping primary care patients to derive maximum benefit from their medicines, of identifying medication-related problems and of reducing wastage of medicines. OBJECTIVE: We aimed to determine whether 'brown bag' medication review could be used successfully in the UK, and particularly whether it represents an efficient and potentially cost-effective means of identifying medication problems. METHOD: 'Brown bag' medication reviews were carried out on 205 volunteer patients in 23 pharmacies in south-east London. Pharmacists' interventions to improve patients' knowledge and usage of their medicines were analysed. Potential clinical problems identified by pharmacists were analysed in order to identify the drug groups most likely to cause problems. RESULTS: Interventions were made in 87% of reviews; interventions to improve patients' knowledge of the purpose and correct usage of their drugs were made in 65% of reviews. In 12% of reviews, problems were identified that could potentially result in a hospital admission, and the potential for an improved outcome for the patient if drug therapy was changed was identified in a further 34% of cases. Beta-blockers, NSAIDs and verapamil were identified as being associated with potential problems of the highest clinical significance. Patients taking psychoactive medication were at greatest risk of a medication-related problem from any cause. CONCLUSION: Pharmacists could contribute to patients' welfare and reduce health care costs by carrying out 'brown bag' medication reviews on behalf of GPs.

Aged↗
PubMed1999

Drug resistance mutations can effect dimer stability of HIV-1 protease at neutral pH.

The monomer-dimer equilibrium for the human immunodeficiency virus type 1 (HIV-1) protease has been investigated under physiological conditions. Dimer dissociation at pH 7.0 was correlated with a loss in beta-sheet structure and a lower degree of ANS binding. An autolysis-resistant mutant, Q7K/L33I/L63I, was used to facilitate sedimentation equilibrium studies at neutral pH where the wild-type enzyme is typically unstable in the absence of bound inhibitor. The dimer dissociation constant (KD) of the triple mutant was 5.8 microM at pH 7.0 and was below the limit of measurement (approximately 100 nM) at pH 4.5. Similar studies using the catalytically inactive D25N mutant yielded a KD value of 1.0 microM at pH 7.0. These values differ significantly from a previously reported value of 23 nM obtained indirectly from inhibitor binding measurements (Darke et al., 1994). We show that the discrepancy may result from the thermodynamic linkage between the monomer-dimer and inhibitor binding equilibria. Under conditions where a significant degree of monomer is present, both substrates and competitive inhibitors will shift the equilibrium toward the dimer, resulting in apparent increases in dimer stability and decreases in ligand binding affinity. Sedimentation equilibrium studies were also carried out on several drug-resistant HIV-1 protease mutants: V82F, V82F/I84V, V82T/I84V, and L90M. All four mutants exhibited reduced dimer stability relative to the autolysis-resistant mutant at pH 7.0. Our results indicate that reductions in drug affinity may be due to the combined effects of mutations on both dimer stability and inhibitor binding.

Circular Dichroism↗
PubMed1995

Tissue engineered perivascular endothelial cell implants regulate vascular injury.

Molecular biomaterial engineering permits in vivo transplantation of cells and tissues, offering the promise of restoration of physiologic control rather than pharmacologic dosing with isolated compounds. We engrafted endothelial cells on Gelfoam biopolymeric matrices with retention of viability, normal growth kinetics, immunoreactivity, and biochemical activity. The production of heparan sulfate proteoglycan and inhibition of basic fibroblast growth factor binding and activity by engrafted cells were indistinguishable from endothelial cells grown in culture. Perivascular implantation of Gelfoam-endothelial cell scaffolds around balloon-denuded rat carotid arteries reduced intimal hyperplasia 88.1%, far better than the isolated administration of heparin, the most effective endothelial mimic compound. In concert with a reduction in intimal area, cell proliferation was reduced by > 90%. To our knowledge, there have been no previous reports of extravascular cell implants controlling vasculoproliferative disease. Tissue engineered cells offer the potential for potent methods of vascular growth regulation and insight into the complex autocrine-paracrine control mechanisms within the blood vessel wall.

Animals↗
PubMed1993

A comparison of community pharmacists' and general practitioners' opinions on rational prescribing, formularies and other prescribing related issues.

A postal survey of Community Pharmacists (CPs) and General Medical Practitioners (GPs) in the Enfield and Haringey (E&H) and North Yorkshire (N Yorks) Family Health Services Authority (FHSA) areas was carried out to investigate: a. their opinions regarding clinically oriented 'extended' roles for CPs, and the possibility of interprofessional collaboration on them, and b. their views on a range of prescribing related issues. The overall response rate was 67% for CPs and 42% for GPs. There were no significant differences in responses to questions between CPs in both FHSAs, but significant differences in answers to some questions between the two groups of GPs, due to a large proportion of dispensing GPs in N Yorks. Results were therefore expressed as comparisons between total numbers of CPs and GPs, and between dispensing and non-dispensing GPs. The results showed an affinity of outlook between CPs and GPs on a range of prescribing related issues, and considerable goodwill between the two groups on which future cooperation could be founded. GPs were, however, significantly less enthusiastic than CPs about collaboration in areas which would concede a role to CPs in making prescribing decisions. GPs were most favorably disposed to collaboration in areas such as the provision of drug information, which could be considered as within GPs' domain of specialist expertise.

Attitude of Health Personnel↗
PubMed1993

Differential rate of neuropsychological dysfunction in psychiatric disorders: comparison between the Halstead-Reitan and Luria-Nebraska batteries.

This report examined the rate of agreement between scores of the Halstead-Reitan and Luria-Nebraska Neuropsychological Batteries in the classification of impaired and nonimpaired performance of 55 schizophrenic and 64 affective disorder patients: 65.2% for schizophrenics and 67.5% for those with affective disorder, with greater impairment on the Halstead-Reitan battery.

Adult↗
PubMed1991

Suicidal behavior among inner-city Hispanic adolescent females.

Suicidal behavior is disproportionately frequent among inner-city Hispanic adolescent girls. In an attempt to generate a multifactorial set of hypotheses to explain this behavior, 33 such subjects consecutively admitted for suicidal behavior and 15 demographically identical nonsuicidal subjects were assessed by means of a structured interview. Mothers of all subjects were also assessed. Attempts were nearly always impulsive and nonlethal, though often with a stated wish to die. Nearly all were overdoses, and were precipitated by conflicts with mother or boyfriend. Mothers could usually identify the precipitants. Attempters' parents were less often born in the U.S., their mothers seemed medically less healthy, and their extended families were more often supported by public assistance, and had a higher incidence of criminal and psychiatric problems. School performance was poorer among attempters, who had suffered more and earlier losses, especially of biologic fathers, with whom fewer had ongoing relationships. They more often had boyfriends, had begun sexual activity, had recently lost friends, and expressed a mistrustful stance toward friendships. Similarly, their mothers had fewer friends and more often expressed a mistrustful stance. Relationships with mothers seemed more intense, desperate, and even violent, and attempters were much more often parentified, i.e., mothering their mothers. Although both groups often assumed caretaking roles in their families, attempters were more negatively described by themselves and by their mothers. While knowledge of suicidal models was common in both groups, attempters' mothers knew of even more models than did their daughters or the nonsuicidal subjects or their mothers. Notably, more attempters' mothers had themselves made attempts. Families of most attempters were usually mobilized by the attempt. These findings permit the construction of a putative profile of risk factors that can be tested more rigorously.

Adolescent↗
PubMed1989

Periodate-modified gangliosides enhance surface binding of tetanus toxin to PC12 pheochromocytoma cells.

The interaction of 125I-labeled tetanus toxin with PC12 pheochromocytoma cells in monolayer cultures has been examined. Under regular growth conditions, the PC12 cells bind 125I-tetanus toxin to a limited degree compared with dissociated cerebral neuron cultures. After exposure to nerve growth factor for 2 days in low serum-containing media with growth factor supplements, binding of toxin increases over twofold compared with untreated PC12 cells. Binding can also be enhanced (greater than 2.5-fold) after treatment of cells with 2 mM sodium metaperiodate for 20 min. Dissociated cerebral neurons but not fibroblasts in cell culture bind more toxin after periodate treatment. The effect of periodate can be abolished by 5 mM sodium borohydride. A ganglioside isolated from periodate-treated PC12 cells and tentatively identified as GT1b [(N-acetylneuraminyl)galactosyl-N-acetylgalactosaminyl(N- acetylneuraminyl-N-acetylneuraminyl)-galactosyl-glucosylceramide] binds 125I-tetanus toxin on silica gel chromatoplates and on nitrocellulose paper. There are no indications to suggest binding to a polypeptide from treated cells after polyacrylamide gel electrophoresis. Cells artificially supplemented with GT1b and subsequently treated with periodate effectively bind the toxin. The data suggest that modified sialyl groups linked to gangliosides, and not to proteins, are preferential targets for tetanus toxin.

Borohydrides↗
PubMed1989

Current concerns of community pharmacists.

The community pharmacist is a familiar and apparently unchanging figure, and people's most frequent contact with the health service. Alan Nathan explains that the profession is in fact going through a difficult period of change.

Community Pharmacy Services↗
PubMed1987

Effects of lateralized cerebral dysfunction on the Continuous Paired-Associate Test.

Some authorities have advocated matching tests on several critical psychometric properties before inferring the presence of a differential pattern of deficit. This study examined the effects of lateralized cerebral dysfunction on the matched Verbal and Design subtests of the Continuous Paired-Associate Test (CPAT). Patients with lateralized destructive lesions were studied in Experiment 1. Epileptic patients with lateralized electroencephalographic findings were studied in Experiment 2. Left but not right hemispheric abnormalities impaired performance on the Verbal CPAT, but only for destructive lesions. The Designs CPAT was a nonspecific indicator of cerebral dysfunction. For studies with the goal of predicting laterality of cerebral dysfunction, we advocate a two-step strategy of test development. The first step would make use of the principle of double dissociation in selecting items to compose subtests. The second step would involve an item analysis of subtests to determine the need for matching.

Adolescent↗
PubMed1986

Tetanus toxin receptors on nerve cells contain a trypsin-sensitive component.

Cerebral neurons in monolayer cultures, subjected to 25 micrograms/ml trypsin, lose after 10 min about 43.5% and 40.5% of the ability to bind 125I-labeled tetanotoxin as measured at 0-4 degrees C and 37 degrees C respectively. These losses are maximal by 30 min and can be prevented by 1.5 mg/ml soybean trypsin inhibitor. Chymotrypsin but not collagenase or hyaluronidase is also effective in reducing binding of toxin to cells. The trypsin-insensitive toxin-binding activity can be further eliminated by treatment with sialidase or by cell extraction with methanol. Fixation of cells with 3.5% paraformaldehyde or 2% glutaraldehyde also results in a marked decrease of 52.4% and 25% respectively in the toxin-cell association. Methanol or sialidase but not trypsin removes the remaining binding activity. About one-third of the lipid-linked and protein-linked sialic acid is removed after sialidase treatment whereas 1% and 9.4% respectively are removed after trypsin treatment. The data are consistent with the possibility that, in addition to a sialic acid component, binding of tetanotoxin to nerve cells is facilitated by a trypsin-removable and formaldehyde-inactivated component. There was no evidence for a polypeptide to substitute gangliosides as receptors for tetanotoxin. On the contrary, solubility in organic solvents and interaction of the extracted products with labeled toxin remain the major proof that gangliosides are the putative receptors for tetanotoxin.

Animals↗
PubMed1985

Computer simulation of dual chamber pacemaker algorithms using a realistic heart model.

Single and dual chamber pacing algorithms have been incorporated into a realistic computer model of cardiac electrical activation. The model enables different pacemaker algorithms to be tested, it allows prediction of their behavior, and it produces a simulated ECG record for each case. The computer model has been used to test eight different modifications of a simple DDD mode to prevent or terminate pacemaker-mediated "endless loop" tachycardia: (1) constant prolongation of the atrial channel refractory period; (2) prolongation of the atrial refractory period after a ventricular premature beat (VPB); (3) atrial pacing synchronously with a VPB; (4) simple rate control; (5) rate control in which the VA counter is not reset; (6) no ventricular pacing after an atrial premature beat; (7) rate limitation of atrial sensing; and (8) a combination of DDD and high frequency atrial stimulation modes. These modifications were tested with VPBs, atrial premature beats, atrial stimulation without capture, and accelerating sinus tachycardia. Only the pacemaker designed not to pace the ventricles following an atrial premature beat behaves satisfactorily in all four circumstances. Further possibilities for the development and use of a pacemaker-oriented computer heart model are discussed.

Computers↗
PubMed1982

Rate-related accelerating (autodecremental) atrial pacing for reversion of paroxysmal supraventricular tachycardia.

Twenty consecutive patients with paroxysmal intra A-V nodal or atrio-ventricular tachycardia had a new tachycardia reversion pacing modality evaluated during routine electrophysiological study. The pacing was controlled by a micropressor interfaced with a stimulator connected to a right atrial pacing electrode. On detection of tachycardia the first pacing cycle interval is equal to the tachycardia cycle length minus a decrement value D. Each subsequent pacing cycle is further reduced by the same value of D, thus accelerating the pacing burst until a plateau of 100 beats/min faster than tachycardia (with an absolute lower limit of 275 beats/min) is reached. Seven different values of D (2, 4, 8, 16, 24, 34, 50 msec) were assessed in combination with three different durations of pacing P (500, 5000 msec). With P:500, only 2/20 tachycardias were terminated, but with P:1000, 16/20 were terminated. With P:5000 all were terminated and the combination successful in all patients was P:5000 and D:16. No unwanted arrhythmias were induced. In contrast, competitive constant rate overdrive atrial pacing accomplished tachycardia termination in all cases, but in four instances resulted in atrial flutter or fibrillation. Autodecremental pacing, which tends to avoid stimulation in the vulnerable period, allowed safe and successful termination of all tachycardias evaluated in this study.

Atrial Fibrillation↗
PubMed1982

Clinical evaluation of an adaptive tachycardia intervention pacemaker with automatic cycle length adjustment.

An external version of a new pacemaker designed for automatic tachycardia termination is described. In response to a tachycardia, defined as four successive beats occurring at a rate faster than a variable preset value, a number of stimuli (1-15) are generated. The initial coupling interval and subsequent pacing cycle intervals (where applicable) are always the same. Failure to terminate tachycardia results in the reduction of the pacing cycle length by 6 ms before termination of tachycardia is re-attempted. Pacing cycle length reduction may be repeated up to 16 times. If all coupling intervals of a single extrastimulus fail to achieve tachycardia termination, a second stimulus is scanned with the first through the same range of decrements. Additional stimuli, to a total of 15, could be used. A memory function is incorporated to retain and re-use a successful sequence. The pacemaker was evaluated in 16 patients with recurrent "supraventricular" (atrioventricular and intra A-V nodal) tachycardia, using right ventricular pacing. Termination was successful in all patients. More than two stimuli were necessary in only two patients, one of whom required five, and the other six stimuli. No unwanted arrhythmias were induced.

Adolescent↗
PubMed1979

Successful treatment of exophthalmos and pretibial myxoedema with plasmapheresis.

A patient with Graves's disease with acute progressive exophthalmos and pretibial myxoedema was treated twice with plasmapheresis. Two weeks after the first treatment the symptoms recurred, but 20 weeks after the second treatment the exophthalmos was much improved and the pretibial myxoedema had disappeared. Analysis of sequential serum IgG concentrations and the thyroid-stimulating immunoglobulin index suggested that the two conditions were caused by specific IgGs. The results suggest that plasmapheresis has a useful place in the treatment of acute and rapidly progressive ophthalmopathy and pretibial myxoedema in patients with Graves's disease.

Acute Disease↗